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1.
Horm Metab Res ; 49(4): 269-275, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28103616

RESUMEN

In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.


Asunto(s)
Enfermedades de las Glándulas Suprarrenales/tratamiento farmacológico , Glándulas Suprarrenales/metabolismo , Aldosterona/metabolismo , Lisina/administración & dosificación , Receptores de Serotonina 5-HT4/metabolismo , Antagonistas del Receptor de Serotonina 5-HT4/administración & dosificación , Serotoninérgicos/administración & dosificación , Enfermedades de las Glándulas Suprarrenales/metabolismo , Enfermedades de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/patología , Células Cultivadas , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Serotonina/metabolismo
2.
Mol Hum Reprod ; 22(12): 819-832, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27671755

RESUMEN

STUDY QUESTION: Does vitamin A (retinol, Rol) prevent round spermatid nuclear damage and increase the production of motile sperm during in vitro maturation of vitrified pre-pubertal mouse testicular tissue? SUMMARY ANSWER: The supplementation of an in vitro culture of ~0.75 mm3 testicular explants from pre-pubertal mice with Rol enhances spermatogenesis progression during the first spermatogenic wave. WHAT IS KNOWN ALREADY: The production of functional spermatozoa in vitro has only been achieved in the mouse model and remains a rare event. Establishing an efficient culture medium for vitrified pre-pubertal testicular tissue is now a crucial step to improve the spermatic yield obtained in vitro. The role of Rol in promoting the differentiation of spermatogonia and their entry into meiosis is well established; however, it has been postulated that Rol is also required to support their full development into elongated spermatids. STUDY DESIGN, SIZE, DURATION: A total of 60 testes from 6.5 days post-partum (dpp) mice were vitrified/warmed, cut into fragments and cultured for 30 days: 20 testes were used for light microscopy and histological analyses, 20 testes for DNA fragmentation assessment in round spermatids and 20 testes for induced sperm motility assessment. Overall, 16 testes of 6.5 dpp were used as in vitro fresh tissue controls and 12 testes of 36.5 dpp mice as in vivo controls. Testes were vitrified with the optimal solid surface vitrification procedure and cultured with an in vitro organ culture system until Day 30 (D30). Histological analysis, cell death, degenerating round spermatids, DNA fragmentation in round spermatids and induced sperm motility were assessed. Testosterone levels were measured in media throughout the culture by radioimmunoassay. MAIN RESULTS AND THE ROLE OF CHANCE: At D30, better tissue development together with higher differentiation of spermatogonial stem cells, and higher global cell division ability were observed for vitrified/warmed testicular fragments of ~0.75 mm3 with a culture medium supplemented with Rol compared to controls. During in vitro culture of vitrified pre-pubertal testicular tissue, Rol enhanced and maintained the entry of spermatogonia into meiosis and promoted a higher spermatic yield. Furthermore, decreased round spermatid nuclear alterations and DNA damage combined with induced sperm motility comparable to in vivo highlight the crucial role of Rol in the progression of spermatogenesis during the first wave. LIMITATIONS, REASONS FOR CAUTION: Despite our promising results, the culture media will have to be further improved and adapted within the context of a human application. WIDER IMPLICATIONS OF THE FINDINGS: The results have potential implications for the handling of human pre-pubertal testicular tissues cryopreserved for fertility preservation. However, because some alterations in round spermatids persist after in vitro culture with Rol, the procedure needs to be optimized before human application, bearing in mind that the murine and human spermatogenic processes differ in many respects. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by a Ph.D. grant from the Normandy University and a financial support from 'la Ligue nationale contre le cancer' (both awarded to L.D.), funding from Rouen University Hospital, Institute for Research and Innovation in Biomedicine (IRIB) and Agence de la Biomédecine. The authors declare that there is no conflict of interest.


Asunto(s)
Espermátides/efectos de los fármacos , Espermátides/metabolismo , Testículo/citología , Vitamina A/farmacología , Animales , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Criopreservación , Fragmentación del ADN/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Vitrificación
3.
J Chemother ; 19(2): 115-22, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17434818

RESUMEN

This manuscript summarizes recent progress in the adjuvant treatment of colon cancer. 5-Fluorouracil plus leucovorin, that have been considered standard therapy over the last 15 years, have now been replaced by combination chemotherapy, at least in stage III disease. The treatment of stage II disease is still somewhat less established. Prognostic and predictive biological markers are urgently needed for further fine-tuning of therapy. Molecular targeted agents have been developed with proven activity in advanced disease and are now being assessed in the adjuvant setting. It is expected that the inclusion of these new agents will lead to a further enhancement of treatment outcome. Those involved in the treatment of colorectal cancer should be encouraged to continue to provide optimal patient care and to participate in clinical trials in order to increase the evidence on which they can base their clinical judgement and to make further progress.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina , Quimioterapia Adyuvante/tendencias , Neoplasias del Colon/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Infusiones Intravenosas , Irinotecán , Leucovorina/administración & dosificación , Levamisol/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Tasa de Supervivencia
4.
Ann Oncol ; 17(3): 443-9, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16500914

RESUMEN

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Calidad de Vida , Terapia Recuperativa
5.
Ann Oncol ; 17(2): 262-9, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16293676

RESUMEN

BACKGROUND: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil+adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm. PATIENTS AND METHODS: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial. RESULTS: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P=0.87) or OS (hazards ratio: 0.98, P=0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively. CONCLUSION: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/cirugía , Adulto , Anciano , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/cirugía , Análisis de Supervivencia
6.
J Clin Oncol ; 23(22): 4856-65, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-15939923

RESUMEN

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento
7.
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
8.
Ann Oncol ; 15(9): 1330-8, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15319237

RESUMEN

BACKGROUND: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according to the standard therapy. Although there is evidence that elderly patients benefit from adjuvant (radio-) chemotherapy to the same extent as younger patients, no large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a retrospective analysis using source data of 3825 patients who received 5-fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of > or = 70 years. RESULTS: We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (CI) 9.7-11.8] and in younger patients (11.3 months, 95% CI 10.9-11.7; P = 0.31). Response rate did not differ between age groups > or = 70 and <70 years (23.9% and 21.1%; respectively; P = 0.14). Progression-free survival was marginally prolonged in elderly patients (5.5 months, 95% CI 5.2-5.8; compared with 5.3 months, 95% CI 5.1-5.5; P = 0.01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression-free survival compared with bolus 5-FU. CONCLUSIONS: 'Fit' elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Factores de Edad , Anciano , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Europa (Continente) , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Análisis de Supervivencia , Resultado del Tratamiento
9.
Eur J Surg Oncol ; 30(6): 643-9, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15256239

RESUMEN

AIMS: Gastric cancer in Western countries is often diagnosed in an advanced stage and prognosis is poor. We performed a randomised trial with pre-operative FAMTX vs. surgery alone in order to evaluate the effect of pre-operative chemotherapy on resectability and survival. METHODS: Patients with proven adenocarcinoma of the stomach were randomised to receive four courses of chemotherapy using 5-Fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery alone. RESULTS: Fifty-nine patients were randomised; 29 patients were allocated to the FAMTX regimen prior to surgery and 30 patients had surgery alone. Resectability rates were equal for both groups. Complete or partial response was registered in 32% of the FAMTX group. With a median follow-up of 83 months the median survival since randomisation is 18 months in the FAMTX group vs. 30 months in the surgery alone group (p=0.17). CONCLUSIONS: This trial could not show a beneficial effect of pre-operative FAMTX. Until large randomised studies prove otherwise, adequate surgery without delay is the best treatment for operable gastric cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/uso terapéutico , Fluorouracilo/uso terapéutico , Gastrectomía/métodos , Metotrexato/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Adenocarcinoma/patología , Quimioterapia Adyuvante/métodos , Humanos , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del Tratamiento
10.
J Clin Oncol ; 21(20): 3721-8, 2003 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-12963704

RESUMEN

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Adulto , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Calidad de Vida , Tasa de Supervivencia , Resultado del Tratamiento
11.
Eur J Cancer ; 39(3): 346-52, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12565987

RESUMEN

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácido Aspártico/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Ácido Fosfonoacético/análogos & derivados , Adulto , Anciano , Ácido Aspártico/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Ácido Fosfonoacético/administración & dosificación , Análisis de Supervivencia , Resultado del Tratamiento
13.
Ann Oncol ; 12(1): 13-22, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11249040

RESUMEN

BACKGROUND: Despite early scepticism, several studies of systemic adjuvant 5-fluorouracil (5-FU)-based chemotherapy demonstrated significant benefits in high-risk colon cancer. As many clinical investigations have since been conducted in this setting, a comprehensive literature review was undertaken to clarify the role of adjuvant therapy in the treatment of colorectal cancer. DESIGN: Current and future adjuvant treatment approaches in colorectal cancer were reviewed, and differences in the present-day North American and European practices were highlighted. RESULTS AND CONCLUSIONS: 5-FU plus leucovorin for six months is generally considered the 'standard' adjuvant treatment in Dukes' stage C (stage II) colon cancer. Large-scale international trials of other strategies are required to provide further advances in treatment outcome. Following the lead of the USA Intergroup trials, a recently initiated cooperative effort, the Pan-European Trials in Adjuvant Colon Cancer (PETACC), may serve as a European model for such investigations. In T3 and/or lymph-node positive rectal cancer, postoperative (chemo)radiotherapy in the USA is considered the adjuvant treatment of choice. However, most European investigators have advocated for preoperative intensive short-course irradiation instead. Randomized trials in this area are ongoing. In the near future, new drugs for the treatment of colorectal cancer may lead to tailored therapies.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/radioterapia , Neoplasias Colorrectales/cirugía , Esquema de Medicación , Europa (Continente) , Fluorouracilo/administración & dosificación , Humanos , Cooperación Internacional , Leucovorina/administración & dosificación , Pautas de la Práctica en Medicina , Radioterapia Adyuvante , Estados Unidos
14.
J Clin Oncol ; 18(14): 2648-57, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10894863

RESUMEN

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Levoleucovorina , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/patología , Análisis de Supervivencia
15.
Oncology (Williston Park) ; 14(12 Suppl 14): 22-5, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11200144

RESUMEN

Metastatic gastric cancer is a relatively chemosensitive disease. With current regimens, 25% to 40% of patients can be expected to respond, and median survival of 6 to 8 months is achievable. These outcomes may be improved by the use of infusional fluorouracil (5-FU) in combination with cisplatin (Platinol) or the newer agents docetaxel (Taxotere) and irinotecan (Camptosar). Phase II studies using these approaches have reported response rates of 50% to 60% and median survival of 11 months. Chemotherapy may also have a role in earlier stages of gastric cancer. However, the value of adjuvant therapy in improving survival following successful resection has still to be demonstrated, as has the survival benefit of preoperative treatment. Nevertheless, primary chemotherapy has demonstrated a capacity to downstage disease in certain otherwise inoperable cases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Paclitaxel/análogos & derivados , Neoplasias Gástricas/tratamiento farmacológico , Taxoides , Camptotecina/administración & dosificación , Cisplatino/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Docetaxel , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Irinotecán , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia
16.
Anticancer Drugs ; 10(3): 257-61, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10327029

RESUMEN

Cisplatin is the most important drug in the treatment of advanced ovarian cancer. The role of anthracyclines is controversial. We compared a combination of epirubicin plus cisplatin (EP) with a regimen of cyclophosphamide, epirubicin and cisplatin (CEP). Patients with stage Ic-IV ovarian cancer were randomized to receive either epirubicin 100 mg/m2 plus cisplatin 75 mg/m2 q 4 weeks or cyclophosphamide 500 mg/m2 plus epirubicin 75 mg/m2 plus cisplatin 50 mg/m2 q 4 weeks, which we considered the reference treatment based on our previous experience. Patients were initially debulked, followed by six cycles of chemotherapy, or in case primary debulking was insufficient or considered inappropriate, secondary debulking was attempted in selected cases after sufficient chemotherapy-induced regression. Optimal debulking was defined as residual lesions < or = 2 cm. A total of 210 patients (191 eligible) were randomized. Results did not show significant differences in all major endpoints (pathologically documented complete response and survival). The median survival for all patients was 34 months, for patients with stage III 26 months, for patients with stage IV 20 months and it has not been reached for patients with stage Ic-II. As no significant differences between an equitoxic regimen of EP and CEP were detected, it might be more useful to look again at the anthracyclines as part of combination chemotherapy instead of the alkylating agents.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Humanos , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Análisis de Supervivencia
17.
Ann Surg ; 230(6): 776-82; discussion 782-4, 1999 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-10615932

RESUMEN

OBJECTIVE: The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA: A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS: Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS: Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS: Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.


Asunto(s)
Adenocarcinoma/cirugía , Ampolla Hepatopancreática , Antimetabolitos Antineoplásicos/uso terapéutico , Fluorouracilo/uso terapéutico , Neoplasias Pancreáticas/cirugía , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Humanos , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/radioterapia , Estudios Prospectivos , Radioterapia Adyuvante , Análisis de Supervivencia
18.
Lancet ; 351(9117): 1677-81, 1998 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-9734883

RESUMEN

BACKGROUND: There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS: 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS: 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION: PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.


Asunto(s)
Anticoagulantes/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Fluorouracilo/administración & dosificación , Heparina/administración & dosificación , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Anciano , Anticoagulantes/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Neoplasias del Colon/mortalidad , Progresión de la Enfermedad , Combinación de Medicamentos , Femenino , Fluorouracilo/uso terapéutico , Heparina/uso terapéutico , Humanos , Infusiones Intravenosas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Masculino , Vena Porta , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Neoplasias del Recto/mortalidad , Análisis de Supervivencia , Resultado del Tratamiento
19.
Eur J Cancer ; 33(8): 1209-15, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9301444

RESUMEN

In this phase III clinical trial conducted by the Gastrointestinal Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (GITCCG-EORTC), we evaluated the effect of adjuvant intraportal infusion of heparin (HEP) and 5-fluorouracil (5-FU) on overall survival, disease-free survival and time to progression in patients with resectable colon cancer. From January 1983 to June 1987, 235 patients were randomised from 14 institutions in seven European countries: 79 patients made up the control group (control): 72 the portal vein infusion group given heparin alone (5000 IU daily x 7 consecutive days) (HEP); 84 the portal vein infusion group given heparin (5000 IU daily x 7 consecutive days) and 5-FU (500 mg/m2 daily x 7 consecutive days) (HEP/5-FU); 34 patients were considered ineligible. The 199 patients considered eligible were well balanced for age, sex, Karnofsky index, tumour location, surgery, surgical procedure and Dukes' stage. Four patients (2 control, 1 HEP, 1 HEP/5-FU) died of surgical complications. No differences were observed between control group and treatment groups (HEP, HEP/5-FU) for postoperative complications and number of hospitalisation days. Severe toxicity (grade 3-4, WHO) was found in 12% of patients in the HEP group and 8% in the HEP/5-FU group. After a median follow-up of 9 years, disease progression was reported in 40% of patients in the control group, 40% in the HEP group and 29% in the HEP/5-FU group. Five-year survival, time to progression and disease-free survival were 69%, 58% and 56%, respectively, in the control arm, 61%, 58% and 56% in the HEP arm, and 71%, 69% and 65% in the HEP/5-FU arm. Based on all randomised patients, the effect of treatment was not statistically significant with respect to any of the endpoints. It is confirmed that intraportal 5-FU infusion is safe and has a tolerable toxicity, but cannot be considered standard treatment for patients with resectable colon cancer.


Asunto(s)
Anticoagulantes/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Heparina/administración & dosificación , Adulto , Anciano , Anticoagulantes/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Neoplasias del Colon/cirugía , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Heparina/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Vena Porta , Complicaciones Posoperatorias , Tasa de Supervivencia
20.
Anticancer Drugs ; 8(5): 432-5, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9215604

RESUMEN

A total of 34 patients with advanced ovarian cancer, who relapsed 1-72 months after at least one first-line cisplatin-based chemotherapy protocol, were treated with carboplatin, 350 mg/m2 q 4 weeks, with the adjunct of primary prophylactic granulocyte colony stimulating factor (G-CSF; filgrastim), 300 or 480 microg daily, days 5-9. Over 90% of the anticipated dose of carboplatin could be administered. Partial response, defined as a decline in CA-125 of 50% or more on two consecutive samples, occurred in 42%, while 15% of patients achieved a complete response (no clinical signs of disease with normalization of CA-125). Survival from start of carboplatin treatment was 23 months. Myelosuppression was the most important toxicity with 35% of patients experiencing grade 4 thrombocytopenia of short duration. Grade 4 leucopenia occurred in only one patient. It is concluded that single-agent carboplatin, with the adjunct of prophylactic G-CSF, can be administered with adequate dose intensity, and is an effective and acceptable palliative treatment for patients with relapse after first-line cisplatin-based chemotherapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/efectos adversos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Antieméticos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Filgrastim , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Proteínas Recombinantes , Recurrencia , Trombocitopenia/complicaciones , Trombocitopenia/tratamiento farmacológico
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