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1.
Br J Cancer ; 99(8): 1239-45, 2008 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-18797458

RESUMEN

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Adulto , Anciano , Antineoplásicos Fitogénicos/sangre , Área Bajo la Curva , Camptotecina/sangre , Camptotecina/farmacología , Carboxilesterasa/genética , Cromatografía Líquida de Alta Presión , Femenino , Glucurónidos/sangre , Glucuronosiltransferasa/genética , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Regiones Promotoras Genéticas/genética
2.
Pharmacogenomics J ; 8(4): 256-67, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17700593

RESUMEN

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/farmacología , Estudios de Seguimiento , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Polimorfismo de Nucleótido Simple/genética , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del Tratamiento
3.
Cancer Lett ; 249(2): 271-82, 2007 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-17064846

RESUMEN

UNLABELLED: 5-Fluorouracil (5-FU)-related early toxicity, due to a metabolic deficiency, is rare but is potentially severe and even lethal (0.1%). It is due to dihydropyrimidine dehydrogenase (DPYD) gene polymorphism or some epigenetic factors. The detection of metabolic change could prevent severe toxicity, but until now it has not been carried out in clinical practice. PURPOSE: To find the simplest and most accurate pretherapeutic test to predict DPD deficiency in patients treated with 5-FU by comparing different approaches. RESULTS: Two hundred and fifty two French Caucasian patients treated by 5-FU infusion were studied. A two-step strategy, combining firstly SNP detection and uracil plasma measurement, followed, in cases where metabolic deficiency was suspected, by dihydrouracil/uracil ratio determination to confirm deficiency and to determine the optimum 5-FU dosage, appeared the best approach, with 83% and 82% sensitivity and specificity, respectively. CONCLUSION: These data support the future use of this approach, suitable to clinical practice, as screening test to identify DPD deficiency before 5-FU-based therapy.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Deficiencia de Dihidropirimidina Deshidrogenasa , Fluorouracilo/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacocinética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Femenino , Fluorouracilo/farmacocinética , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , ARN Mensajero/análisis , Uracilo/análogos & derivados , Uracilo/sangre
4.
Cancer Radiother ; 17(1): 10-20, 2013 Feb.
Artículo en Francés | MEDLINE | ID: mdl-23270680

RESUMEN

PURPOSE: To assess the outcome of esophageal cancer according to therapeutic strategy. PATIENTS AND METHODS: One-hundred and twenty patients with esophageal cancer treated by an association of radiotherapy and chemotherapy and possibly surgery, between 2004 and 2010, were retrospectively studied. The first site of relapse was classified as follows: local (tumour), locoregional (tumour and/or nodal: celiac, mediastinal, sus-clavicular) or metastatic. RESULTS: With a 15.7-months (1.4-62) median follow-up, there were 89 deaths and 79 recurrences. Three types of treatments were performed: 50Gy exclusive chemoradiotherapy (47 patients) or 50 to 65Gy exclusive chemoradiotherapy (44 patients) or chemoradiotherapy followed by surgery (27 patients). The local first relapse was as much frequent as distant relapse (50 patients). With a-5cm margin up and down to the tumour, there was only one nodal relapse. Two-year survival was 39.5% (95% confidence interval [IC]: 30.5-40.8) and relapse-free survival was 26.5% (CI: 18.6-35). Multivariate analysis revealed that treatment type and disease stage had a significant impact on survival, relapse-free survival and locoregional control. Compared to exclusive chemoradiotherapy, surgery improved locoregional control (40.2 versus 8.7 months, P=0.0004) but in a younger population. Despite postoperative mortality, the gain was maintained for distance relapse-free survival (40.2 versus 10 months, P=0.0147) and overall survival (29.3 versus 14.2 months, P=0.0088). Compared to 50Gy chemoradiotherapy, local control was improved if high dose chemoradiotherapy was performed (13.8 versus 7.5 months, P=0.05) but not overall survival (14.0 versus 15.4 months, P=0.24). CONCLUSION: More than one-third relapse is local. Locoregional control is better with high dose chemoradiotherapy. In this study, surgery performed in selected patients only, improved locoregional control, relapse-free disease and overall survival.


Asunto(s)
Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/estadística & datos numéricos , Neoplasias Esofágicas/terapia , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Quimioradioterapia/efectos adversos , Cisplatino/administración & dosificación , Terapia Combinada , Supervivencia sin Enfermedad , Relación Dosis-Respuesta en la Radiación , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Esofagectomía/estadística & datos numéricos , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Radiofármacos , Dosificación Radioterapéutica , Radioterapia Conformacional/efectos adversos , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único/normas , Resultado del Tratamiento
5.
Cancer Radiother ; 17(1): 21-5, 2013 Feb.
Artículo en Francés | MEDLINE | ID: mdl-23332126

RESUMEN

PURPOSE: Evaluation of perioperative treatment of keloid scars with electron beam therapy or iridium 192 low dose rate brachytherapy. PATIENTS AND METHODS: From 1994 to 2010, 95 patients with 142 keloid scars have been treated by immediate perioperative irradiation and retrospectively reviewed in our institute: 116 scars were treated by electrontherapy and 26 by brachytherapy. RESULTS: In the electrontherapy group treated locations were: earlobe (n=88, 76%), thorax (n=14, 12%), neck (n=9, 8%), limbs (n=5, 4%). The median size of lesions was 3cm (range [R]: 0.5-18cm). In 95.6% of cases, a dose of 15Gy was delivered in five fractions of 3Gy. The median follow-up was 70 months (R: 7-161 months). The 2-year and 5-year local control were respectively 69% (95% confidence interval [95% CI]: 59-76%) and 55% (95% CI: 45-64%). In the brachytherapy group treated locations were: neck (n=3, 11%), earlobe (n=8, 32%), abdomen (n=3, 11%), thorax (n=2, 8%), limbs (n=10, 38%). The median size of lesions was 6.6cm (R: 1.7-28cm). The median dose delivered at 5mm from the source was 20Gy (R: 15-20.69). The median follow-up was 113 months (R: 21-219 months). The 2-year and 5-year local control were respectively 84.6% (95% CI: 64-94%) and 73.5% (95% CI: 49-87%). So far, no radiation-induced cancer has occurred. A trend to a better local control with brachytherapy was noted (compared to electrontherapy, 2-year relapse is halved with brachytherapy) though this difference did not reach the significance (P=0.0991), probably due to the reduced number of patients in the brachytherapy group. CONCLUSION: Brachytherapy seems to provide better local control compared to electrontherapy, and should be proposed as first line treatment. However, electrontherapy is an interesting alternative in case of difficulty to realize brachytherapy. There is probably a dose effect: according to published data, 25 to 30Gy should at least be proposed.


Asunto(s)
Braquiterapia , Electrones/uso terapéutico , Radioisótopos de Iridio/uso terapéutico , Queloide/radioterapia , Radioterapia Adyuvante/métodos , Adolescente , Adulto , Anciano , Braquiterapia/efectos adversos , Niño , Relación Dosis-Respuesta en la Radiación , Electrones/efectos adversos , Femenino , Humanos , Queloide/cirugía , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Radiodermatitis/etiología , Dosificación Radioterapéutica , Recurrencia , Estudios Retrospectivos , Pigmentación de la Piel , Resultado del Tratamiento , Adulto Joven
6.
Transfus Clin Biol ; 17(5-6): 357-61, 2010 Dec.
Artículo en Francés | MEDLINE | ID: mdl-21050789

RESUMEN

Blood transfusion's repercussions on quality of life are less well studied in cancer research, and rarer in palliative situation. It is necessary to look for studies dealing with anaemia to estimate its effects. In curative palliative situation, the situation is similar to that of curative stage patients. It is necessary landing quickly for anaemia to assure the patient's quality of life. Blood transfusion and more recently erythropoïesis-stimulating agents are effective treatments. In advanced palliative stage, transfusion improves symptoms (weakness and dyspnoea bound anaemia) and the patients' well being. The treatment choice must be individual and has to follow an ethical behaviour in respect with the legislation.


Asunto(s)
Anemia/terapia , Transfusión Sanguínea , Neoplasias/complicaciones , Calidad de Vida , Anemia/tratamiento farmacológico , Anemia/etiología , Transfusión Sanguínea/ética , Transfusión Sanguínea/legislación & jurisprudencia , Transfusión Sanguínea/psicología , Disnea/etiología , Disnea/terapia , Hematínicos/uso terapéutico , Humanos , Cuidados Paliativos , Aceptación de la Atención de Salud , Encuestas y Cuestionarios , Cuidado Terminal
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