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1.
PLoS One ; 13(9): e0204117, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30226855

RESUMO

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting. METHODS: Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics. RESULTS: Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators. CONCLUSIONS: Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/administração & dosagem , Adulto , Idoso , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Edema/induzido quimicamente , Edema/patologia , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-kit/genética , Resultado do Tratamento
2.
PLoS One ; 10(8): e0135907, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26308942

RESUMO

PURPOSE: Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. EXPERIMENTAL DESIGN: One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. RESULTS: Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients. CONCLUSION: This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT01416662.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Citidina Desaminase/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacocinética , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Gencitabina , Neoplasias Pancreáticas
3.
Expert Opin Biol Ther ; 6(11): 1175-92, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17049015

RESUMO

A growing understanding of the molecular mechanisms involved in cancer biology and continuous refinement of available technologies for drug discovery have prompted the development of new therapeutic tools targeting specific cancer-associated molecular pathways. Among these so-called biological therapies, monoclonal antibodies have now reached the time of clinical application. Besides initial development of the murine antibody edrecolomab, the impact of monoclonal antibodies on cancer therapy has recently been clearly demonstrated in colorectal cancer by targeting two major pathways critical to tumourigenesis: the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signalling pathways. These antibodies showed significant clinical activity in advanced colorectal cancer, especially when combined with chemotherapy. This paper reviews the status of the monoclonal chimeric antibody cetuximab (Erbitux) and other anti-EGFR antibodies, and of bevacizumab (Avastin; an anti-VEGF humanised monoclonal antibody), in colorectal cancer treatment.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Imunização Passiva/métodos , Imunização Passiva/tendências , Animais , Humanos
4.
J Clin Oncol ; 22(21): 4319-28, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15514373

RESUMO

PURPOSE: To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. PATIENTS AND METHODS: One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m(2) (2-hour infusion) followed by FU 400 mg/m(2) (bolus) and FU 600 mg/m(2) (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m(2) (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m(2) (2-hour infusion) on day 1 (arm C). RESULTS: The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. CONCLUSION: Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Análise de Variância , Camptotecina/administração & dosagem , Cisplatino/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , França , Humanos , Infusões Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Neoplasias Gástricas/patologia , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento
5.
Gastroenterol Clin Biol ; 28(4): 371-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15146153

RESUMO

AIM: Two consensus conferences on management of colorectal cancer were conducted in France during the last ten Years: one regarding rectal cancers in 1994 and the other regarding colonic cancer in 1998. In the present study, we examined data collected in a local gastrointestinal cancer registry to investigate changes in management practices for colorectal cancer in a well-defined population seen between 1990 and 1999. METHODS: The study population consisted of 3 135 patients with colorectal cancer diagnosed in Calvados (an administrative district in northern France) from 1990 to 1999. Two periods were defined: P1=1990-1994 and P2=1995-1999. Multivariate logistic regression analysis was performed. RESULTS: No trends in stage of disease at diagnosis or rate of surgical resection were observed. For patients with cancer of the rectum, the rate of sphincter preservation increased significantly from 65.6% in P1 to 72.3% in P2, in men and in all patients under the age of 75 Years. For patients with cancer of the colon, the number of resection specimens with at least eight examined lymph nodes increased from 50.7% in P1 to 60.2% in P2. This trend predominated in university centers; for rectal cancer patients it was significant only in university centers. Prescription of adjuvant chemotherapy for stage III colonic cancer increased significantly: 41.4% in P1 and 52.5% in P2. No changes in prescription of adjuvant radiotherapy for rectal cancer were observed, irrespective of the stage at diagnosis. The proportion of patients managed in university centers decreased significantly over time from 30.5% in P1 to 27.6% in P2, with a corresponding increase in private clinics. CONCLUSION: Most of the trends observed during the study period began before the consensus conference guidelines were Issued. The consensus guidelines appear to have influenced management practices mainly in university centers, while the majority of patients are managed in non-university centers.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Fatores Etários , Idoso , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Quimioterapia Adjuvante/estatística & dados numéricos , Neoplasias Colorretais/patologia , Feminino , França , Hospitais Universitários/estatística & dados numéricos , Humanos , Masculino , Análise Multivariada , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos
6.
Mutagenesis ; 18(3): 299-306, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12714698

RESUMO

We investigated TP53 mutation patterns in cancers of the esophagus and cardia of patients coming from Lower Normandy, a region situated in the highest incidence area in Europe. To screen tumor samples, we first used denaturing gradient gel electrophoresis (DGGE), a well-characterized technique which constituted our reference method. Then the results were compared with those obtained by denaturing high performance liquid chromatography (DHPLC), a recent and automatic screening technology. Analysis of the TP53 mutations profile showed that the detected alterations were mainly point mutations. Ninety-seven percent (33/34) of esophageal squamous cell carcinoma samples presented at least one mutation or polymorphism. The proportion of somatic, non-silent and sequence-confirmed mutations was 76% (26/34). The most common substitutions were G-->A transitions, which could be related to nitrosamines, acetaldehyde or factors prone to producing mucosal irritation, like hot beverages. G-->T transversions, which were also frequently detected, could originate from benzo[a]pyrene in tobacco smoke. A-->T transversions were not revealed in our series, which constitutes a discordance with mutational spectra already performed in north-western France. Concerning adenocarcinoma of the esophagus and cardia, the alteration frequency was 69% (11/16), with a majority of G-->A transitions at CpG dinucleotides. They are probably related to endogenous process mediated by inflammatory diseases like gastro-esophageal reflux and Barrett's esophagus. The main advantage provided by DHPLC was its ease of application. However, the optimization steps turned out to be quite critical, especially for sequences with high melting temperatures embedded in lower melting temperature fragments. Considering only the common sequences analyzed by the two techniques, four of the 46 positive samples detected by DGGE were not revealed by DHPLC. This result stresses the limited sensitivity of DHPLC compared with DGGE under the conditions described in this study.


Assuntos
Cárdia/patologia , Neoplasias Esofágicas/genética , Mutação , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel de Poliacrilamida , França , Humanos
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