Biomedical subjects

Roger Favre

Publications and source records attributed to Roger Favre.

11 recordsLinked to original sources

PubMed2006

Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax (Cend) of 1.95 mg/L of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmax with achieved Cmax. The mean+/-SD Cmax achieved was 1.93+/-0.16 mg/L. No statistically significant difference was observed between experimental and target values (P>0.05, t test), and Cend achievement was done with an overall 6.6% precision, a performance to be compared with the initial 54% interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r=0.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (+20%, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.

Adult↗

PubMed2006

Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Aged↗

PubMed2006

A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy.

Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.

Adult↗

PubMed2006

[Suffering: representations and challenges].

Research that we carried out aimed to analyzing the suffering as an object of the relation of care and common experiment of this relation. In this way, we have conducted 55 interviews with patients and nurses in an oncology unit. The results underline the central role of the relation for giving meaning to the suffering. The knowledge of the suffering representations appears as a tool for understanding the complex realities connected to the experiences of suffering, and allows to imagine more adapted evaluation methods which could be anchored on "practical knowledge".

Adaptation, Psychological↗

PubMed2005

[Morphine prescription to terminal cancer patients suffering from severe pain: results of a French survey].

This study aimed to determine factors associated with the prescription of morphine to terminal cancer patients suffering from severe pain. A phone survey was conducted among a sample of French GPs, neurologists and oncologists. Two short clinical cases described a terminally-ill patient with either a peritoneal carcinosis and intestinal occlusion, or a lung cancer, and in both cases suffering from severe pain. Overall, 917 agreed to participate among the 1,743 physicians contacted (global response rate 53%). About half of respondents did not support the prescription of morphine if the patient had an intestinal occlusion. Beliefs toward morphine, uneasiness with terminally-ill patients, age and female gender were independently associated with reluctance to prescribe morphine in presented cases. Specialised training has not completely remove reluctance toward morphine prescription in end-of-life care. Non-medical factors correlated to such reluctance, and especially gender, deserve more attention.

Adult↗

PubMed2004

[Impact of a brochure on pain destined for thoracic oncology patients].

OBJECTIVE: To assess the impact of a brochure supplied on pain and analgesic treatment on the knowledge, attitude, belief and perception of patients consulting oncology departments. METHOD: A prospective, comparative, study on patients consulting a thoracic oncology and a general oncology department, suffering from pain and motivating a treatment level > or = to 2 (WHO scale). A group of patients having been given a brochure (case) was compared with a group who had not been given the brochure (controls). The assessment questionnaire, developed according to the KABP (Knowledge, Attitudes, Belief, Practice) method, was distributed to the 2 groups. A second assessment was made 4 weeks after the patients having received the brochure. Visual analog scales (VAS) followed the intensity of the pain. RESULTS: Twenty-one cases and 33 controls were assessed. There was no modification in their belief (risk of addiction) but an improvement in their knowledge (duration of action of morphine agents, management of treatment, multi-disciplinary management). This improvement in knowledge was accompanied by improved control of pain: 2/3 of the patients exhibited a VAS < 1 at the time of the second assessment versus 1/3 during the initial assessment. CONCLUSION: Improvement, if only partial, in the patients' knowledge of pain and its treatment using a brochure, is one of the routes for optimising the management of pain.

Female↗

PubMed2004

[A study of the social representations in chemotherapy: a way to analyse the relations between patients and oncologists].

This research aims to study social representations throughout chemiotherapy, out of a population composed of doctors specialized in Oncology on one hand, and patients dealing with cancer during their chemiotherapy on the other hand. Our methodology is situated among quantitative methods using SPSS for Anovas to analyze statistics datas, EVOQ and Alceste for the pragmatic analysis of the discourse. The datas were collected from a questionnaire including items and words associations. We were interested in chemiotherapy which appears as a social object likely to generate a representative process from which emerges a serie of adaptative strategies belonging to both cognitivo-behaviourism and emotional spheres. chemiotherapy leads to an adaptation of the patient and remains a mediator in the doctor-patient's relation. As far as representations are "action guides", the existence of a representation specific to patients and doctors, allowes us to point out, through a semantic and emotional gap a technical medicine which is, in the future, likely to tend to existentialism.

Antineoplastic Agents↗

PubMed2003

[Opinion of general and specialized physicians toward euthanasia. Results from the French survey on attitudes and practices against palliative care, 2002].

OBJECTIVES: To evaluate opinion of physicians about the legalization of euthanasia according to their professional characteristics, their attitudes toward morphine, their attitudes toward communication with end-of-life patients, and their perception of specific types of terminal care. METHOD: Univariate and multivariate analyses were carried out from data collected among 1.000 general practitioners, oncologists, neurologists and HIV specialists (French cross-sectional survey on palliative care, 2002). RESULTS: 42.5% of physicians agreed with the statement that euthanasia should be legalized as it is already the case in the Netherlands. Inadequate prescription of morphine and calling terminal sedation as active euthanasia were associated with a favorable opinion toward legalization of euthanasia. CONCLUSION: Specific training on pain management and terminal sedation would help physicians to have a better view of the problem of euthanasia.

Attitude↗

PubMed2003

French physicians' attitudes toward legalisation of euthanasia and the ambiguous relationship between euthanasia and palliative care.

In 1999, the French Parliament established a "right to palliative care", which reactivated public debate about euthanasia. In order to investigate jointly physicians' attitude toward palliative care and euthanasia, we conducted a cross-sectional survey of a national sample of French GPs, oncologists, and neurologists. Overall, 917 physicians participated in the survey. Significant proportions of respondents, especially among GPs and neurologists, considered that palliative sedation and withdrawing life-sustaining treatments (WLST) were euthanasia. Multivariate analysis showed that the physicians who had special medical training in palliative care, and those who distinguish palliative sedation and WLST from euthanasia were more likely to oppose legalisation of euthanasia. Thus, French physicians' attitude to the legalisation of euthanasia is strongly influenced by whether or not they distinguish palliative care from euthanasia. Improved palliative care requires better training of the entire medical profession, and clearer guidelines about which end-of-life care practices are legally and ethically acceptable.

Adult↗

PubMed2002

Population pharmacokinetics of etoposide: application to therapeutic drug monitoring.

Antineoplastic agent etoposide (VP16) displays narrow therapeutic index and erratic pharmacokinetics, and dose individualization is a convenient way for overcoming the interpatient variability, so as to maintain the drug exposure within a therapeutic range. The authors proposed a population-based Bayesian methodology to adjust routinely VP16 dosage when given as a 5-day infusion. The mean VP16 pharmacokinetic parameters of the reference population calculated from 14 patients following the two-stage method were CL = 1.92 +/- 0.512 L/h and t(1/2) = 6.7 +/- 2 hours. The reference population was next used prospectively for Bayesian dose individualization for 25 patients (47 courses) undergoing 5-day infusions of VP16. Resulting steady-state concentrations proved to be successfully adjusted to the target values in 77% of the courses. Therefore, the method presented here meets the requirements for routine therapeutic drug monitoring of VP16, a major anticancer drug extensively used in clinical oncology.

Adult↗

PubMed2002

[Interest of studying the in vitro genotoxicity of an antineoplastic drug on healthy human cells: paclitaxel example].

Paclitaxel is often used as an adjuvant antineoplastic agent. However, very little data is available in literature on its potential genotoxicity on healthy human cells. Our objective is to study the potential in vitro genotoxicity of paclitaxel, by using the cytokinesis-blocked micronucleus assay in combination with fluorescent in situ hybridization of nonspecific centromeric probes on human T-lymphocytes. Paclitaxel was found to significantly increase the micronucleated lymphocyte rates with a concentration-dependant manner. This increase is observed as early as with the weakest concentration tested (2,5 nM). Over 85% of those micronuclei contained one or more whole chromosomes, indicating that paclitaxel is a strong aneugenic drug. Paclitaxel induces the formation of aneuploid daughter cells, as a consequence of abnormalities in the distribution of chromosomes during the cell division. However, aneuploidy is probably one of the first events in the oncogenesis process, and it often seems to be linked to a dysfunction of the centrosome. An interaction between paclitaxel and centrosome could explain a considerable amount of the centromere-positive micronuclei due to multipolar mitosis. Paclitaxel, whose influence is being questioned in clinical practice in the occurrence of secondary acute myeloid leukemia, is therefore an in vitro aneugenic drug, which could be carcinogenic.

Aneuploidy↗