DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.

BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.

Impact of the prophylactic gastrostomy for unresectable squamous cell head and neck carcinomas treated with radio-chemotherapy on quality of life: Prospective randomized trial.

BACKGROUND AND PURPOSE: Concomitant radio-chemotherapy is the gold standard treatment for unresectable head and neck carcinomas. Placement of prophylactic gastrostomy has been proposed to provide adequate nutrition during the therapeutic sequence. The objectives of this study were to assess the impact of prophylactic gastrostomy on the 6-month quality of life, and to determine the factors related to this quality of life. MATERIALS AND METHODS: Design. randomized, controlled, open study ("systematic percutaneous gastrostomy" versus "no systematic gastrostomy"). Patients. squamous cell head and neck carcinoma (stages III and IV, UICC 1997). Setting. oncological departments of French university teaching hospitals. Treatment. optimal concomitant radio-chemotherapy. Evaluations. T0 baseline evaluation, T1 during the treatment, T2 end of the treatment, and T3 6-month post-inclusion. Primary endpoint. 6-month quality of life (Qol) assessed using SF36, EORTC QLQ-C30, EORTC QLQ H&N35 questionnaires. RESULTS: The Qol changes from baseline included a decline (T1 and T2) followed by an improvement (T3). Qol at 6 months was significantly higher in the group receiving systematic prophylactic gastrostomy (p=10(-3)). Higher initial BMI and lower initial Karnofsky index were significant factors related to a higher 6-month Qol. CONCLUSIONS: The study results suggest that prophylactic gastrostomy improves post-treatment quality of life for unresectable head and neck cancer patients, after adjusting for other potential predictive quality of life factors.

District nurses' attitudes toward patient consent: the case of mechanical ventilation on amyotrophic lateral sclerosis patients: results from a French national survey.

PURPOSE: In France, a recent law emphasizes patient rights and prohibits unwanted therapies in end-of-life care. As end-of-life home care is increasing, we aimed to assess French district nurses' attitudes toward terminally ill patients' autonomy. MATERIALS AND METHODS: We used data from a nationwide telephone survey conducted in 2005 among a random sample of French district nurses (n = 602). Nurses' attitudes were assessed with a clinical case describing a patient (randomly defined as a male or a female aged 50 years) having amyotrophic lateral sclerosis (ALS) who urgently needs mechanical ventilation. Nurses were asked whether patient consent was necessary before performing intubation/tracheotomy, and the analysis took into account various covariates, including nurses' religiosity, nurses' attitudes toward living wills, and patient sex. RESULTS: Overall, 44% of nurses considered that an ALS patient with respiratory failure should always be intubated (53% for a female patient, 40% for a male patient, P < .01), and after intubation, 27% upheld tracheotomy without considering patient consent as a necessary prerequisite (39% among male nurses, 30% among female nurses, P < .05). Poor communication with terminal patients and hostility toward living will were also predictive of willingness to perform both mechanical ventilation and tracheotomy without patient consent. CONCLUSIONS: A significant part of French district nurses may have a disturbing propensity to support intubation and tracheotomy with insufficient attention paid to the patient's will. Further research should investigate potential causal factors (such as increased workload) as well as sex-related attitudes in nurse-patient relationship.

High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy.

Preoperative high-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is still a mainstay in the treatment of osteosarcoma. This anticancer agent is characterized by a narrow therapeutic index and wide interpatients variability. To ensure effective and safe administration of HD-MTX, we had earlier developed an adaptive-dosing schedule with a feedback strategy. In our institute, the MTX dosage was tailored according to individual pharmacokinetics parameters, determined in real time both from two blood samples (3.5 and 4.5 h) and from Bayesian population parameters. Up to 20 g of MTX was safely administered as 8-h infusions. Low MTX elimination rate has, however, been reported in 15-20% of the patients, and forecasting the MTX elimination phase and the management of leucovorin rescue is still a challenging issue in clinical oncology. This study aims at identifying the clinical or biological covariates related to impaired MTX clearance, and at validating a new limited sampling strategy (LSS), allowing for the accurate prediction of the MTX terminal elimination phase. This retrospective study was carried out on 49 patients (30 men, 19 women; mean age, 26.7 years) treated for osteosarcoma with HD-MTX. The population and individual pharmacokinetics parameters were computed, before the identification of the relevant covariates. Different LSSs were then tested, to predict accurately when the MTX plasma concentrations would drop below 0.2 micromol/l, the threshold associated with the end of the rescue of leucovorin with alkaline hydration. Two main covariates (creatinemia clearance and alanine aminotransferase) were correlated with MTX clearance. Conversely, the impact of body surface area on MTX pharmacokinetics was weak, suggesting that dosing schedules based on body surface area were inadequate and potentially hazardous. A new LSS predicting accurately when the MTX concentration would reach 0.2 micromol/l has been validated; blood samples are stopped as soon as the MTX concentration drops to 1 micromol/l. With this LSS, our retrospective study suggests that 60% of the patients would have left the hospital earlier than they actually did owing to a better forecasting of the MTX decrease, thus improving their quality of life while improving the cost-effectiveness for the institute. HD-MTX can be administered safely using an adaptive-dosing strategy with drug monitoring. Moreover, pharmacokinetic modeling permits the accurate forecasting of the MTX elimination profile, thus allowing for a better management of the postinfusion care of cancer patients treated with particularly high doses of this drug.

Nutritional factors as predictors of response to radio-chemotherapy and survival in unresectable squamous head and neck carcinoma.

BACKGROUND AND PURPOSE: This study sought to evaluate nutritional prognostic factors before treatment in patients with unresectable head and neck cancer treated by concomitant radio-chemotherapy. METHODS AND MATERIALS: Seventy-two consecutive patients were treated. We studied the potential effects of CRP, Alb, preAlb, orosomucoid, weight, weight history, BMI, PINI, OPR and NRI on response to treatment, Event-Free Survival (EFS) and Overall Survival (OS). Effects of potential risk factors on OS and on EFS were analyzed by computing Kaplan-Meier estimates, and curves were compared using the log-rank test. RESULTS: All biological nutritional factors were statistically correlated with the response to radio-chemotherapy. In multivariate analysis, only CRP (p=0.004) remained statistically significant. A statistical correlation was found between Alb and EFS in multivariate analysis (p=0.04). The factors influencing OS in univariate analysis were Alb (p=0.008), CRP (p=0.004), orosomucoid (p=0.01) and NRI (p=0.01), response to radio-chemotherapy (p<0.001) and staging (p=0.04). In multivariate analysis, only the response to radio-chemotherapy (p<0.001) remained significant. CONCLUSIONS: This study illustrates the prognostic value of nutritional status. CRP and Alb may be useful in the assessment of advanced head and neck cancer patients at diagnosis and for stratifying patients taking part in randomized trials.

Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation.

Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.

Pseudomonas aeruginosa may accumulate drug resistance mechanisms without losing its ability to cause bloodstream infections.

In this study, we systematically investigated the resistance mechanisms to beta-lactams, aminoglycosides, and fluoroquinolones of 120 bacteremic strains of Pseudomonas aeruginosa. Pulsed-field gel electrophoresis genotyping showed that 97 of these strains were represented by a single isolate, 10 by 2 and 1 by 3 clonally related isolates, respectively. Seventy-five percent (90 out of 120) of the bacteremic P. aeruginosa strains displayed a significant resistance to one or more of the tested antimicrobials (up to 11 for 1 strain). These strains were found to harbor a great diversity of resistance mechanisms (up to 7 in 1 strain), leading to various levels of drug resistance. Interestingly, 11 and 36% of the isolates appeared to overproduce the MexAB-OprM and MexXY-OprM efflux systems, respectively. Altogether, our results show that P. aeruginosa may accumulate intrinsic (overproduction of cephalosporinase AmpC, increased drug efflux, fluoroquinolone target mutations, and deficient production of porin OprD) and exogenous (production of secondary beta-lactamases and aminoglycoside-modifying enzymes) resistance mechanisms without losing its ability to generate severe bloodstream infections. Consequently, clinicians should be aware that multidrug-resistant P. aeruginosa may remain fully pathogenic.

Morphine prescription in end-of-life care and euthanasia: French home nurses' opinions.

OBJECTIVE: This study aimed to investigate factors that might lead French homecare nurses to consider the prescription of high-dose morphine to terminally ill patients to be euthanasia. METHODS: The researchers conducted an anonymous telephone survey among a random sample of 602 French homecare nurses (response rate = 75 percent) in 2005. RESULTS: Overall, 27 percent of responding home nurses considered prescribing high-dose morphine to terminally ill patients to be euthanasia. Such an opinion was more frequently held by older nurses, those who had not followed terminally ill patients during the previous three years, and those with less knowledge about pain management involving opioid analgesics. CONCLUSION: There is an urgent need to strengthen pain management education among French homecare nurses--especially regarding the use of morphine--in order to both improve their technical skills and correct some misconceptions about opioid analgesics.

[Knowledge and attitudes of private practice nurses about end-of-life pain. Results of a national survey on nurses' attitudes and practices for end-of-life patients, 2005-2006]. / Connaissances et attitudes des infirmiers libéraux face à la douleur en fin de vie. Résultats de l'enquête nationale française "Attitudes et pratiques des infirmiers face aux patients en fin de vie, 2005-2006".

BACKGROUND: Nurses play a crucial role in end-of-life care, especially for outpatients. It is important to assess their knowledge and attitudes regarding pain management during the end-of-life period. METHODS: A random national sample of 602 French nurses providing home care responded to a telephone survey. The questionnaire included a scale of knowledge about pain and a short clinical case related to severe pain management, requiring WHO level 3 analgesia, for a dying patient. RESULTS: The pain knowledge score depended on nurses' training and was higher for those living with another health professional. For the clinical case, only 60% of nurses favored the prescription of the analgesia recommended by international guidelines. This support depended on objective skills in pain management, but was less frequent for elderly or women patients. DISCUSSION: Attitudes toward pain management at the end of life do not depend only on book learning. They are also influenced by more subjective factors that may cause inequality in care for women and the elderly. Nurse training programs should take such factors into account.

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.

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.

[Suffering: representations and challenges]. / La souffrance: représentations et enjeux.

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".

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.

[Morphine prescription to terminal cancer patients suffering from severe pain: results of a French survey]. / Prescription de morphine en cas de douleur intense en phase terminale de cancer: résultats d'une enquête nationale.

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.

Morphine prescription to terminally ill patients with lung cancer and dyspnea: French physicians' attitudes.

This study aimed to investigate factors associated with analgesic use of morphine in end-of-life care. French general practitioners (GPs) and oncologists (N = 719) were asked whether they would prescribe morphine as first-line therapy to patients with terminal lung cancer suffering from dyspnea associated with cough and great anxiety. Overall, 54 percent of oncologists and 40 percent of GPs stated that they would prescribe morphine in the presented case. This prescriptive attitude correlated with physicians' age, professional background, communication skills, and attitude toward terminally ill patients. The findings of this study indicate that improving analgesic use of opioids in end-of-life care is not only a matter of enhancing technical skills acquired through training or experience but also a matter of improving communication and empathy between physicians and patients.

[Impact of a brochure on pain destined for thoracic oncology patients]. / Impact d'un livret d'information sur la douleur destiné aux patients en oncologie thoracique.

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.

[A study of the social representations in chemotherapy: a way to analyse the relations between patients and oncologists]. / Etude des représentations sociales de la chemiothérapie: une voie d'analyse des relations entre patients et médecins oncologues.

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.

[Opinion of general and specialized physicians toward euthanasia. Results from the French survey on attitudes and practices against palliative care, 2002]. / Opinion des médecins généralistes et spécialistes sur l'euthanasie. Résultats de l'enquête française << Attitudes et pratiques face aux soins palliatifs--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.

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.

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.