Roger Favre

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.

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.

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.

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 patients 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 (r2=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r2=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.

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 t1/2 = 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.

Dosage adjustment of high-dose methotrexate using bayesian estimation : a comparative study of two different concentrations at the end of 8-h infusions

Summary Bayesian estimation (BE) of pharmacokinetic parameters enables the clinician to adjust the dosage of high-dose methotrexate (HDMTX) to correct the inter- and intraindividual variation of concentrations that are responsible for severe toxicity. In this study of 672 HDMTX infusions, we validated an approach that consisted of reaching as nearly as possible a theoretical concentration of 5.10-4 M or 10-3 M at the end of an 8-h infusion by adjusting, when necessary, the dosage at the 6th h. The BE of the clearance was compared with that obtained by maximum likelihood estimation (MLE), which was used as reference. BE performance was evaluated by calculating the bias and precision that indicated an overestimation of clearances obtained by BE compared with the higher clearance of the MLE in the group of patients receiving the higher dose (15 and 37.9%). Linear regression analysis of clearance obtained by BE and MLE showed a correlation (p < 0.0001) in both groups of patients with a closer link in those with the lower dose. However, in current clinical practice the important point is to obtain MTX concentration that is as close as possible to the desired concentration. Adjustments were evaluated by comparing the obtained concentrations with the desired theoretical concentration. There was no bias and precision was satisfactory in both groups of patients (15 and 12%, respectively, for 5.10-4 M and 10-3 M). This method makes it possible to limit the inter- and intraindividual variations of concentrations. As a result, severe complications were essentially nonexistent and were never life threatening.

Clinical pharmacokinetics of vindesine: Repeated treatments by intravenous bolus injections☆

Vindesine was administered intravenously to 12 patients with advanced cancer. Treatment was repeated after 2 weeks or more with a 1.5-to 2-fold increased dose of vindesine. Five patients received one or two additional injections at the higher dose level. One patient was given 0.4, 1 and 4 mg of vindesine on days 1, 3 and 6 and then 8 mg on days 19 and 34. Plasma samples and urine were collected over 3 days after injection and monitored for vindesine by radioimmunoassay. Significant time-dependence of vindesine plasma concentration decay kinetics at a constant dose was observed in four patients out of six. The comparison of the kinetics after administration of different doses to the same patient revealed frequent deviations from linearity with no obvious general trend. Urinary excretion was very low (1-12% of the dose), and urinary excretion rates correlated with plasma concentrations. Renal clearances were variable from one patient to another and also for the same patient from one injection to another. These data were interpreted in terms of time- and dose-dependence of vindesine pharmacokinetics.

Methotrexate and 7-hydroxy-methotrexate pharmacokinetics following intravenous bolus administration and high-dose infusion of methotrexate

The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m2) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 X 10(-4) M methotrexate (infusion rates greater than 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotrexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant (P less than 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.

Impact d’un livret d’information sur la douleur destiné aux patients en oncologie thoracique

Resume Objectif Evaluer l’impact de la mise a disposition d’un livret d’information concernant la douleur et les traitements antalgiques sur les connaissances, attitudes, croyances et perceptions des patients consultant dans des services d’oncologie. Methode Etude prospective, comparative, incluant des sujets consultant dans un service d’oncologie thoracique et un service d’oncologie generale, ayant une symptomatologie douloureuse motivant un traitement de niveau ≥ 2 (echelle OMS). Un groupe de sujets ayant recu un livret d’information (cas) a ete compare a un groupe de sujets sans livret (temoins). Le questionnaire d’evaluation, elabore selon la methode KABP ( Knowledge, Attitudes, Belief, Practice ), a ete distribue aux 2 groupes. Une seconde evaluation a ete realisee 4 semaines apres pour les sujets avec livret. Des echelles visuelles analogiques (EVA) ont permis de suivre l’intensite de la douleur. Resultats Vingt et un cas et 33 temoins ont ete evalues. Il existait une absence de modification des croyances (risque de dependance), mais une amelioration des connaissances (duree d’action des morphiniques, gestion du traitement, prise en charge multidisciplinaire). Cette amelioration des connaissances s’accompagnait d’une amelioration du controle de la douleur : 2/3 des patients avaient une EVA ≤ 1 au moment de la seconde evaluation contre 1/3 lors de l’evaluation initiale. Conclusion Ameliorer, meme partiellement, les connaissances des patients sur la douleur et ses traitements au travers d’un livret d’information, est l’une des voies pour optimiser la prise en charge de la douleur.

Utilisation de la kétamine en soins palliatifs : revue de la littérature

Resume La ketamine a montre depuis ces dix dernieres annees son interet comme antalgique . A des doses inferieures a celles utilisees en anesthesiologie, la ketamine augmente l’antalgie induite par les opioides. Elle appartient a la famille des antagonistes des recepteurs N-methyl-D-aspartate (NMDA). Son implication dans les douleurs neuropathiques a ete demontree. Il s’agit d’un traitement adjuvant aux opioides dans la prise en charge des douleurs cancereuses refractaires. Cette revue de la litterature a pour but de determiner l’etat actuel des connaissances concernant l’utilisation de cet anti-NMDA dans le domaine des soins palliatifs : indications, efficacite, voies d’administration, posologies, effets secondaires, complications. Actuellement, il n’existe pas de niveau de preuve suffisant pour pouvoir affirmer de facon formelle l’efficacite de la ketamine en soins palliatifs. Des etudes amenant a des consensus nous paraissent indispensables pour permettre la diffusion de cette pratique.