Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model-based population pharmacokinetic analysis.

PURPOSE: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. DESIGN/METHODS: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m2 of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m2, unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. RESULTS: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. CONCLUSION: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.

Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low-grade glioma.

AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS: A multicentre, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumours, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS: PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg m-2 dose level, were 472 L h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (P = .004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION: Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among paediatric patients.

Imaging biomarkers of outcome after radiotherapy for pediatric ependymoma.

BACKGROUND AND PURPOSE: Ependymoma is the third most common brain tumor in children. Radiation therapy (RT) is systematically administered after maximum surgical resection, utilizing recent advances in radiation delivery. Imaging can make a significant contribution to improving treatment outcome. This prompted us to look for significant preoperative and postoperative imaging markers for survival. MATERIAL AND METHODS: We undertook a national retrospective review of 121 patients who had undergone resection followed by RT. Preoperative tumor volumes on T1 and FLAIR images were delineated, together with postoperative hyperintense volumes on FLAIR images. Overall survival (OS) and disease-free survival (DFS) analyses included clinical data and volumes extracted from images. RESULTS: After a median follow-up of 38.5 months, 80.2% of patients were alive, but 39.7% had experienced at least one event. Statistically significant differences between patients with and without postoperative FLAIR abnormalities were found for both DFS (71.9% vs. 40.3%; p = 0.006) and OS (93.7% vs. 72.4%; p = 0.023) in the univariate analyses, and for OS (p = 0.049) in the multivariate analyses. CONCLUSIONS: Postoperative FLAIR hyperintensities are a negative prognostic factor for intracranial ependymoma and may be a surrogate for residual disease. They could therefore prove helpful in patients' surgical and radiotherapeutic management.

Prognostic and predictive values of diffusion and perfusion MRI in paediatric intracranial ependymomas in a large national study.

OBJECTIVE: To assess the relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) derived, respectively, from perfusion and diffusion pre-operative MRI of intracranial ependymomas and their predictive and prognostic values. METHODS: Pre-operative MRI and clinical data for intracranial ependymomas diagnosed between January 2000 and December 2013 were retrospectively retrieved from a web-based national database. MRI data included diffusion (62 patients) and perfusion (20 patients) MRI. Patient age, histopathological diagnosis, tumour location, ADC, relative ADC (rADC) and rCBV were considered as potential factors in a survival analysis. Survival rates were estimated using the Kaplan-Meier method. Univariate analyses were performed using the log-rank test to compare groups. We also performed a multivariate analysis, applying the Cox proportional hazards model. RESULTS: ADC and rADC values within hypointense regions differed significantly between grades II and III (p = 0.01). The 75th percentile of ADC within hypointense regions and the 25th percentile of rCBV within non-enhancing lesions were prognostic of disease-free survival (p = 0.004, p = 0.05). A significant correlation was found between the 75th percentile of rCBV and the 25th percentile of rADC (p = 0.01) in enhancing regions of grade-III tumours. CONCLUSION: Pre-operative rADC and rCBV could be used as prognostic factors for clinical outcome and to predict histological grade in paediatric ependymomas. ADVANCES IN KNOWLEDGE: Prognostic value of diffusion and perfusion MRI in paediatric ependymoma was found and may play a role in the prognostic classification of patients in order to design more tailored treatment strategies.

[Fertility preservation in adolescent cancer patients]. / La fertilité des adolescents atteints d'un cancer.

Recent advances in cancer therapy have improved the survival rate of infant and adolescent facing cancers. The objective of treatment is not only to cure cancer but also to limit its secondary consequences. Impaired fertility is an important sequel of numerous treatments against cancer. Therefore, efforts to maintain fertility must be a major consideration in the treatment plan. This review focuses on various options for preserving fertility in adolescents. In female patients, ovarian transposition out of the radiation field may considerably reduce the radiation received by the ovaries. The benefits of GnRH analogue are not yet clear and apoptosis inhibiting agents are unavailable. Embryo freezing is the most reliable method to preserve fertility. This method is time-intensive, requires a partner, and ovarian stimulation may not always be compatible with the need of starting treatment against cancer immediately. Oocyte cryopreservation is an experimental technique that can be used in post-pubertal patients irrespective of their marital status. The cryopreservation of mature oocytes has similar constrains as embryo freezing ; in addition the technique is not as well-established and the pregnancy rates obtained are much lower than those achieved with embryos. Freezing of immature oocytes followed by in vitro maturation in spite of its theoretical advantages is inefficient in current practice. Ovarian tissue cryopreservation offers great hope because it has the potential to preserve a large number of primordial follicles without any ovarian stimulation and preliminary trials have shown some success. For male adolescents cancer patients semen cryopreservation is a successful alternative that should be offered systematically when cancer therapies that may impair gonadal function are indicated. For prepubertal males there is presently no standardized technique for preserving fertility ; however, the development of testicular germ-cell harvest needs to be considered.

[Compliance to treatment of adolescents with cancer]. / L'observance des adolescents atteints de cancer.

Compliance is a very important issue in medicine for three major reasons. Non-compliance has a considerable financial cost for health care systems. Adherence to treatment is the main link between intention to treat and the desired health outcome. Finally, the influence of non-compliance on the conclusions of clinical research trials can have severe consequences. Despite the importance of these issues, our literature review found very few recent studies concerning the compliance of adolescents with cancer. Non-compliance has many causes. The relationship between patient and health care team, the organisational aspects of care and the youth's perception of his/her illness and its treatment all significantly affect adolescents'compliance. The influence of the treatment on young people's lifestyles as well as the physical transformations induced by the treatment are also important factors, due to adolescents desire to conform to their peer group. Family relationships also play a significant part in adolescents'therapeutic adherence. Since the end of the 1990s, research on adherence has focused more on the importance of the doctor-teenager relationship and the strong influence of the patients'perception concerning health in general and his/her illness in particular. Negotiation is an essential component of a successful treatment in teenagers due to their increasing desire for autonomy. Despite numerous recommendations international research has not succeeded in using standardised terms concerning compliance to treatment regimens or come to an agreement on valid assessment methods. Longitudinal studies should be carried out in order to determine causal links between factors and compliance in a methodologically correct manner. Research should be quantitative but must also include the conceptual elements which have been put forward by qualitative research, namely the importance of teenagers'point of view concerning their treatment.

[Schooling of young people with cancer]. / Scolarisation des jeunes porteurs de cancer.

The schooling of young people with cancer poses various problems, similar to those experienced by disabled or chronically ill children. Published data on this subject in the medical literature comes mainly from studies carried out in the USA and the UK. Cancer and its treatment can cause both direct (learning difficulties or other disabilities...) and indirect (discrimination...) problems. Academic failure, and other problems linked to school absenteeism, can affect the future of adolescents with cancer. Sustaining schooling during the illness enables such patients to avoid falling behind academically, and to maintain his or her social status as a student. Due to the organisation of treatment regimes, education is provided in three environments : in hospital (during in-patient stays), at home (generally whilst the patient is convalescing), or at school. Paediatric oncologists have underlined the importance of establishing links between hospital and educational personnel (with parental approval), and suggest that a teachers'illness information manual should be produced. School re-entry is recommended as soon as possible. During the illness, the patient's presence in class is dependent on his or her general health, the progress of the cancer, and the treatment regime being followed. School absenteeism, inevitable during treatment periods and the year following diagnosis, is often associated with academic problems or failure. While many cancer patients worry about their school work and future educational progress, such problems remain rare. In the long term, the educational level of childhood or adolescent cancer survivors remains similar to that of the general population. In order to understand the issues surrounding the schooling of young cancer patients in France, long-term multi-centre studies, focusing on adolescents, must be initiated.