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Biomedical subjects

F Doz

Publications and source records attributed to F Doz.

At least 37 records · Page 2Linked to original sources
PubMed2003

Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy.

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml x min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.

Adolescent↗
PubMed2003

Peripheral blood stem cell collection in 24 low-weight infants: experience of a single centre.

Peripheral blood stem cells (PBSC) harvest may be difficult in young children. Extracorporeal separator line priming by red blood cells is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 24 children weighing less than 15 kg treated between January 1997 and September 1999, in whom we tried to avoid systematic blood priming. The median age and weight at the time of apheresis were 2.4 years and 12 kg, respectively. A total of 48 PBSC were performed. When haemoglobin was less than 12 g/dl, packed red cells were transfused before collection (40% of aphereses). The median cell yield per apheresis was 7.1 (2.2-30.6)x10(6)/kg CD34(+) cells and 16.0 (3.3-44.3)x10(5) CFU-GM/kg. Initial collection failed in three cases. Four children required an additional haematopoietic progenitor mobilization. This procedure allowed PBSC collection without transfusion in 37.5% of children, and was safe (two serious and five mild transient side effects) and effective (median CD34(+) cells collected per child: 7.1 x 10(6)/kg (4.6-30.6) and CFU-GM: 15.1 x 10(5)/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter was avoided in 43% of children.

Blood Component Removal↗
PubMed2003

Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.

AIM: The role of neoadjuvant chemotherapy was studied when first line enucleation cannot be safely performed in unilateral extensive retinoblastoma (major buphthalmia or radiologically detectable optic nerve involvement). METHODS: Six patients, referred for unilateral retinoblastoma, presented with major buphthalmia (two) or optic nerve invasion (four): they were treated by neoadjuvant chemotherapy using etoposide and carboplatin. RESULTS: Good tumour response was observed in the two patients with buphthalmia and in three of four cases with optic nerve involvement. Meningeal progressive disease was observed in the last patient. The five patients without disease progression were then operated on: anterior enucleation in the patients with buphthalmia and enucleation via a double neurosurgical and ophthalmological approach with prechiasmatic optic nerve section in the other three cases. Postoperative chemotherapy was performed in these five patients. Local radiotherapy to the chiasmatic region and posterior part of the optic canal was necessary in only one patient. The non-operated patient died with disease progression 6 months after the diagnosis. The other five patients are alive with a follow up of 12, 15, 21, 36, and 40 months after stopping treatment. CONCLUSION: Neoadjuvant chemotherapy can be useful in extensive unilateral retinoblastoma with buphthalmia and/or radiological optic nerve invasion at diagnosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

[Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma].

INTRODUCTION: The use of transpupillary thermotherapy alone or associated with systemic chemotherapy is a therapeutic modality of ocular retinoblastoma that allows ocular preservation without external beam irradiation of the eye. We present our experience with thermotherapy in the treatment of selected cases of retinoblastoma. MATERIAL AND METHODS: This paper reports a retrospective case series of patients treated for retinoblastoma by thermotherapy or chemothermotherapy (carboplatin IV followed by thermotherapy) in a single institution from October 1994 to December 2000. Data collected include general characteristics of the treated children, tumor characteristics, and the results of the treatments on local tumor control. Transpupillar thermotherapy was delivered with a diode laser through an operating microscope. Each tumor was treated separately and laser intensity, spot size, and duration were adapted to the size of the tumor and the clinical response. Chemothermotherapy consisted in thermotherapy delivered shortly after an intravenous injection of carboplatin (560 mg/m(2)) at day 1, followed by thermotherapy alone at day 8 if the lesion was 6mm or more in diameter. This cycle was administered every 28 days. The choice between thermotherapy and chemothermotherapy depended on the initial size of the lesions. Thermotherapy was used when the lesion measured 3mm or less. Lesions measuring more than 15 mm, or associated with substantial vitreous seeding, retinal detachment, or optic nerve head involvement are not suitable for these techniques. RESULTS: During the study period, 239 children were treated in our institution and 109 of them (147 eyes, 372 tumors) could be treated conservatively without external beam radiation. The median tumor diameter at the moment of thermotherapy or chemothermotherapy was 2mm (range, 0.2-15.0mm). One hundred and ninety-four tumors were treated by chemothermotherapy and 18 by thermotherapy alone. In 75% of the cases, the treatment was administered after two courses of chemotherapy (etoposide and carboplatin). After a mean follow-up of 55 months (range, 16-89 months), tumor control was obtained in 87.1% of lesions after chemothermotherapy and 77.8% after thermotherapy. Salvage enucleation was necessary for seven lesions (seven eyes) but none in the cases where thermotherapy was used alone. No severe systemic side effects were noted. DISCUSSION: Diode laser delivers hyperthermia on the tumor bed and its use alone or in association with systemic administration of carboplatin makes it possible to preserve the eye without external beam irradiation, with few side effects and less cumulative doses of chemotherapy. CONCLUSION: Thermotherapy and chemothermotherapy provide excellent local tumor control and eye preservation in selected cases of retinoblastoma.

Antineoplastic Agents↗
PubMed2002

Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study.

PURPOSE: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans. RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication. CONCLUSION: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.

Adolescent↗
PubMed2002

Supratentorial embryonal tumors in children under 5 years of age: an SFOP study of treatment with postoperative chemotherapy alone.

BACKGROUND: To determine the effectiveness of multiagent chemotherapy as sole post-operative treatment of supratentorial central nervous system (CNS) embryonal tumors in young children. PROCEDURE: The data of 25 children under 5 years of age diagnosed with supratentorial embryonal tumors (17 primitive neuroectodermal tumors, four pinealoblastomas, and four medulloepitheliomas) treated exclusively by postoperative chemotherapy (CT) between 1990 and 1997 were reviewed. RESULTS: Fifteen tumors were hemispheric and 10 were deeply seated. Four children presented with disseminated leptomeningeal disease. Total resection was performed in nine patients, subtotal in 9, partial in 3, and a diagnostic biopsy only in 2. Two children did not undergo surgery. Twenty-four children relapsed with a median time of 5.5 months. The median overall survival was 12 months, and the 2-, and 5- year survivals were 30 and 14%, respectively. The 2- year disease-free survival was 4%. There was a significantly worse prognosis in patients undergoing incomplete resection and in the group with deeply situated tumors. Four relapses were treated by second surgery followed by high-dose chemotherapy and radiotherapy. Two of them remain in CR2, and all these children are free of late sequelae. CONCLUSIONS: CT alone failed to maintain disease-free survival in most of the children, although, disease progression was delayed to some extent. Children under 5 years with supratentorial embryonal tumors should undergo total surgical resection if possible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

[Neurofibromatosis 1: recommendations for management].

Twenty experts, members of a French medical network devoted to neurofibromatosis 1 have elaborated recommendations for the management of the disease. Bibliography was obtained through a Medline of articles from 1966 to 1999 for the terms neurofibromatosis, NF1, neurofibroma and from textbooks. A consensual document was written taking into account extracted data. An annual careful clinical examination is recommended except in cases with complications. Screening investigations are not recommended due to the rarity of complications, generally symptomatic and easily detected during the clinical follow-up. The only controversial exception might be magnetic resonance imaging for early detection of optic pathway gliomas in young children. A co-ordinated follow-up in specialised multidisciplinary centres, providing patients with a rational management, is recommended.

Adolescent↗
PubMed2002

Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Adolescent↗
PubMed2002

Pharmacokinetic modelling of total and unbound plasma carboplatin--a population study in 75 children.

AIMS: A compartmental open model was developed to describe the relationship between plasma unbound (C.) and bound (CT) carboplatin concentrations. A population pharmacokinetic study was then undertaken to investigate the effect of demographic covariates on unbound and bound carboplatin clearance and volume parameters. METHODS: Carboplatin and demographic data were collected from 75 children (1-17 years old, 10 children with unilateral nephrectomy) treated using 1-hour daily infusions for various malignancies. Concentration-time data, C(U) and C(T), from children with rich data were used to develop the model. The data from all children were then simultaneously analyzed using a population approach. RESULTS: The average population values for total unbound carboplatin clearance, CL(U), and distribution volume of unbound carboplatin, VI, were 3.87 l/h and 6.26 l/h, respectively. The clearance of plasma-bound carboplatin was comparatively low, 0.11 l/h. CL(U) was dependent on weight, nephrectomy status and serum creatinine. A constant fraction of CL(U), 0.17 l/h, included the disappearance of unbound compound due to irreversible plasma binding. V1 was dependent on body weight. The unbound plasma carboplatin fraction (fu) was simulated and rapidly decreased with post-infusion time. CONCLUSIONS: The body weight was a better predictor for unbound carboplatin clearance than body surface area, and UNP and SCr caused a reduction in clearance of unbound carboplatin, as previously reported. The rate ofcarboplatin plasma binding was low and not dependent on demographic patient characteristics. The f(U) of plasma carboplatin could be predicted as a function of time, infusion rate and covariates affecting CL(U), weight, UNP and SCr.

Adolescent↗
PubMed2001

Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma.

Genome alterations of seven secondary tumors (five osteosarcomas, one malignant peripheral sheath nerve tumor, one leiomyosarcoma) occurring in the field of irradiation of patients treated for bilateral retinoblastoma have been studied. These patients were predisposed to develop radiation-induced tumors because of the presence of a germ line mutation in the retinoblastoma gene (RB1). Tumor cells were characterized by a high chromosome instability whereas microsatellites and minisatellites were found to be stable. In all tumors, the normal RB1 allele was lost with the corresponding chromosome 13, whereas the germ line mutated allele was retained. The two alleles of TP53 were inactivated, one by deletion of the short arm of chromosome 17, the other by mutation. As compared with non-radiation-induced tumors, the observed panel of TP53 mutations was uncommon with sites not recurrently found otherwise and a high rate of deletions (3/7). In these predisposed patients, the loss of the single normal allele of RB1 is rather due to the radiation-induced chromosome instability than a direct effect of ionizing radiation.

Cytogenetic Analysis↗
PubMed2001

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m(2)). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity.

Adolescent↗
PubMed2001

Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. PATIENTS AND METHODS: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy. RESULTS: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection. CONCLUSION: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Comparison of nonlinear mixed-effect and non-parametric expectation maximisation modelling for Bayesian estimation of carboplatin clearance in children.

OBJECTIVE: The pharmacodynamic-pharmacokinetic relationships for carboplatin involve the area under the curve of ultrafiltrable plasma concentrations versus time (AUC). The objective of the study was to compare two specific population pharmacokinetic methodologies, nonlinear mixed-effect model (NONMEM) and non-parametric expectation maximisation (NPEM), when they are applied to sparse carboplatin pharmacokinetic data in order to obtain an individual value for carboplatin clearance by Bayesian estimation. METHODS: The data from 117 patients (from 1 month to 18 years old) were available. For 20 patients randomly selected, the carboplatin clearance obtained by Bayesian estimation using two plasma ultrafiltrable concentrations was compared with that obtained by individual analysis using all concentrations. RESULTS: Both methodologies were unbiased with mean relative percentage errors (95%CI) of -1.9% ( 7.8; +4.1%) and +6.4% (-2.1; +14.9%) for NONMEM and NPEM, respectively. A comparison of precision between the two methods showed that they were not significantly different (12.5% for NONMEM, and 18.9% for NPEM), but the percentage error ranged between -21% and + 19% for NONMEM, and -35% and + 42% for NPEM. A NONMEM analysis was also performed with all the data available (117 children) in order to update an equation describing the relationship between carboplatin clearance and the patients' covariates. The best relationship corresponded to the equation: clearance (ml/min) = [4.47 x body weight x (1 -0.22 x Np)/(l + 0.0156 x Scr)] +6.4, with body weight in kilograms and where Scr is serum creatinine in micromoles per litre and Np= 1 or 0 for unilateral nephrectomy or not, respectively. CONCLUSION: These methodologies may be useful for dose individualisation and drug monitoring of carboplatin in paediatric patients. Since the mode of administration of carboplatin in paediatric practice in some protocols is daily 1-h i.v. infusion repeated up to five times, dose individualisation may be performed from the clearance observed after the first administration, given an overall target AUC.

Adolescent↗
PubMed2001

Osteosarcoma following retinoblastoma: age at onset and latency period.

In order to assess the role of genetic predisposition in the induction of radiation-induced tumors, we performed statistical analysis on data from the literature and from our own Institute with regard to the age at onset and the latency period of osteosarcoma as the second primary tumor for retinoblastoma with or without subsequent radiotherapy. In retinoblastoma survivors who subsequently developed osteosarcoma, the age at onset of retinoblastoma was young (average of 12 months) in both unilateral and bilateral forms. This suggests that all or almost all of the patients were genetically predisposed by a mutation of one allele of the RB1 gene. For retinoblastoma patients, osteosarcomas occurred 1.2 years earlier inside than outside the radiation field. The latency period between radiotherapy and osteosarcoma onset was 1.3 years shorter inside than outside the radiation field. Interestingly, a bimodal distribution of latency periods was observed for osteosarcomas arising inside, but not outside the radiation field: 40% occurred after a short latency, while the latency of the remaining 60% was comparable to that of osteosarcoma occurring outside the radiation field. This suggests that different mechanisms may be involved in radiocarcinogenesis. A radiation-induced mutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be affected in those occurring after a longer delay.

Adolescent↗
PubMed2001

Brain stem gliomas.

Brainstem gliomas are now regarded as a heterogeneous group of tumors that can be distinguished by age of onset, clinical and radiological presentation and biological behavior. This paper will focus on each subtype of tumor, in children and in adults, and on recent advances in diagnostic criteria and therapeutic options.

Adolescent↗