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Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.

Background: A medical staff and an administrative staff of our paediatric oncology department have contracted a pulmonary tuberculosis. This is a rare situation and the management of this infection threat in a paediatric oncology department is not clearly defined. Recommendations tell we must treat all patients. Nevertheless, antituberculosis agent expose to increased toxic effects and immunocompromised patients have an increased risk of experiencing progression of latent mycobacterium tuberculosis infection to active tuberculosis disease., Objective: This study aims at the evaluation of a screening and a treatment strategy adapted for a paediatric oncology department., Method: From April 2004 to April 2005, 80 children with a solid tumour were screened for tuberculosis according to a screening and treatment protocol established by a multidisciplinary committee. Two risk groups were defined according to age and immunodepression status. The "high risk" group is composed of less than 2 years old children and children who underwent an haematological peripheral stem cell transplantation. All other children were included in the "low risk" group. The screening was based on clinical, biological and radiological data performed three times spaced out by 2 or 3 months. At the end of each part of screening, the multidisciplinary committee analyzed the results and discussed the utility of an antituberculosis treatment., Results: 80 children (31 boys and 49 girl) with a median age of 7,3 years (0,3-24) participated to the screening. Sixty children were still undergoing anticancer treatments. Twenty belonged to the high risk group. The complete screening was performed in 32% of the patients. Three antituberculosis' treatment were initiated: 2 for prophylaxis purpose and 1 for a tuberculosis prime-infection. A child had an additional check-up because of an abnormal chest X-ray. Our management strategy allowed us to treat significantly less patients when compared to national guidelines (3 vs 80 test Chi-2 p<0.001). No side effects of antituberculosis agents were noted. No tuberculosis has been observed in our population 28 months after the completion of the treatment., Conclusion: The proposed screening allowed us to treat a minimum of children and thus, to reduce the potential toxicity induced by antituberculosis' treatments.

Introduction: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability., Purpose: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated., Method: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years)., Results: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

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.

Our objective was to adapt and validate the Health Utilities Index Mark 2 (HUI 2) and HUI 3 health status classification systems self-report questionnaire in a population of children with cancer, a group of 42 children already included in a multi-centre database designed by the Group on Brain Tumors in Children of the French Society for Pediatric Oncology. Children were recruited during a routine consultation. Most of them had completed treatment. The version of the questionnaire for French adults was adapted linguistically for children. Open-ended queries by children about the comprehensiveness of the questions and very low non-response rates showed a good acceptability of the questionnaire. The main psychometric properties of the HUI 2 and HUI 3 classification systems were assessed in 3 groups of raters (child, parent, physician): construct validity was tested against the rating of the child's health state on a Likert scale and through comparison with clinical data, and internal consistency was determined through multi-trait analysis. Weighted and unweighted kappa values were used to measure the inter-rater agreement between the child's, parent's and physician's assessment of the child's health state. The convergent validity was satisfactory, with better results when the physician's assessment was used. The most affected attributes were the expected ones (i.e., cognition, pain and emotion). Disagreement was observed between the 3 raters, more often in the same direction: taking the child's assessment as the reference, the parents tended to under-estimate the health status while physicians tended to over-estimate it., (Copyright 1999 Wiley-Liss, Inc.)

Background: Adequate treatment of pain in children with cancer is a critical issue, and is of equal importance as discussions concerning chemotherapy, surgery and radiotherapy., Objective: To evaluate the treatment of refractory pain by peridural analgesia., Methods: Seven children (1-15 years) with solid tumors were treated with long term epidural analgesia for refractory pain. Catheters were inserted in epidural space (L1-L2) and infused with sufentanil, bupivacaine and clonidine., Results: Three out of five children with good response to peridural therapy could be discharged. A 12-month-old infant had a poor response. Treatment was discontinued in a teenager boy because of patient refusal. The side effects were: early catheter displacement in two patients and a bacterial contamination in one. Serious adverse effects related to high doses of opiates were not observed. However, toxicity of bupivacaine was observed in three patients leading to treatment discontinuation in one., Conclusion: Long-term epidural analgesia looks promising in selected children with refractory pain.

Since about 15 years intensive chemotherapy followed by autologous bone marrow transplantation has been used on the basis of "dose-response" principle to treat certain children with tumours of sombre prognosis. At present, the main indications for this method are metastatif neuroblastoma in less than one-year old children, non-Hodgkin's malignant lymphomas in partial remission or relapse, refractory or recurrent Hodgkin's disease and some peculiar forms of Wilms' tumour. In other tumours, such as rhabdomyosarcoma, Ewing's sarcoma or brain tumours, the indications have not yet been clearly determined. The treatment must be administered as part of multicentre French or European trials conducted in specialized centres. The practice and application of autologous bone marrow transplantation are being revolutionized by the availability of haematopoietic growth factors and the development of the peripheral blood stem cells reinjection technique. Genic therapy will soon have major repercussions in this field.

A prospective registration of incident cancers in childhood in two south-east regions of France since 1 January 1984 allows us to collect pertinent data on 875 cases throughout a period of 8 years. World age-standardised overall incidence rate is 137.63 cases/million/year. It is close to that reported in other white European. North American and Oceanian populations. The age-adjusted (age-standardised) relative frequency of each pathological group is: leukaemias 29.71%; central nervous system tumours 20.61%; lymphomas 12.75%; sympathetic tumours 9.03%; soft tissues tumours 7.37%; bone tumours 5.89%; kidney tumours 4.82%; epithelial tumours 3.83%; germinal and gonadal tumours 3.24%; retinoblastomas 2.11%; liver tumours 0.45% and others 0.14%. The comparison of these results with international available data shows that we record the world highest adjusted incidence rates for neuroblastomas (15.46) and rhabdomyosarcomas (7.04) and a high rate for Ewing's sarcomas (3.30); this fact will need to be confirmed by a longer period of observation, but even now the total number of cases (particularly for neuroblastoma) is high when compared with the data of other children registries which give rates for longer periods and for similar or larger populations.