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Aim: Improvement of EFS of children older than 3 years with high risk medulloblastoma., Methods: Between 1993 and 1999, 115 patients (3-18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy ('8in1' and etoposide/carboplatin) before and after craniospinal radiotherapy., Results: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9-119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3., Conclusion: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected 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.

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.

This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m2/day from day 1 to day 5 for the 6 first patients and 350 mg/m2/day from day 1 to day 5 for the other patients), etoposide (350 mg/m2/day from day 1 to day 5) and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.

The aim of this phase II study was to determine the efficacy of high-dose ifosfamide with moderate dose etoposide in childhood osteosarcoma. From January 1992 to January 1995, 27 children (15 male, 12 female) with relapsed or refractory evaluable osteosarcoma were included in a phase II study of two courses of ifosfamide 3g/m2/day and etoposide 75 mg/m2/day for 4 days. Median age was 14 years (7-19 years). All but one had received high-dose methotrexate and doxorubicin as first-line treatment. 22 patients had previously received ifosfamide. This regimen was given as first-line in 1 patient, second-line in 23 and third-line in 3. Evaluable disease was lung metastases in 21 patients, local relapse in 5 and adenopathy in 1. There were six complete responses, seven partial responses, three minor responses, six stable disease and five progressive disease (including one mixed response). Response rate was 48% (95% confidence interval, 29-67%). Duration of response was not available (10 responding patients had other treatments). Response rate was equivalent in the subgroup of 22 patients who had previously received ifosfamide (4 CR, 6 PR). Among 3 patients who received the phase II regimen as third-line chemotherapy, there was 1 PR. All but 4 patients had a well tolerated grade 4 neutropenia. Transient mild confusion or seizures were each observed once. 5 patients are alive 15-31 months after the beginning of chemotherapy. This combination of drugs at this dosage has tolerable toxicity, is efficient and deserves evaluation in phase III studies.

A retrospective analysis was performed to determine the outcome of children with metastatic medulloblastoma given a standardised treatment programme. Of 68 consecutive patients treated in the French M7 protocol for medulloblastoma, 23 presented with metastatic disease. They were uniformly treated with surgery, and the same protocol of chemotherapy and craniospinal radiotherapy. The 7-year relapse-free survival rate is 43% for metastatic patients compared to 68% for patients with localised disease. Survival did not correlate with age, sex, location of metastases, extent of initial surgery and the dose of radiation therapy on the posterior fossa. Survival did correlate with the dose to the cranial field with a threshold dose of 30 Gy. Patients with metastatic disease have a worse prognosis and require more aggressive therapies at initial presentation. The prognostic impact of the different sites of metastatic disease requires further evaluation in cooperative studies.

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.