[Proton beam therapy in pediatric radiotherapy]. / La protonthérapie en radiothérapie pédiatrique.

Pediatric tumors still represent a formidable challenge despite the considerable therapeutical advances that have been reported for the past 30 years. This is largely related with the untowards side-effects of local therapy that are still acknowledged as the "price for cure". In this setting, Proton therapy a sophisticated radiotherapeutical modality seems to represent a real breakthrough due to its unique ability to spare close and distant normal organs compared with modern photons techniques. We summarize in this paper current clinical and dosimetrical evidences including an update of the Orsay series on 108 children.

[Childhood cerebral tumors: morbidity and follow-up into adulthood]. / Tumeurs cérébrales de l'enfant: morbidité et suivi à l'âge adulte.

This chapter presents guidelines for the follow-up of children with brain tumors, whether benign or malignant, in their transition to adulthood. The consequences of their disease and its treatment overlap greatly. The complications and long-term follow-up are detailed based on the specialists involved.

[A multidisciplinary consultation for children with brain tumors]. / Une consultation multidisciplinaire pour les enfants traités pour une tumeur cérébrale.

UNLABELLED: School achievement of children with brain tumors is hampered by progressive neurologic and cognitive sequelae. To help the children and their family, we have created in 1997 a multidisciplinary consultation together with Necker's hospital. MATERIAL AND METHODS: The study describes the organization of the consultation and analyses the files of 69 children seen between September 2001 and June 2002. RESULTS AND CONCLUSION: The authors conclude that this consultation is an irreplaceable mean to coordinate the complex rehabilitation process of a child treated for a brain tumor.

Outcome of children treated with preradiation chemotherapy for a high-grade glioma: results of a French Society of Pediatric Oncology (SFOP) Pilot Study.

BACKGROUND: To evaluate the efficacy of BCNU, cisplatin, and vincristine (BCV regimen) in a prospective nonrandomized study among newly diagnosed children with high-grade glioma. PROCEDURE: Following surgery, patients received a combination of BCNU + cisplatin + VP16 (BCV), over 3 consecutive days. Patients with residual tumor continued this regimen unless no further improvement was observed on MRI, for a maximum of six courses. Patients who underwent complete surgical resection received six courses of adjuvant BCV. RESULTS: Seventy-three patients were enrolled. Out of 66 eligible patients with central pathology review, the diagnosis of high-grade glioma was confirmed in 53 cases. The response rate was 20%. With a median follow-up of 128 months, 5- and 10-year event free survival rates are 16 +/- 9 and 13.3 +/- 9.4%. In univariate analysis, two prognostic factors were statistically significant: extent of resection and tumor location, while macroscopic total resection was the only significant prognostic factor in the multivariate analysis. The response to BCV did not translate into improved event free survival. Interstitial pneumonitis occurred in seven patients, leading to six deaths. CONCLUSION: This BCV regimen could not be recommended in the treatment of high-grade gliomas in children, according to its lack of efficacy and its unacceptable pulmonary toxicity.

Treatment of high risk medulloblastomas in children above the age of 3 years: a SFOP study.

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.

High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol.

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.

Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study.

BACKGROUND: The current Phase II study was conducted to evaluate the survival and toxicity observed in children with newly diagnosed brainstem gliomas who were treated with the daily radiotherapy with topotecan used as a radiosensitizer. METHODS: Eligible patients were those ages 3-18 years with previously untreated tumors arising in the pons diagnosed within the previous 6 months. Histologic confirmation was not mandatory provided that the clinical and magnetic resonance imaging findings were typical for a diffusely infiltrating brainstem lesion. Treatment was comprised of a 6-week course of topotecan administered intravenously at a dose of 0.4 mg/m(2)/day over 30 minutes within 1 hour before irradiation. Radiotherapy was comprised of a once-daily treatment of 1.8 grays (Gy) per fraction to a total dose of 54 Gy. RESULTS: Thirty-two patients were included in the current study between August 2000 and October 2002. All patients completed the combined treatment in accordance with the treatment design. Only partial responses were observed, occurring in 40% of the patients. The 9-month and 12-month survival rates were 34.4% +/- 8% and 25.5% +/- 8%, respectively. The median duration of survival for these 32 patients was 8.3 months. An intratumoral cystic/necrotic change was observed in five patients, with clinical impairment noted in two patients. One intratumoral hemorrhage occurred during radiotherapy, and was associated with transitory neurologic impairment. CONCLUSIONS: The findings of the current study regarding newly diagnosed brainstem glioma patients treated with topotecan given as a radiosensitizing agent did not reproduce the encouraging results obtained in preclinical studies. Therefore, the concomitant combination of topotecan and radiotherapy at this schedule and these doses cannot be recommended for the treatment of patients with brainstem gliomas.

High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy.

We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.

Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study.

OBJECTIVE: The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. PATIENTS AND METHODS: Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin (500 and 800 mg/m(2) per course, respectively) were administered after surgery. Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. RESULTS: Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. CONCLUSION: Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.

Temozolomide in paediatric high-grade glioma: a key for combination therapy?

This report describes a single-centre study with temozolomide (TMZ) (200 mg m(-2) day(-1) x 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery+/-radiotherapy+/-chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3-20.5 years). In total, eight patients had >8 cycles (range 3-30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after >4 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks-34+ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy.

Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases.

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.

Neuropsychological outcome in children with optic pathway tumours when first-line treatment is chemotherapy.

Standard treatment of optic pathways gliomas consists of radiotherapy and surgery when feasible. Owing to the toxicity of irradiation, chemotherapy has emerged as an interesting therapeutic option, especially in young children. This study describes the neuropsychological profile of 27 children (aged between 1.5 and 15.7 years) with optic pathways gliomas treated with chemotherapy as first-line treatment. Eight of them also received radiotherapy as salvage treatment. Eight had neurofibromatosis type 1 (NF1). Intellectual outcome was preserved in children treated with chemotherapy only (mean=107+/-17) compared to children also receiving radiotherapy (mean IQ=88+/-24) or children having NF1 and treated with chemotherapy (mean IQ=80+/-13). Scores for abstract reasoning, mental arithmetic, chessboard/coding, perception, judgement of line orientation were lower in children irradiated than in those treated only by chemotherapy. Children with Nf1 showed subnormal IQ scores with marked impairment of short- and long-term memory. With respect to long-term neuropsychological outcome, our study shows that a chemotherapy-first strategy can preserve the intellectual outcome of these patients either by avoiding the need of radiotherapy or by delaying its use as much as possible.

In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa).

A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m(-2). In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201+/-607 h ng ml(-1)) than those who did not (5024+/-978 h ng ml(-1)) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.

Genetic alterations in primary osteosarcoma from 54 children and adolescents by targeted allelotyping.

At present, the only recognised prognostic factor for primary osteosarcoma is the histological response to preoperative chemotherapy. Our study was designed to identify new diagnostic markers that could eventually have a prognostic value. A total of 54 patients under 20 years of age with primary osteosarcomas were studied while under treatment by the French Society of Paediatric Oncology OS 94 protocol. Paired normal and biopsy samples were collected. In addition, surgical resection specimens, following preoperative chemotherapy, were obtained in 13 cases. After genomic DNA extraction, an allelotyping analysis targeting microsatellites linked to Rb and p53 genes, and 9p21, 7q31 and 5q21 regions was performed. In all, 94% of the samples at diagnosis showed allelic imbalance and the biopsies were highly rearranged except for the microsatellite targeting 7q31. The same panel was highly informative at surgical resection. Microsatellites investigating Rb, p53 and the 9p21 region were particularly altered without a significant correlation with prognosis. On the other hand, the alteration of the 7q31 locus at diagnosis was significantly correlated with a worse prognosis and a new frequently altered locus, 5q21, was described. In conclusion, this panel allowed us to characterise paediatric osteosarcomas. Correlation of prognosis with the altered 7q31 region could be a useful tool and further studies are required to confirm the importance of 5q21.

[Post-radiotherapy hyperthyroidism: a rare complication of cancer treatment in the child]. / Hyperthyroïdie post-radique: une complication rare du traitement des cancers de l'enfant.

UNLABELLED: Abnormalities of thyroid function, specially hypothyroidism, are common complications of head and neck irradiation for childhood cancer. Hyperthyroidism is rare and can be misdiagnosed. We report two observations of this condition. OBSERVATIONS: The first patient received conventional craniospinal irradiation for a localized medulloblastoma. Three years later, he presented with profuse sweating, irritability and paroxysmal tachycardia. Biologic evaluation revealed a peripheral hyperthyroidism. The patient was treated with antithyroidian hormonal treatment. The second patient received an irradiation for an undifferentiated nasopharyngeal carcinoma. Three years later, she developed a progressive thyrotoxicosis which was attributed to hyperthyroidism after six months of evolution. Hormonal treatment improved the clinical state after several weeks. CONCLUSION: Hyperthyroidism is a rare complication of head and neck irradiation. This condition justifies a periodic and prolonged evaluation of thyroid function.

[Optic pathway gliomas in neurofibromatosis type I. Longitudinal study of 30 cases in two multidisciplinary practices]. / Les gliomes des voies optiques dans la neurofibromatose de type 1. Etude longitudinale de 30 cas suivis dans deux consultations multidisciplinaires.

UNLABELLED: The aim of this study was to analyse the outcome of optic pathway gliomas in 30 children with neurofibromatosis type 1, the indications of treatment, and the follow-up and screening protocol. PATIENTS AND METHODS: All patients with a minimal two years follow-up (median six years, range two to 19 years), in two multidisciplinary consultations of Saint-Vincent-de-Paul (Paris) and Purpan (Toulouse) hospitals, were included in the study. In our series, we practiced systematic screening MRI in children under six years' of age or with neuropsychological deficiency that may imply an unreliable ophthalmological examination. RESULTS: Thirty-seven percent (11 patients) had progressive ophthalmological signs and were treated, and 63% (19 patients) were not progressive. Our study confirmed that most of optic pathway gliomas were stable during evolution, but rare cases may have bad prognosis. CONCLUSION: Our study supported the importance of close ophthalmological follow-up during childhood for which screening methods are discussed. There is a consensus to limit treatment for patients with progressive ophthalmological symptoms.

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.