[Show abstract][Hide abstract] ABSTRACT: Background:
Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children.
1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment.
to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013).
Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma.
Data collection and analysis:
Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results.
The search identified seven RCTs, including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The meta-analysis of EFS/DFS not including disease progression during therapy as an event in the definition showed a difference in favour of treatment including chemotherapy (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54 to 0.91; P value = 0.007; 2 studies; 465 children). However, not including disease progression as an event might not be optimal and the finding was not confirmed in the meta-analysis of EFS/DFS including disease progression during therapy as an event in the definition (HR 1.02; 95% CI 0.70 to 1.47; P value = 0.93; 2 studies; 300 children). Two individual studies using unclear or other definitions of EFS/DFS also showed no clear evidence of difference between treatment arms (one study with unclear definition of DFS: HR 1.67; 95% CI 0.59 to 4.71; P value = 0.34; 48 children; one study with other definition of EFS: HR 0.84; 95% CI 0.58 to 1.21; P value = 0.34; 233 children). In addition, it should be noted that in one of the studies not including disease progression as an event, the difference in DFS only reached statistical significance while the study was running, but due to late relapses in the chemotherapy arm, this significance was no longer evident with longer follow-up. There was no clear evidence of difference in OS between treatment arms (HR 1.06; 95% CI 0.67 to 1.67; P value = 0.80; 4 studies; 332 children). Out of eight reported adverse effects, of which seven were reported in one study, two (severe infections and fever/neutropenia) showed a difference in favour of treatment not including chemotherapy (severe infections: risk ratio (RR) 5.64; 95% CI 1.28 to 24.91; P value = 0.02; fever/neutropenia: RR not calculable; Fisher's exact P value = 0.01). There was no clear evidence of a difference between treatment arms for other adverse effects (acute alopecia: RR 1.00; 95% CI 0.92 to 1.08; P value = 1.00; reduction in intelligence quotient: RR 0.78; 95% CI 0.46 to 1.30; P value = 0.34; secondary malignancies: Fisher's exact P value = 0.5; haematological toxicity: RR 0.54; 95% CI 0.20 to 1.45; P value = 0.22; hepatotoxicity: Fisher's exact P value = 1.00; treatment-related mortality: RR 2.37; 95% CI 0.43 to 12.98; P value = 0.32; 3 studies). Quality of life was not evaluated. In individual studies, the results in subgroups (i.e. younger/older children and high-risk/non-high-risk children) were not univocal.The search found one RCT comparing standard-dose RT with reduced-dose RT plus chemotherapy. There was no clear evidence of a difference in EFS/DFS between groups (HR 1.54; 95% CI 0.81 to 2.94; P value = 0.19; 76 children). The RCT did not evaluate other outcomes and subgroups.The presence of bias could not be ruled out in any of the studies.
Based on the evidence identified in this systematic review, a benefit of chemotherapy cannot be excluded, but at this moment we are unable to draw a definitive conclusion regarding treatment with or without chemotherapy. Treatment results must be viewed in the context of the complete therapy (e.g. the effect of surgery and craniospinal RT), and the different chemotherapy protocols used. This systematic review only allowed a conclusion on the concept of treatment, not on the best strategy regarding specific chemotherapeutic agents and radiation dose. Several factors complicated the interpretation of results including the long time span between studies with important changes in treatment in the meantime. 'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The fact that no significant differences between treatment arms were identified could, besides the earlier mentioned reasons, also be the result of low power or too short a follow-up period. Even though RCTs are the highest level of evidence, it should be recognised that data from non-randomised studies are available, for example on the use of chemotherapy only in very young children with promising results for children without metastatic disease. We found only one RCT addressing standard-dose RT without chemotherapy versus reduced-dose RT with chemotherapy, so no definitive conclusions can be made. More high-quality research is needed.
[Show abstract][Hide abstract] ABSTRACT: Purpose
To compare quality of survival in “standard-risk” medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial.
Methods and Materials
Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded.
Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011).
Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.
International journal of radiation oncology, biology, physics 02/2014; 88(2):292–300. DOI:10.1016/j.ijrobp.2013.09.046 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medulloblastoma is curable in approximately 70 % of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Numerous cytotoxic drugs used to treat childhood cancers, as well as pelvic or hypothalamo- pituitary irradiation and gonadal surgery, can affect subsequent hormonal function and fertility. Prevention of these adverse consequences is based primarily on therapeutic de-escalation when possible, and now also on gonad or gamete preservation. These patients and their parents must receive thorough information, taking into account the child's age, the proposed treatments, and the length of follow-up. Teams treating childhood cancers must receive appropriate training, and access to innovative fertility-preserving techniques must be guaranteed at the national level.
Bulletin de l'Académie nationale de médecine 04/2013; 197(4-5):865-76; discussion 876. · 0.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).
Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials.
Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population.
These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.
European journal of cancer (Oxford, England: 1990) 03/2013; 49(10). DOI:10.1016/j.ejca.2013.02.028 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinoblastoma (RB) is a rare embryonic tumour that represents 1/16,000 births in France. In Mali, a study showed the characteristics of a hospital series of cases seen in Bamako in the Pediatric Oncology Unit of Gabriel Touré Teaching Hospital and in the Tropical Ophthalmology Institute of Africa (IOTA) between January 2005 and June 2007. Median age was 4 years versus 2 years in France for unilateral disease. Near two third of children with RB had extra-ocular extension at diagnosis, which is now exceptional in France. Only 11% were bilateral versus 35% in France. Cure rate was around 50%, but it is estimated only on the cases arriving in Bamako and with at least 20% lost of follow-up. Cure rate is over 95% in France within an exhaustive register. RB appears as an exemplary tumor and rapid improvements could be obtained in low-income countries with relatively limited means. This is why, the Alliance mondiale contre le cancer (AMCC), the Institut Curie in Paris, which is the reference center in France for RB, and teams in Bamako were proposing a program to help the development of early diagnosis, treatments, including eye preservation, and rehabilitation of children with RB in sub-Saharan Africa in collaboration with the Groupe franco-africain d'oncologie pédiatrique (GFAOP). The official launching of this program was held in Bamako November 4(th), 2011 for Mali and the surrounding regions. After this first experience, this program is now implemented in other countries.
Bulletin du cancer 02/2013; 100(2). DOI:10.1684/bdc.2013.1703 · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinoblastoma (Rb) results from inactivation of both alleles of the RB1 gene located in 13q14.2. Whole-germline monoallelic deletions of the RB1 gene (6% of RB1 mutational spectrum) sometimes cause a variable degree of psychomotor delay and several dysmorphic abnormalities. Breakpoints in 12 Rb patients with or without psychomotor delay were mapped to specifically define the role of chromosomal regions adjacent to RB1 in psychomotor delay. A high-resolution CGH array focusing on RB1 and its flanking region was designed to precisely map the deletion. Comparative analysis detected a 4-Mb critical interval, including a candidate gene protocadherin 8 (PCDH8). PCDH8 is thought to function in signalling pathways and cell adhesion in a central nervous system-specific manner, making loss of PCDH8 one of the probable causes of psychomotor delay in RB1-deleted patients. Consequently, we propose to systematically use high-resolution CGH in cases of partial or complete RB1 deletion encompassing the telomeric flanking region to characterize the putative loss of PCDH8 and to better define genotype/phenotype correlations, eventually leading to optimized genetic counselling and psychomotor follow-up.European Journal of Human Genetics advance online publication, 22 August 2012; doi:10.1038/ejhg.2012.186.
European journal of human genetics: EJHG 08/2012; 21(4). DOI:10.1038/ejhg.2012.186 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy.
Patients and methods:
In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine.
After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up.
In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.
[Show abstract][Hide abstract] ABSTRACT: Retinoblastoma (RB) is the most frequent eye tumour in children, with an incidence of 1 in 15-20,000 births. It accounts for 11% of all cancers in the first year of life. Except for the hereditary forms, its causes are not well-known. Studies have recently suggested an increased risk of RB among children born after IVF, but the relevant literature is sparse. We assessed the association between infertility treatment, subfertility and RB.
We included all children living in France diagnosed with RB between 1 January 2000 and 31 December 2006 at the Institut Curie, the national reference centre for RB diagnosis and treatment. We used multiple logistic regression to compare them with a national sample of births in France in 1998 and 2003 (n = 28 170).
The study included 244 non-familial RB cases. The risk of RB increased with maternal age [adjusted odds ratio (adj OR) = 2.07, 95% confidence interval (CI) 1.33-3.22 at 35-39 years compared with younger than 25 years and adj OR = 2.42, 95% CI 1.22-4.81 at 40 years or older], but the associations with IVF (adj OR = 1.37, 95% CI 0.64-2.95) and ovarian stimulation or intrauterine insemination (adj OR = 1.35, 95% CI 0.77-2.38) were not statistically significant after adjustment for maternal age and tobacco use. Among women who had no infertility treatment, the risk of RB was significantly increased when time to pregnancy exceeded 24 months (adj OR = 2.02, 95% CI 1.17-3.48) compared with time to pregnancy ≤ 24 months.
Our study did not observe a significantly increased risk of RB associated with infertility treatment, in particular with IVF. But we did find an increased risk for women for whom time to pregnancy exceeded 24 months.
Human Reproduction 05/2012; 27(7):2186-92. DOI:10.1093/humrep/des149 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design.
The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials.
R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target.
These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed.
[Show abstract][Hide abstract] ABSTRACT: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae.
This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome.
The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup.
We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.
PLoS ONE 04/2012; 7(4):e33415. DOI:10.1371/journal.pone.0033415 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality-of-life (QoL).
This retrospective study analysed QoL, mood disorders, everyday executive functioning and disease's impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SD = 4.1); mean follow-up period 6 years 2 months (SD = 4.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi-structured interview and standardized scales evaluating self-report of QoL (Kidscreen 52) and depression (MDI-C) and proxy-reports of QoL (Kidscreen 52), executive functioning (BRIEF) and disease's impact (Hoare and Russel Questionnaire).
Twenty-three families answered the questionnaires completely. Overall QoL self-report was within the normal range. QoL proxy-report was lower than self-report. Eleven patients reported depression; 24-38% had dysexecutive symptoms. A majority of families felt 'very concerned' by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction.
Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented.
[Show abstract][Hide abstract] ABSTRACT: Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-012-0958-8) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.
[Show abstract][Hide abstract] ABSTRACT: Diffuse brainstem glioma is the most common subtype of brainstem tumor and remains a devastating malignancy, particularly in children. Recent advances in radiological diagnostic techniques may improve the classification of these heterogeneous tumors and contribute to differential diagnosis. However, biopsy remains indicated in many contrast-enhancing brainstem masses in adults because of the great variety of differential diagnoses. New magnetic resonance imaging techniques can also help neurosurgeons in removing resectable brainstem tumors. Conventional radiotherapy is the standard of care. Classical chemotherapy drugs have been disappointing to date, suggesting that a better understanding of the biology of this tumor may be the key to more targeted therapy. Improvement in the pattern of care of brainstem gliomas is strongly needed.
Handbook of Clinical Neurology 01/2012; 105:585-605. DOI:10.1016/B978-0-444-53502-3.00010-0