Opocher, Enrico
Children with Neurofibromatosis type 1 and Optic Pathway Glioma: a collaborative research to design innovative clinical trials based on functional outcomes [Tesi di dottorato]

Neurofibromatosis type 1 associated optic pathway gliomas (OPG) are relatively frequent (10-15%) among childhood low-grade glioma (LGG), the most common pediatric brain tumor neoplasm. Overall therapeutic strategy includes the use of first line chemotherapy for progressive tumor and has shown to be well tolerated and effective to control tumor growth, considering a 5 yrs-PFS of 74.5%, in the prospective SIOP-LGG NF1+ 2004 study data. However, preliminary data regarding visual outcome reveal how, despite good tumor control rate, the functional outcome of many children with NF1 OPG is still unsatisfactory. In fact from the SIOP prospective series, about 45% of children treated with chemotherapy had a bilaterally compromised visual acuity at last follow-up, with some degree of visual improvement in a minority of children. These data pinpoint the importance of considering vision rather than radiology as a primary outcome measure in these patients. Prognostic factors analysis showed that surgery is a risk factor for worse PFS. These data failed to demonstrate significant differences by age, gender, tumor site, indication to treatment. A retrospective study was undertaken during the French period at the Institut Gustave Roussy to identify possible radiology factors that may predict response to chemotherapy. Results have shown that OPG involving the optic radiation (PLAN 4) and multi-site tumors have a worse response to chemotherapy. The prognostic impact of these factors needs to be confirmed in a larger and prospective population. A multidisciplinary workshop was held in Europe, with the aim to analyse case by case, clinical presentation and radiological tumor aspects. From this clinical ground we tried to analyse factors influencing the risk of progression and the possible benefit of chemotherapy. We discussed and proposed factors determining treatment indication according to a risk-based strategy. This strategy includes an observation arm for children at low risk, a randomization between observation and treatment in children at uncertain or intermediate risk and a further, multiple treatments randomized arm for children at high risk. This innovative multi-arms multi-stage (MAMS) study design will speed up the results of randomised trials by “picking the winner” between multiple arms by interim analysis and will reduce number of patient required to answer scientific questions for such rare diseases. A US-lead NF1 OPG natural history study with the aim to develop evidence based criteria for treatment indication, to which European Centres will collaborate, will prospectively generate additional information that could implement and modify this risk based proposed strategy within the next years. The collaborative guideline for visual assessment and visual outcome interpretation in OPG clinical trials is presented. Visual outcome, based on a standardized visual assessment, will be the primary outcome of new trials evaluating treatment efficacy, in children with NF1 OPG. These aspects are of paramount relevance for a successful interpretation and comparison of data from the upcoming international studies.

In relazione con http://paduaresearch.cab.unipd.it/7907/
MED/38 - Pediatria generale e specialistica

Tesi di dottorato. | Lingua: | Paese: | BID: TD16055124