BackgroundPediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.MethodsThe primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.DiscussionTrametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.Trial registrationClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.
Response criteria for pediatric high-grade glioma (pHGG) has varied both historically and across different cooperative groups. The Response Assessment in Neuro-Oncology (RANO) working group has developed response criteria for adult HGG and was not created for the unique challenges in pHGG. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was established to develop response assessment criteria for pHGG. Current practice and literature were reviewed to identify major issues. In areas where scientific investigation was lacking, consensus was reached through an iterative process. Recommendations from RAPNO for response assessment include the use of magnetic resonance imaging (MRI) of both the brain and spine, assessing clinical status, and the use of corticosteroids or anti-angiogenic agents. Imaging standards for brain and spine are defined. Compared to the adult RANO, there is a higher reliance on T2/FLAIR imaging and inclusion of diffusion-weighted imaging. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.
Little is known about the impact of cancer on family relationships from the perspective of the pediatric cancer patient and their sibling(s). This study assessed and compared children's experiences of family relationships in patients receiving active cancer therapy, those who have completed therapy, and siblings. A cross‐sectional study of children with cancer and their siblings aged 8–17 years old was conducted. Children completed the PROMIS Pediatric Family Relationships short form and the Depressive Symptoms, Anxiety, and Peer Relationships short forms. The Mann–Whitney test assessed differences in Family Relationships scores between therapy groups, while the Wilcoxon signed‐rank test assessed differences between patients and siblings. An actor–partner interdependence model (APIM) was used to assess how patient and sibling variables were associated with their own and each others’ family relationships. Two hundred and sixty‐five children completed the assessments. Siblings of patients on‐therapy had worse family relationships than patients on‐therapy (P = 0.015). Family relationships of patients off‐therapy did not differ from their siblings or the patients on‐therapy. Family relationships scores did not differ between the sibling cohorts. The APIM found patient family relationships were impaired when their own peer relationships decreased and when either their own or their siblings had increased depressive symptoms. Sibling family relationships were impaired when their own depression increased, and when the patient counterpart was female, younger age, had less depressive symptoms, more anxiety or a diagnosis of leukemia/lymphoma (compared to solid tumor). Based on these findings, increased psychosocial resources for patients and siblings of children undergoing cancer therapy may be warranted.
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