2019 Background: To date, the first line chemotherapy treatment in the majority of countries for children with NF-1 and OPG is vincristine + carboplatin. Toxicity of this regimen consists mostly in neuropathy, allergic reactions, and hearing loss. Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory low grade glioma (LGG). The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children, and to assess the toxicity profile. Methods: Patients < 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m2 over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: Overall, the study enrolled 54 patients with LGG. A total of 13 patients (24.1%) had NF-1. Patients with NF-1were younger at diagnosis: median age 3.84 y (range, 1.74-16.36 y) vs. 7 years in non-NF-1. Tumor location in all NF-1 patients was the optic pathway. Treatment was very well tolerated, however, 5 patients (38%) needed dose reductions. Most common toxicity was hematological: only 1 patient who experienced grade 3+ neutropenia (vs. 10 patients non-NF1). There were only 2 episodes of febrile neutropenia, no RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 2 PR, 1 MR, 8 SD, and 2 PD, for a response rate of 23.1%. At a median follow-up of 5.37 years (3.45 – 6.57 years): Only two NF-1patients had progression. Five year progression free survival (PFS) was 85.1± 9.7% (vs. 42±7,9% for all non-NF1, p = 0.01; and 41.7±14% for non-NF1 with OPG, p = 0.01). None of the NF1 patients received radiation (0 vs. 6 patients non-NF1). No patients died of progression (0 vs. 3 patients non-NF1). Conclusions: Weekly vinblastine is well tolerated and can be used in NF-1 children with OPG as first line chemotherapy with good results. The toxicity profile is lower than with other chemotherapies, offering a better quality of life to these patients. Clinical trial information: NCT00575796.
Low-grade gliomas represent the most frequent primary brain tumors in children, and are also an important category of brain neoplasms in young adults. They are characterized by slow growth, but often associated with increased morbidity, as well as mortality in the subset that develop histologic progression. Pathologically they correspond to WHO grade I or II and include pilocytic astrocytoma (PA), pilomyxoid astrocytoma variant, angiocentric glioma, diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, and pleomorphic xanthoastrocytoma (PXA). Although all low-grade glioma subtypes may develop in children and adults, and be histologically indistinguishable in these two populations, there are important clinical and molecular differences. As a rule, low-grade gliomas in adults have a greater tendency for histologic progression and more aggressive clinical behavior than those in children. With respect to genetic alterations, activating BRAF alterations and increased MAPK pathway signaling are near universal features of the circumscribed low-grade glioma group (e.g., PA and PXA). Whole exome/genome sequencing efforts and high resolution copy number platforms have also provided important biologic insights in these tumors, with adult low-grade diffuse gliomas containing frequent ATRX, TP53 mutations (astrocytomas), as well as 1p19q co-deletions, CIC, FUBP1 and TERT promoter mutations (oligodendrogliomas). Conversely, alterations in FGFR1, MYB, and MYBL1 are frequent events in pediatric low-grade diffuse gliomas. In this review we summarize our current knowledge of the diagnostic and molecular pathology of these tumors, and explore possible avenues for targeted therapeutics.
Purpose Vinblastine monotherapy has shown promising activity and a low-toxicity profile in patients with pediatric low-grade glioma (PLGG) who experienced treatment failure after initial treatment with chemotherapy and/or radiation. The aim of this study was to assess the activity of vinblastine in therapy-naïve children. Patients and Methods Patients < 18 years old with unresectable and/or progressive therapy-naïve PLGG were eligible. Vinblastine was administered once per week at a dose of 6 mg/m 2 intravenously over a period of 70 weeks. Vision, quality of life, neurofibromatosis type 1 (NF1) status, and BRAF mutation/fusion status were also determined and correlated with outcome. Results Fifty-four patients were enrolled onto the study, with a median age of 8 years (range, 0.7 to 17.2 years). Most patients had chiasmatic/hypothalamic tumors (55.5%), and 13 patients (24.1%) had NF1. The most common histology was pilocytic astrocytoma (46.3%). Seventeen patients were diagnosed using radiologic criteria alone. Best response to chemotherapy was centrally reviewed with a response rate (complete, partial, or minor response) of 25.9%. Disease stabilization (complete, partial, or minor response or stable disease) was achieved in 47 patients (87.0%). Visual improvement was observed in 20% of patients with optic pathway glioma. Five-year overall survival and progression-free survival (PFS) rates were 94.4% (95% CI, 88.5% to 100%) and 53.2% (95% CI, 41.3% to 68.5%), respectively, for the entire cohort. Patients with NF1 had a significantly better PFS (85.1%; 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0%; 95% CI, 29.1% to 60.7%; P = .012). Age< 3 years or > 10 years was not associated with poor outcome. Treatment was well tolerated, and quality of life was not affected during treatment. In this trial, there was no correlation between BRAF alterations and outcome. Conclusion Vinblastine administered once per week is well tolerated in children with treatment naïve PLGG. Overall survival and PFS are comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.
10029 Background: Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory LGG. The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children. Methods: Patients < 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m 2 over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: 54 patients (23 female) were enrolled between 2007 and 2010. Median age at inclusion was 7 years, 13 patients were < 3 years. 32 had chiasmatic/hypothalamic tumours, 6 had evidence of dissemination. 13 had neurofibromatosis type 1. Histology was pilocytic astrocytoma (25), pilomyxoid astrocytoma (4), low grade astrocytoma variant (8); 17 patients had no histological diagnosis. Treatment was well tolerated; however, only 14 patients received full dose for the duration of the study. Most common toxicity was haematological: 40 patients who experienced grade 3+ neutropenia. There were only 6 episodes of febrile neutropenia, 3 RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 1 CR, 10 PR, 3 MR, 28 SD, 12 PD, for a response rate of 24.5%. With a median follow-up of 2 years (9-48 months), progression-free survival at 2 years was 72.1% (95%CI: 58.1-82.2). One patient died of progression. Conclusions: Weekly vinblastine is well tolerated in paediatric LGG patients. Although the response rate appears inferior to other common LGG regimens, progression free survival at 2 years favourably compares to most currently used regimens. Supported by a grant from the Ontario Institute Cancer Research. Clinical trial information: 1000011227.
Objective: To describe the use of temozolomide (TMZ) in Canadian children treated for brain tumours and to evaluate survival and predictors of survival for children treated with this agent. Methods: A survey was conducted within the Canadian Paediatric Brain Tumour Consortium (CPBTC), a group of tertiary care centres in pediatric neurooncology (n = 16) in Canada that are involved in the treatment of children with central nervous system tumours. Results: In 10 of the 16 participating pediatric oncology centres of the CPBTC, 137 children with brain tumours were treated with TMZ between January 2000 and March 2006. Although 33% of the children were enrolled into a clinical trial, 67% were treated outside open studies. Most patients (72%) received TMZ treatment on recurrence of their brain tumour (first or subsequent). The most commonly administered regimen was single-agent TMZ 150–200 mg/ m2 administered on 5 consecutive days every 28 days. The median duration of TMZ treatment was 141 days (range: 4–1102 days). Response data were provided for 127 of the 137 patients, of whom 6 showed a complete response. Sixteen patients experienced a minor or partial response, 53 had stable disease, and 52 had progressive disease. Of 32 patients alive at last follow-up, 19 had a diagnosis of low-grade glioma.
Primary objective was to describe the proportion of children newly diagnosed with cancer enrolled on a therapeutic clinical trial. Secondary objectives were to describe reasons for non-enrollment and factors associated with enrollment on trials.In this retrospective cohort study, we included children newly diagnosed with cancer between 0 and 14 years of age and diagnosed from 2001 to 2012. We used data from the Cancer in Young People in Canada (CYP-C) national pediatric cancer population-based database. CYP-C captures all cases of pediatric cancer (0-14 years) diagnosed and treated at one of the 17 tertiary pediatric oncology centers in Canada. Non-enrollment was evaluated using univariate and multiple logistic regression analysis.There were 9204 children with cancer included, of whom 2533 (27.5%) were enrolled on a clinical trial. The most common reasons cited for non-enrollment were lack of an available trial (52.2%) and physician choice (11.2%). In multiple regression, Asian and Arab/west Asian race were associated with lower enrollment (P = 0.006 and P = 0.032 respectively). All cancer diagnoses were more likely to be enrolled compared to astrocytoma and children with acute lymphoblastic leukemia had an almost 18-fold increased odds of enrollment compared to astrocytoma (P < 0.0001). Greater distance from the tertiary care center was independently associated with non-enrollment (P < 0.0001).In Canada, 27.5% of children with cancer are enrolled onto therapeutic clinical trials and lack of an available trial is the most common reason contributing to non-enrollment. Future research should better understand reasons for lack of trial availability and physician preferences to not offer trials.
<i>Background:</i> Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive malignant brain tumor that, since it was first identified, has been treated with aggressive treatment regimens, e.g. high-dose chemotherapy with stem cell rescue and early radiotherapy. We reviewed our experience because of concerns with respect to treatment-related toxicity in our patients. <i>Methods:</i> Seven patients with a median age at presentation of 18 months were diagnosed with AT/RT between 1996 and 2006. Tumor location was supratentorial in 2 patients, in the posterior fossa in 4 and spinal in 1. Gross total resection was performed in 1 patient, subtotal resection in 5 and biopsy only in 1. Adjuvant treatment consisted of chemotherapy and radiotherapy in 5 patients. <i>Results:</i> Median progression-free survival was 4 months, and median overall survival was 7 months. Two children are alive at 44 and 102 months. Significant surgical and chemotherapy-related morbidity was seen. Biopsy-proven multifocal necrotizing leukoencephalopathy (MNL) was seen in one patient who is alive 44 months after diagnosis. Another patient who was thought to have recurrent tumor in the brainstem 9 months after diagnosis had imaging findings compatible with MNL. <i>Conclusion:</i> Although improving results are reported for AT/RT using intensive treatment regimens, treatment-related morbidity is considerable in this young patient population.
9053 Background: Carboplatin based regimens are widely used in the treatment of unresectable pediatric LGG. Carboplatin hypersensitivity reaction (CHSR) represents a main limiting factor. Objective: To analyse the incidence, characteristics, management and impact on outcome of CHSR. Methods: National retrospective review of children diagnosed with LGG between 1988 and 2004. Inclusion criteria were age <18 years, pathology proven diagnosis of LGG except in NF1 patients, and no chemotherapy or radiotherapy prior to carboplatin chemotherapy. Results: 105 patients (61F/44M) from 10 Canadian centers were included in the study. Median age at diagnosis was 3.5y (0.3–16.8). 33 patients had NF1, 75 had diencephalic tumor. Carboplatin was given monthly or weekly respectively in 46 and 59 patients. 44 (41.9%) patients developed carboplatin HSR at a median time of 6.5 months (0.4–15.4), after a median number of 10.5 (3–39) injections. CHSR occurred significantly earlier with the weekly schedule (p=0.016). Cumulative incidence of CHSR increased with the number of injections with no plateau. Female had significant higher risk to develop CHSR (p=0.02) whereas age, NF1 status and schedule of administration were not significant risk factors. First allergic reaction was rated grade I, II in 36 patients (82%). 34 patients were reexposed to carboplatin with desensitization/premedication, allowing 14 patients (41.2%) to complete their treatment. But the majority (58.8%) had recurrent allergic reaction with a significant worsening of their symptoms (p=0.039). The median number of additional Carboplatin injections delivered was 4 (0.5–34). After Carboplatin discontinuation, 18 patients were switched to another chemotherapy regimen. 5 years PFS was not significantly different in allergic and non allergic patients (53.9% and 45.6%). Conclusions: In our experience, the incidence of CHSR is high (41.9%). Female have higher risk of CHSR. Desensitization/premedication has limited efficacy and does not prevent worsening of CHSR. CHSR did not impact the PFS. However many patients did switch to another chemotherapy regimen and the total duration of treatment was comparable in both groups. No significant financial relationships to disclose.
Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
