Faculty Bibliography

OBJECTIVE: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-alpha-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). METHODS: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. RESULTS: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 mug/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 mug/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 mug/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 mug/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. CONCLUSIONS: The RP2D of PI for pediatric patients with PN is 1 mug/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. Classification of evidence: This study provides Class III evidence that pegylated interferon-alpha-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.

BACKGROUND: The prognosis for recurrent or refractory brain tumors in children is poor with conventional therapies. Topotecan is a topoisomerase I inhibitor with good central nervous system (CNS) penetration following oral administration. Increased efficacy of topotecan has been demonstrated with prolonged low-dose daily treatment in pre-clinical models. To investigate further this drug delivered orally in pediatric CNS malignancies, a phase II study in children with recurrent or refractory brain tumors was performed. PROCEDURE: Patients </= 21 years of age at diagnosis with a recurrent, progressive, or refractory primary CNS malignancy and measurable disease, were eligible. Patients enrolled into four strata: ependymoma (N = 4), high-grade glioma (HGG) (N = 6), brainstem glioma (BSG) (N = 13), and primitive neuroectodermal tumor (PNET) (N = 8). Oral topotecan was administered once daily at a dose of 0.8 mg/m(2)/day for 21 consecutive days repeated every 28 days. Response and toxicity profiles were evaluated. RESULTS: Twenty-six patients were evaluable (median age 9.2 years; 10 males). Two objective responses were observed in PNET patients with disseminated tumor at study entry. These two patients remain alive and in remission 7 and 9.5 years off study. Four other patients (two BSG, one PNET, and one HGG) had stable disease (median 4.6 months). The most common toxicities were hematologic. CONCLUSIONS: Daily oral topotecan at a dose of 0.8 mg/m(2)/day can be safely administered to children with recurrent or refractory brain tumors. This regimen identified activity in recurrent PNET. The prolonged progression free survival (PFS) in two PNET patients justifies consideration of this regimen in more advanced clinical trials

Purpose: Tumors employ multiple pro-angiogenic mechanisms to promote new blood vessel formation needed for growth. We conducted a prospective, open-label, multi-institutional phase II study to evaluate the efficacy and tolerability of a multi-agent ("five-drug") oral antiangiogenic regimen in children and adolescents with treatment-refractory cancer. Method: Patients up to 21 years of age with recurrent or progressive cancer were eligible. Treatment duration was 27 weeks, and included continuous oral administration of fenofibrate, thalidomide, and celecoxib, with alternating 21-day courses of oral etoposide and oral cyclophosphamide. Results: A total of 101 patients were enrolled; 98 began therapy and were evaluable for toxicity. Median age was 10.5 years; 49% were female. Patients were enrolled according to disease strata: Leukemia/lymphoma (4), bone tumors (12), neuroblastoma (3), high-grade glioma (20), low-grade glioma (13), ependymoma (19), medulloblastoma/CNS PNET (9), and miscellaneous (18). Overall, therapy was well-tolerated in this heavily pre-treated population. Best overall response was complete response (CR) in 1, partial response in 11, stable disease (SD) in 37, progressive disease (PD) in 48, and non-evaluable in 1. Twentyfour patients completed all 27 weeks of planned therapy. Reasons for stopping early included PD (66, including 3 who died while still on study), treatment toxicity (2), and patient/family preference (6). Overall survival and progression free survival (PFS) were 63% [90% confidence interval (CI): 55-71%] and 32% [90% CI: 24-40%] at 27 weeks. Best overall response of SD or better was seen in 57% [90% CI: 46-67%] of CNS tumors and 35% [90% CI: 20-51%] of non-CNS tumors. Sustained responses (PFS >2 years) were seen in 11 patients, including 4 with ependymoma, 3 with low-grade glioma, and one each with neurocytoma, anaplastic ganglioneurocytoma, lymphangioma, and meningioma. Conclusion: This five-drug oral antiangiogenic regimen showed clinical efficacy in a subset of children with treatment-refractory tumors

Purpose: To conduct a retrospective analysis of our collective experience over a seven year period of 35 patients with CNS GCT either referred directly or consulted upon for management, assessed from first recurrence. Method: Eleven germinoma patients and 24 mixed malignant GCT (MMGCT)patients were accrued. Of the 11 germinoma patients, seven received chemotherapy initially followed by irradiation, two received irradiation only and two received chemotherapy only. Following recurrence, two germinoma patients received re-induction chemotherapy followed by irradiation, and nine received re-induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR) with subsequent irradiation in five. Of the 23 MMGCT patients, 21 received chemotherapy initially followed by irradiation, one received chemotherapy only (including HDCx+AuHCR) and another received irradiation only. Following recurrence, 22 of 23 MMGCT underwent attempts at remission re-induction with one or more chemotherapy regimens, with or without additional irradiation; one underwent total resection of tumor followed by irradiation only. Results: All 11 recurrent germinoma patients achieved minimal residual disease (MRD) with the first re-induction regimen. Ten of 11 (91%) survive without further recurrence at a mean of 3.5 years following diagnosis of recurrence. Nineteen of 23 MMGCT patients (83%) achieved MRD status; of these, three received further irradiation only, while 16 underwent HDCx+AuHCR either preceded or followed by irradiation in 12. Fourteen of 23 (61%) recurrent MMGCT patients survive without disease at a mean of 4.0 years following diagnosis of first recurrence. Conclusion: In this, the largest cohort of recurrent CNS GCT patients yet reported, most patients undergoing chemotherapy-containing treatment (especially germinoma patients) can be successfully salvaged, provided they achieve MRD status with re-induction chemotherapy. The benefit of consolidation with HDCx+AuHCR seems clear for MMGCT patients, and may obviate the need for further irradiation for germinoma patients, thereby avoiding the late sequelae of CNS re-irradiation

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m(2). Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald's criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference

Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway

We discuss a posterior fossa tumor in a 15-month-old girl who presented with photophobia, epiphora, and torticollis. Early diagnosis and long-term follow-up were possible in this patient. Although the tumor was not treated, her symptoms improved by 6 years of age

Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.