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.

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

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

A 20-year-old male with a prior history of germinoma presented 8 years after the initial diagnosis with progressive lower back pain. The preoperative diagnosis was schwannoma based on the appearances of a tumor in the lumbosacral region on MRI; however, histologically, a germinoma "drop" metastasis was seen. This report emphasizes the need for long-term follow-up in patients with germinoma. In addition, this patient is unusual in that the preoperative assessment favored schwannoma.

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

Prognosis of diffuse intrinsic pontine gliomas (DIPGs) remains poor. Failure has been predominantly local, with leptomeningeal dissemination (LD) occurring in 4-33% of patients in pre-MRI era series. Routine craniospinal imaging after initial treatment may reveal other relapse patterns relapse. Sixteen consecutive pediatric patients with DIPG treated between 2006 and 2009 were retrospectively reviewed. Treatment regimens, recurrence patterns, survival, and pathologic diagnosis were recorded. Fourteen patients received involved-field radiotherapy to 54 Gy, and two patients received craniospinal irradiation for LD at presentation. Neuraxis MRI was performed at diagnosis and at 4 month intervals following radiotherapy. Fifteen patients have had progression of disease (median progression-free survival 5.0 +/- 1.2 months), and 13 patients have died (median survival 9.0 +/- 1.4 months). Local failure occurred in 12 patients (75%). LD occurred in nine patients (56%). LD was present at diagnosis in three patients, after initial staging and treatment in six patients, and during autopsy in two patients. Median overall survival was 12.0 +/- 3.3 months without LD and 8.0 +/- 2.1 months with LD (P = 0.059, log rank test). Median progression-free survival was 9.5 +/- 3.9 months without LD and 3.0 +/- 2.1 months with LD (P = 0.012, log rank test). The high incidence of LD probably reflects liberal use of spine MRI surveillance. All patients should undergo routine craniospinal imaging at diagnosis and follow-up. Central nervous system prophylaxis should be considered in future clinical trials

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.

INTRODUCTION: ACNS 0122 aimed to improve event-free survival (EFS) and OS (overall survival) for intracranial NGGCT, by increasing response rate (complete [CR] and partial [PR]) with neoadjuvant carboplatin/VP-16, alternating with ifosfamide/VP-16, followed by craniospinal irradiation (CSI) plus involved field boost. In patients not obtaining CR/PR by neuro-imaging and tumor marker response after neoadjuvant chemotherapy, second-look surgery was recommended. Patients with persistent radiographic disease or positive markers underwent myeloablative chemotherapy (thiotepa/VP-16) prior to CSI. OBJECTIVES: 1) To determine response rate following three cycles of neoadjuvant chemotherapy; 2) to determine EFS and OS; and 3) To determine whether additional CR can be achieved with high-dose thiotepa/VP-16 for patients not achieving CR/PR. RESULTS: 104 patients enrolled from 1/04-7/08. Median age was 12 (range 3-23) years. 76% were male,. No toxic deaths occurred. Among 84 evaluable patients, response rate was reported as 70% (33 CR, 26 PR). With central imaging review (58/84 patients reviewed to date) response rate was 90%. Nineteen patients underwent second-look surgery, 2 secondary to progression; reviewed pathology in 11 was malignant teratoma or mature teratoma (8), fibrosis (1), and NGGCT (2). Median follow-up for patients without events is 1.9 years (range 0.06-4.9). Fifteen patients have experienced recurrence or progression to date with 6 subsequent deaths. Two-year EFS and OS are 84.4%+/-4% and 93% +/-3%, respectively. Further stratification of responses will be presented. CONCLUSION: Neoadjuvant chemotherapy for NGGCT demonstrates a very high response rate and when administered before CSI may increase survival