Peter C. Phillips

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m2/day or 150 mg/m2/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m2/day or 125 mg/m2/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

The genetic landscape of the childhood cancer medulloblastoma

Genomic analysis of a childhood cancer reveals markedly fewer mutations than what is typically seen in adult cancers. Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

TrkC Expression Predicts Good Clinical Outcome in Primitive Neuroectodermal Brain Tumors

PURPOSE To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity. PATIENTS AND METHODS We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis. RESULTS High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P <.00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P <.00005). CONCLUSION High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.

Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults

PURPOSE The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institutions experience with such patients. METHODS AND MATERIALS Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Childrens Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone. RESULTS Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR. CONCLUSION RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.

Comparative Measurements of Hypoxia in Human Brain Tumors Using Needle Electrodes and EF5 Binding

Hypoxia is known to be an important prognostic marker in many human cancers. We report the use of two oxygen measurement techniques in human brain tumors and compare these data with semiquantitative histological end points. Oxygenation was measured using the Eppendorf needle electrode and/or EF5 binding in 28 brain tumors. These data were compared with necrosis, mitosis, and endothelial proliferation. In some tumors, absolute EF5 binding was converted to tissue pO2 based on in vitro calibrations. Eppendorf electrode readings could not be used to identify WHO grade 1/2 versus WHO grade 3/4 tumors, they could not differentiate grade 3 versus grade 4 glial-derived neoplasms, nor did they correlate with necrosis or endothelial proliferation scores. EF5 binding increased as the tumor grade increased and was significantly associated with necrosis and endothelial proliferation. There was no statistically significant correlation between the two hypoxia detection techniques, although both methods indicated similar absolute ranges of tissue pO2. There was substantial inter- and intratumoral heterogeneity of EF5 binding in WHO grade 4 glial neoplasms. The majority of cells in glial-derived tumor had levels of hypoxia that were mild to moderate (defined herein as 10% to 0.5% pO2) rather than severe (defined as approximately 0.1% pO2). Immunohistochemical detection of EF5 binding tracks histological parameters in adult brain tumors, with increased binding associated with increasing necrosis and endothelial proliferation. The proportion of moderately to severely hypoxic cells is relatively low, even in the high-grade tumors. Human brain tumors are dominated by oxic to moderately hypoxic cells.

Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression.

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.

Surveillance scanning of children with medulloblastoma.

BACKGROUND The standard follow-up care for children with medulloblastoma includes regular clinical evaluations and surveillance scanning of the central nervous system with computed tomography or magnetic resonance imaging. The evaluations and scanning assess the response of the tumor to treatment, detect any recurrence of disease, and monitor any complications of treatment. We compared the effectiveness of a periodic history taking and physical examination with that of surveillance scanning in detecting recurrent tumors. METHODS We reviewed the medical records, including 794 scanning reports or scans, of 86 children with posterior fossa medulloblastoma who were followed regularly between 1980 and 1991. Recurrent tumors were classified as symptomatic if neuroimaging studies had been prompted by clinical symptoms or signs and as radiographic if the tumor had been detected by imaging in an asymptomatic patient. RESULTS Twenty-three of the 86 children (27 percent) had a recurrence of tumor. Four recurrences (17 percent) were detected on scanning only, and 19 (83 percent) were associated with symptoms arising a median of four months after the previous scan. The median and range of survival after a recurrence of the tumor were 5 months and < 1 to 38 months, respectively, for a symptomatic recurrence and 20 months and 10 to 32 months, respectively, for a radiographic recurrence (P = 0.03). No patient survived after a recurrence. The longer survival of patients with recurrent tumors detected by scanning most likely reflects the small number of patients and lead-time and length biases associated with screening. CONCLUSIONS Among children with medulloblastoma, surveillance scanning is of little clinical value. Scanning detected a minority of recurrences, and no patient who had a recurrence survived.

Late cognitive and radiographic changes related to radiotherapy Initial prospective findings

BackgroundAssumptions about the damaging effects of radiotherapy (XRT) are based on studies in which total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension) were excluded. MethodsThe effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade, supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6 years were examined. Radiographic findings were examined regionally. ResultsSelective cognitive declines (in visual memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures, and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-related hyperintensities. ConclusionsThere was no evidence of a general cognitive decline or progression of white matter changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors.

Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012

PURPOSE A phase I trial of the antiangiogenesis agent cilengitide (EMD 121974), an alpha v beta 3,5 integrin antagonist, was performed to estimate the maximum-tolerated dose (MTD) and describe dose-limiting toxicities (DLTs) and the incidence and severity of other toxicities when administered to children with refractory brain tumors. PATIENTS AND METHODS Thirty-one assessable patients received intravenous cilengitide over 1 hour twice a week for up to 52 weeks at dosages from 120 to 2,400 mg/m(2). Serial blood and urine samples for clinical pharmacology studies were obtained in a subset of consenting patients. RESULTS No DLTs were observed, and thus, the MTD was not estimated. Three of 13 patients at the dosage level of 2,400 mg/m(2) experienced grade 3 or 4 intratumoral hemorrhage (ITH) possibly related to the study drug; however, two of the ITH events were asymptomatic and, by the current toxicity criteria, would be classified as grade 1. For patients treated at cilengitide 2,400 mg/m(2), the 6-month cumulative incidence estimate of ITH is 23% (SE = 13%). No ITH was observed at 1,800 mg/m(2). Three patients completed 1 year of protocol therapy; one patient with glioblastoma multiforme demonstrated complete response, and two patients had stable disease (SD). An additional patient had SD for more than 5 months. CONCLUSION The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m(2). A phase II trial to assess the efficacy of cilengitide therapy for children with refractory brain tumors is being developed by the Childrens Oncology Group.