Jaeckle, Kurt A.

Abstract OBJECTIVE AND IMPORTANCE: Magnetic resonance imaging (MRI) is the imaging modality of choice for brain tumors and other lesions of the central nervous system. However, this procedure is contraindicated in patients with orbital metallic foreign bodies. In such cases, the usual clinical strategy is to manage the patient without the benefit of MRI scans and, instead, to rely on less sensitive imaging modalities in particular computed tomographic scanning. CLINICAL PRESENTATION: Two patients, one with a posterior fossa mass and one with suspected central nervous system lymphoma, were seen at our institution. MRI scanning was recommended, but had been precluded in both patients by the presence of metal fragments in the orbit. INTERVENTION: In each case, the orbital foreign body was successfully localized and removed. Postprocedure computed tomographic scanning confirmed complete removal. MRI scanning was then performed without difficulty. The first patient underwent posterior fossa craniotomy and removal of the tumor, which proved to be a medulloblastoma. The second patient was found to have evidence of lymphoma in the cranial base and meninges and was treated with radiotherapy and systemic and intrathecal chemotherapy. MRI scanning provided superior diagnostic information and spared both patients the risks and discomfort of myelography and exposure to ionizing radiation from multiple computerized tomographic scans. CONCLUSION: Two patients with central nervous system tumors underwent removal of a metal fragment in the orbit for the specific purpose of facilitating MRI scans. This is a practical, straightforward concept, which should be considered when MRI scanning is needed for optimal patient management.

Oligodendroglioma frequently (≥ 70%) responds to radiation and chemotherapy, and is the first CNS neoplasm in which a genetic signature (1p and 19q deletion) has been associated with outcome within the context of large clinical trials. Current translational investigations focus on deletions or mutations of potential tumor suppressor genes, epigenetic alterations, amplification or mutation of growth factor and regulatory genes, and characterization of signaling events and regulatory protein expression. The most compelling data has involved 1p and 19q loss, which is observed in over 50% of anaplastic oligodendrogliomas. In two randomized phase III trials (Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951), the addition of neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV; respectively) to radiotherapy did not produce superior survival as compared with radiotherapy alone. A modest increase in progression-free survival was observed with the addition of PCV, but at the cost of increased toxicity. Combined 1p and 19q loss identified a favorable prognostic group in both studies, which appeared to be independent of treatment arms. However, it is unclear whether these deletions represent surrogate markers of a favorable biologic tumor behavior, or are predictive of outcome after specific treatment. Currently, there is insufficient data to allow therapeutic decisions to be made solely on the basis of 1p and 19q gene deletion status. Future phase III trials are evaluating other chemotherapeutic and targeted agents, including temozolomide, and include correlative investigations of aberrant molecular events in these neoplasms, which may lead to future therapeutic strategies that are based on specific molecular signatures.

Background Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme–inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/− decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus–treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.