Sean Grimm

Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation Reduced-Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma: Final Results and Long-Term Outcome

PURPOSE A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma. PATIENTS AND METHODS Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor. RESULTS Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33). CONCLUSION R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

A phase 2 trial of single‐agent bevacizumab given in an every‐3‐week schedule for patients with recurrent high‐grade gliomas

The authors evaluated a 3‐week schedule of bevacizumab in patients with recurrent high‐grade glioma (HGG).

Glioblastoma: a method for predicting response to antiangiogenic chemotherapy by using MR perfusion imaging--pilot study.

PURPOSE To derive a magnetic resonance (MR)-based imaging metric that reflects local perfusion changes resulting from the administration of angiogenic-inhibiting chemotherapy in patients with recurrent glioblastoma multiforme (GBM). MATERIALS AND METHODS In this retrospective Institutional Review Board-approved HIPAA-compliant study, 16 patients (12 men, four women; mean age, 51.8 years + or - 15.1 [standard deviation]) with recurrent GBM received bevacizumab every 3 weeks (15 mg per kilogram of body weight) as part of a clinical trial. Baseline MR images were acquired, and follow-up images were acquired every 6 weeks thereafter until tumor progression or death. Imaging included perfusion and T1-weighted contrast material-enhanced MR imaging. Perfusion images were analyzed both with and without correction for contrast material leakage. The volumes of interest were selected as enhancing voxels on T1-weighted contrast-enhanced MR images. Relative cerebral blood volume (rCBV) maps were created from analysis of MR perfusion images. The volumes of interest were used to calculate the following parameters: size, mean rCBV, mean leakage coefficient K(2), and hyperperfusion volume (HPV), which is the fraction of the tumor with an rCBV higher than a predetermined threshold. Percent change in each parameter from baseline to first follow-up was compared with time to progression (TTP) by using a Cox proportional hazards model with calculation of hazard ratios. RESULTS The most significant hazard ratio was seen with a DeltaHPV cutoff of rCBV greater than 1.00 (hazard ratio, 1.077; 95% confidence interval: 1.026, 1.130; P = .002). The only significant ratios greater than one were those that resulted from perfusion calculated as mean rCBV and DeltaHPV. The ratios were also higher after correction for leakage. CONCLUSION This pilot study derived an imaging metric (HPV) that reflects local perfusion changes in GBMs. This metric was found to show a significantly improved correlation to TTP as compared with more commonly used metrics.

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma.

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma

BACKGROUND Panobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS Patients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study. RESULTS At interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and median overall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%), median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27 months). CONCLUSIONS This phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort.

Hodgkin's Lymphoma: A Review of Neurologic Complications

Hodgkins lymphoma is a hematolymphoid neoplasm, primarily of B cell lineage, that has unique histologic, immunophenotypic, and clinical features. Neurologic complications of Hodgkins Lymphoma can be separated into those that result directly from the disease, indirectly from the disease, or from its treatment. Direct neurologic dysfunction from Hodgkins Lymphoma results from metastatic intracranial spinal disease, epidural metastases causing spinal cord/cauda equina compression, leptomeningeal metastases, or intradural intramedullary spinal cord metastases. Indirect neurologic dysfunction may be caused by paraneoplastic disorders (such as paraneoplastic cerebellar degeneration or limbic encephalitis) and primary angiitis of the central nervous system. Hodgkins lymphoma treatment typically includes chemotherapy or radiotherapy with potential treatment-related complications affecting the nervous system. Neurologic complications resulting from mantle-field radiotherapy include the “dropped head syndrome,” acute brachial plexopathy, and transient ischemic attacks/cerebral infarcts. Chemotherapy for Hodgkins lymphoma may cause cerebral infarction (due to emboli from anthracycline-induced cardiomyopathy) and peripheral neuropathy.

Metastatic glioblastoma: case presentations and a review of the literature

Extracranial metastases from glioblastoma (GBM) are uncommon with an estimated incidence of less than 2%. We report two cases of metastatic GBM seen within an 8-week period followed by a literature review. We attempted to identify common factors or a causative mechanism. Factors that predominated among the reviewed cases included male gender, tumor location, and younger age. Causative mechanisms were not apparent. While metastatic disease remains rare, it might be occurring with increasing frequency. This trend might be due to increased diagnosis, better imaging, a more extensive physician workup, or an increase in survival. Metastatic GBM can present and progress quite rapidly, and repeat evaluations of persistent or worsening complaints among GBM patients are warranted. Early diagnosis of metastatic disease spread can help to expedite alleviation of patients’ discomfort, in an already aggressive disease process.

Adult primary spinal cord tumors

Primary spinal cord tumors represent 2–4% of all neoplasms of the CNS. Primary spinal cord tumors are anatomically separable into two broad categories: intradural intramedullary and intradural extramedullary. Intramedullary tumors are comprised predominantly of gliomas (infiltrative astrocytomas and ependymomas). Resective surgery can usually be accomplished with spinal ependymomas owing to separation of tumor from spinal cord and, when complete, require no further therapy. By contrast, spinal cord gliomas infiltrate the myelon and, consequently, surgery is nearly always incomplete. Involved-field radiotherapy is most often administered after partial resection. Intradural extramedullary tumors are either peripheral nerve sheath tumors (neurofibromas or schwanommas) or meningiomas. In either instance, complete resection may be accomplished and is often curative. Radiotherapy is reserved for rare malignant variants and for patients in whom surgery is contraindicated. Chemotherapy is administered for recurrent primary spinal cord tumors without other options, that is, reoperation or re-irradiation. Problematic, however, is the lack of clinical trials in general for these CNS tumors and for spinal cord tumors in particular. Consequently, treatment is similar to that for intracranial tumors with a similar histology. Early recognition of the signs and symptoms of primary spinal cord tumors allows for early treatment, potentially minimizes neurologic morbidity and improves outcome. Primary treatment is surgery in essentially all spinal cord tumors, and predictors of outcome include preoperative functional status, histological grade of tumor and extent of surgical resection.

Economics of Malignant Gliomas: A Critical Review

PURPOSE Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. METHODS A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the studys publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. RESULTS Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from

Primary CNS lymphoma with bilateral symmetric hypothalamic lesions presenting with panhypopituitarism and diabetes insipidus

50,600 to