Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma.

BACKGROUND: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. METHODS: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease. RESULTS: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. CONCLUSIONS: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control.

Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report.

OBJECTIVE: To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement. METHODS: A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma. RESULTS: Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months. CONCLUSION: This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.

Bacterial and fungal meningitis in patients with cancer.

OBJECTIVE: To analyze cases of bacterial and fungal meningitis in patients with cancer. METHODS: Retrospective chart review from 1993 to 2004 was performed of patients with cancer at our institution who had positive CSF bacterial or fungal culture. RESULTS: We identified 312 positive CSF cultures representing 175 unique presentations. Ninety-six cultures were deemed contaminants, leaving 79 cultures for analysis in 77 patients; 78% had prior neurosurgery. Organisms included 68% gram-positive cocci, 10% gram-positive bacilli, 14% gram-negative bacilli, 7% Cryptococcus, and 1% C. albicans. None had N. meningitidis or H. influenza. Two patients each had S. pneumoniae or L. monocytogenes. Five percent of presentations demonstrated the triad of fever, nuchal rigidity, and mental status changes. Seventy-five percent of presentations demonstrated CSF pleocytosis (> or = 10). Median CSF WBC count was 74 cells/mm(3). CSF protein was elevated and glucose was depressed in 71%. In neutropenic patients (n = 6), 4 had 0 to 1 CSF WBC/mm(3), and 2 had normal CSF. VP shunt infections were more likely to present with mental status changes. Thirty day mortality was 13%. CONCLUSIONS: Patients with cancer do not manifest symptoms of meningitis as often as patients without cancer and display a very different set of CSF organisms compared to a general population. The CSF inflammatory response is muted in patients with cancer with meningitis. Most patients with cancer with meningitis have had prior neurosurgery. Additionally, the organisms causing meningitis in the cancer population have shifted over time, with a decline in the organisms which typically infect immunocompromised hosts and an increase in gram-positive infections.

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines.

BACKGROUND: Treatment-related neurotoxicity has been recognized as a significant problem in patients with primary central nervous system lymphoma (PCNSL) as effective treatment has increased survival rates. There is, however, a paucity of research on cognitive functions in this population. DESIGN: In a review of the literature, a total of 17 articles that described cognitive outcome in adult PCNSL patients were identified. RESULTS: The studies that assessed cognitive functions after whole-brain radiotherapy combined with chemotherapy reported cognitive impairment in most patients. Patients treated with chemotherapy alone had either stable or improved cognitive performance in most studies. Methodological problems, however, limited the ability to ascertain the specific contribution of disease and various treatment interventions to cognitive outcome. On the basis of the literature review, a battery of cognitive and quality-of-life (QoL) measures to be used in prospective clinical trials was proposed. The battery is composed of five standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (attention, executive functions, memory, psychomotor speed), and QoL questionnaires, and meets criteria for use in collaborative trials. CONCLUSION: The incorporation of formal and systematic cognitive evaluations in PCNSL studies will improve our understanding of treatment-related neurotoxicity in this population.

Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial.

Temozolomide (TMZ) has shown modest efficacy in the treatment of recurrent brain metastasis (BM). We designed a new regimen utilizing dose-intensified, protracted course of TMZ in combination with vinorelbine, a lipophilic large-spectrum agent, in an attempt to improve the efficacy of TMZ. This phase I study was conducted to establish the maximum tolerated dose (MTD) of vinorelbine for this combination. Patients with recurrent or progressive BM were eligible. Chemotherapy consisted of 28-day cycles with TMZ (150 mg/m2, days 1-7 and 15-21) and vinorelbine (days one and eight at escalating doses). The starting dose was 15 mg/m2, with increments of 5 mg/m2 for each cohort of 3-6 patients, until MTD was reached (30 mg/m2). A total of 21 patients were enrolled; the median age was 59 (41-77). The primary tumor was lung cancer in 13 patients (NSCLC in 10, SCLC in 3), breast in 6, renal in 1 and endometrial in 1. Vinorelbine dose was 15 mg/m2 in seven patients, 20 mg/m2 in five, 25 mg/m2 in four and 30 mg/m2 in six. Grades 3 and 4 neutropenia developed in six patients, lymphopenia in nine, and thrombocytopenia in six; other toxicities were rare. No dose-limiting toxicity was seen. Out of 18 evaluable patients 2 had a radiographic response (one partial and one minor). Disease was stable in 6 of 18 patients and the median survival was 27 weeks. This regimen was well tolerated and a phase II trial using a dose of 30 mg/m2 of vinorelbine is warranted.

Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma.

BACKGROUND: Magnetic resonance spectroscopy imaging (MRSI) non-invasively evaluates the metabolic profile of normal and abnormal brain tissue. Primary central nervous system lymphoma (PCNSL) is a highly aggressive tumor responsive to high-dose methotrexate based regimens. Patients often have complete responses but relapses are common. We characterized the MR spectra of PCNSL patients, correlated MRSI with MRI and evaluated whether early recurrence could be detected by MRSI. METHODS: Patients with PCNSL had multi-voxel MRSI before, during, and after treatment. The region of interest was defined using axial FLAIR images. Metabolites assessed were N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), lipid, and lactate. Ratios of Cho/Cr, NAA/Cho, and NAA/Cr were calculated and correlated with MRI. Overall survival (OS), progression free survival (PFS), and relative risks of each of the ratios were determined. RESULTS: MRSI was performed on 11 men and seven women; median age of 59. Sixty-seven MRSI studies were performed, 17 baseline and 48 follow-up studies. Median ratios in 16 pretreated patients were Cho/Cr-1.90, NAA/Cho-0.39, and NAA/Cr-1.27. Two patients had lipid at baseline, five had lactate and two had both. MRSI correlated with tumor response or progression on MRI; in three patients MRSI suggested disease progression prior to changes on MRI. Univariate analysis of metabolite ratios, lipid, and lactate revealed that none significantly affected PFS or OS. Kaplan-Meier analysis of the presence or absence of lipid, lactate or both revealed a trend for increased PFS. CONCLUSION: MRSI and MRI correlate with tumor response or progression and may allow early detection of disease recurrence. The presence or absence of lipid and/or lactate may have prognostic significance. Further research using MRSI needs to be done to validate our findings and determine the role of MRSI in PCNSL.

Cognitive functions in survivors of primary central nervous system lymphoma.

BACKGROUND: The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based (MTX) chemotherapy and whole brain radiotherapy (WBRT). This combined regimen prolongs patient survival, but also carries a substantial risk for delayed neurotoxicity particularly in the elderly. However, cognitive outcome evaluations have not been included in most clinical trials. OBJECTIVE: To assess cognitive functioning and quality of life in PCNSL survivors treated either with WBRT +/- MTX-based chemotherapy or chemotherapy alone. METHODS: Twenty-eight PCNSL patients in disease remission received a post-treatment baseline neuropsychological evaluation, and a subset of patients were available for an 8-month follow-up evaluation. Assessment of quality of life and extent of white matter disease on MRI were also performed. RESULTS: Patients displayed mild to moderate impairments across several cognitive domains. These were of sufficient severity to reduce quality of life in half of the patient sample. Comparisons according to treatment type revealed more pronounced cognitive impairment, particularly in the memory and attention/executive domains, among patients treated with WBRT +/- chemotherapy. Extent of white matter disease correlated with attention/executive, memory, and language impairment. CONCLUSIONS: PCNSL survivors treated with WBRT +/- chemotherapy displayed more pronounced cognitive dysfunction than patients treated with MTX-based chemotherapy alone.

A phase II trial of temozolomide for patients with recurrent or progressive brain metastases.

BACKGROUND: Treatment options for patients with recurrent brain metastases are extremely limited. This study was designed to determine the safety and efficacy of temozolomide in the treatment of recurrent or progressive brain metastases. PATIENTS AND METHODS: Forty-one patients (11 men, 30 women) with a median KPS of 80 were treated with temozolomide 150 mg/m2/day (200 mg/m3/day if no prior chemotherapy) for 5 days; treatment cycles were repeated every 28 days. Primary tumor types included 22 non-small cell lung, 10 breast, three melanoma, two small cell lung, two rectal, one ovarian and one endometrial cancer. RESULTS: There were five episodes of grade 3 thrombocytopenia and one grade 4 leukopenia. Significant non-hematologic toxicity possibly related to temozolomide included pneumonitis [21, constipation [1], and elevated liver enzymes [21. Thirty-four patients were assessed for radiographic response; two had a partial response, 15 stable disease and 17 progressed. Both objective responses were seen in patients with non-small cell lung cancer. Overall median survival was 6.6 months. CONCLUSIONS: Single agent temozolomide achieved disease control (PR or SD) in 41% of patients with recurrent brain metastases from a variety of primary malignancies with minimal toxicity. Therefore, temozolomide may be a reasonable treatment option for some patients with recurrent brain metastases.

Temozolomide for treating brain metastases.

The metastasis of solid tumors to the brain is associated with a poor prognosis despite aggressive treatment. Available treatment options are limited, as many chemotherapeutic agents do not penetrate the blood-brain barrier. Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) is a novel chemotherapeutic agent with a good safety profile that crosses the blood-brain barrier and has shown activity against many human solid tumors. In two phase II trials of temozolomide in heavily pretreated patients with various solid tumor brain metastases, temozolomide was safe and generally well tolerated and showed clinical activity, with three partial responses and 19 disease stabilizations. Results of a third randomized phase II trial of concurrent administration of temozolomide and radiation therapy followed by adjuvant temozolomide therapy compared with radiation alone showed a higher rate of complete and partial responses (objective response of 96% v 67%) and significantly more complete responses (38% v 33%, P =.017), primarily in patients with newly diagnosed brain and lung metastases.

Treatment for primary CNS lymphoma: the next step.

PURPOSE: The use of preradiotherapy (RT) methotrexate (MTX) has improved disease control and survival in patients with primary CNS lymphoma (PCNSL). The reported protocol was designed to optimize and enhance the chemotherapeutic component of treatment. PATIENTS AND METHODS: Fifty-two patients were treated with five cycles of high-dose MTX 3.5 g/m(2), procarbazine 100 mg/m(2)/d, and vincristine 1.4 mg/m(2). Thirty patients received whole-brain RT (45 Gy). Twenty-two older patients deferred RT to diminish the risk of delayed neurotoxicity; these patients are compared with 12 older patients who completed the entire treatment regimen. Most patients (n = 35) received high-dose cytarabine after RT. RESULTS: Objective response rate to the induction chemotherapy regimen was 90%; overall median survival is 60 months. Grade 3 or 4 myelosuppression was seen in 30 patients, primarily in association with cytarabine; grade 3 nephrotoxicity due to MTX was seen in two patients. Older patients had similar median survival with or without the addition of RT: 32 versus 33 months, respectively. However, late neurotoxicity was significantly more common in those older patients who received RT (P: =.00004). Patients younger than 60 years who received the complete treatment regimen have not reached median disease-free or overall survival. CONCLUSION: Increasing the dose of MTX and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. Younger patients in particular fared extremely well with this treatment regimen. In older patients, deferring whole-brain RT did not compromise overall survival but did reduce treatment-related toxicity.

Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus.

PURPOSE: To identify serologic markers in children with paraneoplastic opsoclonus-myoclonus (POM). MATERIALS AND METHODS: We examined the sera of 64 children with neuroblastoma (16 with POM and 48 age-matched and stage-matched controls) by immunohistochemistry of rat brain and human cerebellum, and by Western blot analysis of protein extracts from human Purkinje cells, cortical neurons, neuroblastoma cell lines, and HuD. RESULTS: Using immunohistochemistry, IgG reactivity against neurons was identified in 13 of 16 POM sera (81%), and 12 of 48 non-POM sera (25%; P<0.001). IgM antineural antibodies were present in 3 of 16 POM sera (19%) and 11 of 48 (23%) non-POM sera. Except for anti-Hu antibodies detected in 10 sera (4 with POM), no other specific reactivities were identified by Western blot analysis of neuronal or of neuroblastoma protein extracts. CONCLUSIONS: We conclude that: 1) patients with neuroblastoma and POM are more likely to harbor antineuronal antibodies than patients without POM; 2) no specific serologic marker of POM was identified, but the frequent presence of antineuronal antibodies suggests that POM is immune-mediated; and 3) anti-Hu antibodies are present in some sera from patients with neuroblastoma, irrespective of the presence of POM.

Simplified production of a recombinant human angiostatin derivative that suppresses intracerebral glial tumor growth.

Angiostatin is an endogenous inhibitor of tumor neovascularization that inhibits the proliferation of endothelial cells. Production of sufficient quantities of biologically active angiostatin by the enzymatic cleavage of plasminogen has proven difficult in that it has delayed clinical testing. We have cloned, expressed, and purified a recombinant human angiostatin derivative (K1-3) using a mammalian expression system. Through the addition of a secretory signal and polyhistidine sequence tag, K1-3 can be purified from post-culture medium by simple column chromatography. Purified K1-3 protein is apparently folded in an active conformation, as evidenced by its ability to bind to lysine-Sepharose. In vitro, recombinant K1-3 significantly suppressed endothelial cell proliferation in a dose-dependent manner with an IC50 of 50 nM. Using an animal model of intracranial brain tumors in immune-competent rats, systemic administration of purified recombinant K1-3 resulted in up to 85% suppression of tumor growth (P = 0.011). Growth suppression was accompanied by a 32% decrease (P = 0.01) in tumor neovascularization. This study demonstrates a simple method to produce a biologically active recombinant angiostatin derivative. The ability to suppress intracerebral tumor growth after systemic administration suggests that K1-3 is likely to have therapeutic value in the treatment of malignant glial tumors.

Primary intracranial neoplasms in patients with HIV.

OBJECTIVE: To report a series of HIV-infected patients with intracranial tumors not known to be associated with immunodeficiency. BACKGROUND: The spectrum of HIV-associated diseases is changing with improved treatments and prolonged patient survival. Although primary central nervous system lymphoma (PCNSL) and toxoplasmosis continue to be the most common intracranial lesions in HIV-infected patients, the recognition of other pathologic entities is increasingly important. METHODS: The clinical characteristics and outcome of eight HIV-infected patients with nine intracranial neoplasms other than PCNSL are reported. In addition, all available pathologic specimens were tested for evidence of either HIV or Epstein-Barr virus (EBV) infection. An additional 28 patients reported in the literature are summarized. RESULTS: Five of eight patients had a glioblastoma multiforme; other tumors included an anaplastic ependymoma, a low-grade glioma, a subependymoma, and a leiomyosarcoma. More than half of the patients developed their tumor > or =6 years after the diagnosis of HIV infection. Patient prognosis and survival was best predicted by tumor histology. Treatment response and outcome did not appear to be influenced by HIV infection. Only the leiomyosarcoma demonstrated evidence of latent EBV infection. CONCLUSIONS: HIV-infected patients are at risk for intracranial neoplasms other than PCNSL, and benefit from aggressive tumor-specific therapy. It is possible that gliomas are occurring at a higher rate than in the general population. There was no evidence of HIV or EBV infection in any glial tumor.

Neurologic complications of ovarian carcinoma.

BACKGROUND: Neurologic complications of ovarian carcinoma are uncommon and to the authors' knowledge the full spectrum has not been delineated previously. METHODS: The authors reviewed the findings of 121 neurologic consultations on 83 ovarian carcinoma patients between 1993 and 1996; this represents 4% of all ovarian carcinoma patients seen at the study institution in this time period. RESULTS: The most common reasons for consultation were altered mental status, pain, weakness, numbness, headache, and seizure. Twenty-seven consultations diagnosed metastatic disease, 14 diagnosed cerebrovascular disease, and 4 diagnosed paraneoplastic syndromes; however, iatrogenic complications (n=38) comprised the majority of diagnoses. Greater than 50% of patients improved neurologically after diagnosis and treatment. CONCLUSIONS: Neurologic disease accompanying ovarian carcinoma may be more common and more diverse than recognized previously. Definitive neurologic diagnosis and treatment benefits the majority of patients.

High dose chemotherapy with autologous stem cell rescue in adults with malignant primary brain tumors.

High dose chemotherapy (HDCT) with autologous (bone marrow or peripheral blood) stem cell rescue (ASCR) has had success in the treatment of some malignant pediatric brain tumors. We report a series of adults enrolled in one of three HDCT and ASCR protocols for malignant primary brain tumors. Overall toxic mortality was 18%; chemotherapy regimen, tumor type, and prior treatment did not predict transplant-related mortality. Patients over the age of 30 had a higher rate of toxic mortality. Patients with recurrent medulloblastoma had a significant improvement in long-term survival (median: 34 months) as compared with historical reports; two patients with glioblastoma survive beyond four years without progression, but overall, a significant improvement in long-term survival could not be demonstrated for malignant gliomas.

Sarcoidosis of the cauda equina mimicking leptomeningeal malignancy.

Isolated neurosarcoidosis can present with a wide range of central nervous system manifestations. We present two cases of cauda equina sarcoidosis misdiagnosed initially as leptomeningeal malignancy, and review the literature. This unusual manifestation of neurosarcoidosis is typified by an indolent, chronic process with limited response to corticosteroid therapy.

Long-term survival in primary CNS lymphoma.

PURPOSE: We have previously reported on 31 patients with primary CNS lymphoma (PCNSL) treated between 1986 and 1992 with methotrexate (MTX), cranial radiotherapy (RT), and high-dose cytarabine who remained free of disease longer than historical controls. PATIENTS AND METHODS: We performed a follow-up analysis of our original cohort and now report their long-term survival and late treatment-related toxicity. RESULTS: The median cause-specific survival was 42 months, with a five-year survival of 22.3% compared with 3% to 4% in historical controls treated with RT alone. Age less than 50 years at diagnosis was a significant prognostic factor for survival (P = .01). Median disease-free survival was 40.3 months; 15 patients relapsed, all but one in the CNS. Late treatment-related toxicity was observed in nearly one third of patients and those more than 60 years of age were at substantially higher risk (P < .0001). CONCLUSION: Combined modality therapy for PCNSL has improved survival, but relapse is common and late neurologic toxicity is a significant complication. Although this approach is highly effective for younger patients, efficacious but less neurotoxic regimens need to be developed for older patients.

Cerebral neurocytoma: an unusual cause of refractory epilepsy. Case report and review of the literature.

We report a patient with medically refractory complex partial seizures (CPS) caused by a cerebral neurocytoma located near the amygdala. Neurocytoma represents an important addition to the differential diagnosis and, in particular, must be differentiated from oligodendroglioma and dysembryoplastic neuroepithelial tumor. Accurate pathological differential has therapeutic and prognostic implications.