Chemotherapy for brain tumors--a new beginning.
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Adult↗
Biomedical subjects
Lisa M DeAngelis
Publications and source records attributed to Lisa M DeAngelis.
Chemoradiotherapy for primary CNS lymphoma: an intent-to-treat analysis with complete follow-up.
OBJECTIVE: To assess the efficacy and safety of a preradiation chemotherapy regimen in patients with primary CNS lymphoma (PCNSL), with emphasis on long-term outcomes. METHODS: In this prospective phase II trial, patients with a new diagnosis of PCNSL received two cycles of intrathecal (12 mg) and IV (1 g/m2) methotrexate (MTX), thiotepa (30 mg/m2), and procarbazine (75 mg/m2), prior to whole-brain radiotherapy (RT). RESULTS: Seventeen patients were enrolled (ages 26 to 71, median 53). Median Karnofsky performance scale score was 70. After chemotherapy, 7 patients (41%) had a complete response (CR) and 7 (41%) a partial response (PR). After RT, 13 (76%) patients achieved a CR, 2 (12%) a PR, and 2 (12%) had disease progression. Relapse occurred in 7 (41%) patients; median disease-free survival was 18 months. Fifteen (88%) patients have died: 8 (47%) from PCNSL, 5 (29%) from neurotoxicity, and 2 (12%) from unknown causes. Median overall survival was 32 months. Two patients (12%) are alive and disease free at 12 years follow-up. Nephrotoxicity was a minor complication, but grades 3 and 4 myelosuppression were found in 5 (29%) patients. CONCLUSIONS: This regimen resulted in an efficacy and toxicity profile comparable to other combined modality treatments, despite the relatively low dose of methotrexate. It may be a useful option in patients unable to tolerate higher doses. Procarbazine and thiotepa are potential candidates for incorporation into chemotherapy regimens aiming to decrease the incidence of neurotoxicity. First relapse and neurotoxicity within 2 years of diagnosis seem to be critical for predicting long-term outcomes.
Adult↗
Treatment of primary central nervous system lymphoma.
Primary central nervous system lymphoma (PCNSL) describes a malignant non-Hodgkin's lymphoma (NHL) whose sole site of involvement is the central nervous system (CNS). The diagnosis of PCNSL must be differentiated from systemic NHL with metastasis to the CNS, which usually occurs late in the course of systemic disease. PCNSL accounts for approximately 4% to 7% of primary brain tumors, and its incidence has been increasing since the mid-1970s. Compared with other more common malignant primary brain tumors, PCNSL tends to be more amenable to radiotherapeutic and chemotherapeutic intervention. In this article, the authors review the standard treatment for upfront and recurrent PCNSL.
Brain Neoplasms↗
Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells.
We compared the cytotoxicity of the bioreductive antitumor agents mitomycin C (MMC) and streptonigrin (SN) with or without the DT-diaphorase (DTD) inducer dimethyl fumarate (DMF) in four human glioblastoma cell lines with the conventional chemotherapeutic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We also examined four other types of cancer cells to compare with glioblastoma cells. Cytotoxicity was measured with the sulforhodamine B (SRB) assay and was represented by 50% inhibition concentration (IC50). Enzymatic activities of DTD, cytochrome b5 reductase and glutathione-S-transferase (GST) in cells were measured spectrophotometrically. IC50 for BCNU was in a range of 28-300 microM in the glioblastoma cell lines. Glioblastoma cells were more sensitive to MMC or SN than to BCNU. Pretreatment with DMF significantly increased cytotoxicity of MMC and SN in glioblastoma cell lines and the NCI-H1299 lung cancer cell line, but had no effect on BCNU cytotoxicity. DMF significantly increased DTD and cytochrome b5 reductase activity, and decreased GST in three of four glioblastoma cell lines. Addition of the DTD inhibitor, dicumarol, significantly inhibited cytotoxicity of MMC and SN, and reversed the increased cytotoxicity seen when DMF was combined with either MMC or SN in all glioblastoma cell lines. Combining inducers of DTD and cytochrome b5 reductase with bioreductive agents may be a potential therapeutic strategy for glioblastoma.
Antineoplastic Agents↗
Central nervous system cancers: Clinical Practice Guidelines in Oncology.
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Age Factors↗
Leptomeningeal metastasis.
Leptomeningeal metastasis is a common complication of cancer. Often the diagnosis can be difficult, but early diagnosis and aggressive treatment can prevent irreversible neurologic deficits. Diagnosis is usually established by the demonstration of malignant cells in the cerebrospinal fluid (CSF) or by the presence of enhancing tumor nodules on cranial or spinal MRI. Treatment may require focal radiotherapy to symptomatic sites accompanied by chemotherapy. Intra-CSF chemotherapy requires normal CSF flow dynamics and is typically limited to the use of methotrexate, cytarabine or thiotepa. Intrathecal chemotherapy is rarely efficacious, except for hematopoietic neoplasms and, to a lesser extent, breast cancer. Increasingly, systemic chemotherapy is recognized as efficacious in the treatment of leptomeningeal metastasis in part because it has the ability to penetrate into bulky disease seen on neuroimaging. The optimum choice of therapy depends upon a thorough assessment of the neurologic extent of disease, which should include complete neuraxis imaging. Patients with extensive bulky disease may be best treated with systemic chemotherapy, whereas those with a positive CSF cytology but negative imaging may be treated with intrathecal chemotherapy and spared the systemic toxicity of intravenous drug. Despite vigorous therapy, many patients do poorly and the median survival is only about four months. Nevertheless, some patients, particularly those with leukemia, lymphoma, and breast cancer, respond and a substantial minority will be alive one to two years after diagnosis.
Antineoplastic Combined Chemotherapy Protocols↗
Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide.
The authors evaluated the efficacy of a combination of rituximab and temozolomide for recurrent or refractory primary CNS lymphoma (PCNSL). Fifteen patients with a median age of 69 years had a 53% objective response rate with acceptable toxicity. Median overall survival is 14 months and median progression free survival of responding patients is 7.7 months. This combination merits further study and provides a reasonable therapeutic alternative for older patients with progressive PCNSL.
Aged↗
Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study.
BACKGROUND: Treatment-related leukoencephalopathy is the leading toxicity after successful treatment of primary CNS lymphoma (PCNSL). Its mechanism is poorly understood and there are no autopsy data available on such patients. METHODS: From a database of immunocompetent patients with PCNSL diagnosed between 1985 and 2001, the authors identified five autopsied patients who died of leukoencephalopathy. The authors reviewed their clinical records, MRI, and autopsy findings. RESULTS: The median age was 74 years (range 41 to 79) at PCNSL diagnosis. Symptoms of neurotoxicity developed a median of 1 month after treatment completion, and median survival was 30 months (range 22 to 68 months) after neurotoxicity onset. All had white matter hyperintensity on T2-weighted MRI, and two developed enhancing lesions 5 and 14 months following completion of treatment. At autopsy no PCNSL was identified. Myelin and axonal loss, gliosis, pallor, spongiosis, and rarefaction of the white matter were found in all; two patients had tissue necrosis that correlated with the enhancement on MRI, and one had fibrinoid necrosis of vessels. Four of the five patients had atherosclerosis of large cerebral vessels in the circle of Willis and all had small vessel disease; two had recent strokes at autopsy. CONCLUSIONS: Treatment-induced leukoencephalopathy is not a late delayed consequence of neurotoxic treatment but can be seen very early in some patients. Vascular disease may be a component of this white matter injury.
Adult↗
Nonconvulsive status epilepticus in patients with cancer: imaging abnormalities.
BACKGROUND: Convulsive status epilepticus may cause reversible neuroimaging abnormalities. These cortical changes have been reported rarely in association with nonconvulsive status epilepticus. OBJECTIVE: To describe patients with cancer who had reversible magnetic resonance (MR) imaging abnormalities from nonconvulsive status epilepticus and whose altered mental status and MR imaging findings were initially considered to result from a structural lesion related to their underlying tumor. DESIGN: Retrospective study. SETTING: Department of Neurology at Memorial Sloan-Kettering Cancer Center, New York, NY. PATIENTS: Eight patients with a diagnosis of nonconvulsive status epilepticus who underwent MR imaging. RESULTS: Enhancing cortical abnormalities were observed on MR images in 4 (50%) of 8 patients with cancer who had impaired mental status and an electroencephalogram demonstrating seizure activity. Follow-up MR images showed neuroimaging improvement or resolution in all patients. CONCLUSIONS: Cortical enhancement on MR images in patients with cancer who have altered mental status may be due to nonconvulsive status epilepticus and not recurrent or metastatic tumor. If electroencephalography is not immediately available at initial evaluation, a trial of anticonvulsant therapy deserves consideration.
Adult↗
Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment.
Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0.05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.
Adult↗
Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis.
PURPOSE: To assess the safety and efficacy of intensive methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Twenty-eight patients received induction chemotherapy using high-dose systemic methotrexate (3.5 g/m2) and cytarabine (3 g/m2 daily for 2 days). Fourteen patients with chemosensitive disease evident on neuroimaging then received high-dose therapy using carmustine, etoposide, cytarabine, and melphalan with autologous stem-cell rescue. RESULTS: The objective response rate to the induction-phase chemotherapy was 57%, and median overall survival is not yet assessable, with a median follow-up time of 28 months. The overall median event-free survival time is 5.6 months for all patients and 9.3 months for 14 patients who underwent transplantation. Six of these 14 patients (43%) remained disease-free at last follow-up. Treatment was well tolerated; there was one transplantation-related death. Prospective neuropsychologic evaluations have revealed no evidence of treatment-related neurotoxicity. CONCLUSION: This treatment approach is feasible in patients with newly diagnosed PCNSL without evidence of significant related neurotoxicity. Although the transplantation results are similar to those achieved in patients with aggressive or poor-prognosis systemic lymphoma, the low response rate to induction chemotherapy and the significant number of patients who experienced relapse soon after HDT suggest that more aggressive induction chemotherapy may be warranted.
Adult↗
Primary central nervous system lymphoma: a curable brain tumor.
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Antineoplastic Combined Chemotherapy Protocols↗
Brain metastases.
Brain metastases are one of the most feared complications of cancer because even small tumors may cause incapacitating neurologic symptoms. This article reviews the epidemiology, clinical features, treatment, and prognosis of brain metastases from system malignancies.
Brain Neoplasms↗
Prophylactic anticonvulsants in patients with brain tumour.
OBJECTIVE: We conducted a clinical trial to determine if prophylactic anticonvulsants in brain tumour patients (without prior seizures) reduced seizure frequency. We stopped accrual at 100 patients on the basis of the interim analysis. METHODS: One hundred newly diagnosed brain tumour patients received anticonvulsants (AC Group) or not (No AC Group) in this prospective randomized unblinded study. Sixty patients had metastatic, and 40 had primary brain tumours. Forty-six (46%) patients were randomized to the AC Group and 54 (54%) to the No AC Group. Median follow-up was 5.44 months (range 0.13-30.1 months). RESULTS: Seizures occurred in 26 (26%) patients, eleven in the AC Group and 15 in the No AC Group. Seizure-free survivals were not different; at three months 87% of the AC Group and 90% of the No AC Group were seizure-free (log rank test, p = 0.98). Seventy patients died (unrelated to seizures) and survival rates were equivalent in both groups (median survival = 6.8 months versus 5.6 months, respectively; log rank test, p = 0.50). We then terminated accrual at 100 patients because seizure and survival rates were much lower than expected; we would need > or = 900 patients to have a suitably powered study. CONCLUSIONS: These data should be used by individuals contemplating a clinical trial to determine if prophylactic anticonvulsants are effective in subsets of brain tumour patients (e.g. only anaplastic astrocytomas). When taken together with the results of a similar randomized trial, prophylactic anticonvulsants are unlikely to be effective or useful in brain tumour patients who have not had a seizure.
Anticonvulsants↗
High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma.
PURPOSE: Anaplastic oligodendroglioma is a chemosensitive glial neoplasm. To improve disease control and postpone cranial radiotherapy, we designed a phase II study of intensive procarbazine, lomunstine and vincristine followed by high-dose thiotepa with autologous stem cell rescue for patients with newly diagnosed anaplastic or aggressive oligodendroglioma. PATIENTS AND METHODS: Sixty-nine patients with a median age of 42 (range: 18-67) and a median Karnofsky Performance Score of 90 (range: 70-100) were enrolled. Sixteen patients had a prior diagnosis of low-grade oligodendroglioma and 16 had mixed oligoastrocytoma pathology. Only patients with demonstrably chemosensitive enhancing tumors or those free of enhancing tumor after surgery and induction therapy were eligible to receive high-dose thiotepa. RESULTS: Thirty-nine patients (57%) completed the transplant regimen; their estimated median progression-free survival is 69 months and median overall survival has not been reached. Twelve transplanted patients (31%) relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with relapse; however, persistent non-enhancing tumor at transplant conferred an increased risk of relapse (p = 0.028). The transplant regimen was well-tolerated; median hospital stay was 20 days (range: 7-43) with a median time to ANC and platelet engraftment of 10 days. Thirty patients (43%) did not receive high-dose thiotepa because of stable or progressive disease (n = 21), excessive toxicity (n = 4), refusal of further therapy (n = 2), failure to obtain insurance coverage (n = 2), or other (n = 1). No treatment-related or long-term neurotoxicity was seen in the transplanted patients. CONCLUSIONS: High-dose chemotherapy with stem cell rescue as initial treatment for anaplastic oligodendroglioma is feasible and associated with prolonged tumor control in some patients.
Adolescent↗
Benefits of adjuvant chemotherapy in high-grade gliomas.
The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving >/=18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.
Antineoplastic Agents, Alkylating↗
Primary ocular lymphoma: clinical features, diagnosis, and treatment.
Primary ocular lymphoma involves the globe in the absence of any systemic or central nervous system lymphoma. Diagnosis is frequently delayed and often made only after the tumor has progressed to the brain and meninges. Clinical features, cues in ancillary tests, and immunologic and molecular advances that support the diagnosis are reviewed. The current treatment options are discussed. Although advances have been made, the optimal treatment for primary ocular lymphoma remains to be identified
Antineoplastic Agents↗
Cognitive functions in primary central nervous system lymphoma patients treated with chemotherapy and stem cell transplantation: preliminary findings.
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Antineoplastic Combined Chemotherapy Protocols↗