Biomedical subjects
Publications and source records attributed to Lisa M DeAngelis.
Radiation retinopathy is a well-known complication of irradiation for diseases of the globe, orbit, or neighboring tissues but is rare after whole-brain radiation therapy (WBRT), even though the treatment port includes the posterior retina. We describe five patients with long-term primary CNS lymphoma who were diagnosed with retinopathy several years after treatment with chemotherapy and WBRT.
PURPOSE: The purpose of this study was to analyze prognostic factors for patients with newly diagnosed primary CNS lymphoma (PCNSL) in order to establish a predictive model that could be applied to the care of patients and the design of prospective clinical trials. PATIENTS AND METHODS: Three hundred thirty-eight consecutive patients with newly diagnosed PCNSL seen at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) between 1983 and 2003 were analyzed. Standard univariate and multivariate analyses were performed. In addition, a formal cut point analysis was used to determine the most statistically significant cut point for age. Recursive partitioning analysis (RPA) was used to create independent prognostic classes. An external validation set obtained from three prospective Radiation Therapy Oncology Group (RTOG) PCNSL clinical trials was used to test the RPA classification. RESULTS: Age and performance status were the only variables identified on standard multivariate analysis. Cut point analysis of age determined that patients age < or = 50 years had significantly improved outcome compared with older patients. RPA of 282 patients identified three distinct prognostic classes: class 1 (patients < 50 years), class 2 (patients > or =50; Karnofsky performance score [KPS] > or = 70) and class 3 (patients > or = 50; KPS < 70). These three classes significantly distinguished outcome with regard to both overall and failure-free survival. Analysis of the RTOG data set confirmed the validity of this classification. CONCLUSION The MSKCC prognostic score is a simple, statistically powerful model with universal applicability to patients with newly diagnosed PCNSL. We recommend that it be adopted for the management of newly diagnosed patients and incorporated into the design of prospective clinical trials.
PURPOSE: Biomarkers can facilitate diagnosis, monitor treatment response, and assess prognosis in some patients with cancer. YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins highly differentially expressed by malignant gliomas. We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers. EXPERIMENTAL DESIGN: Serum samples were obtained concurrently with magnetic resonance imaging scans. YKL-40 and MMP-9 were determined by ELISA and the values correlated with the patient's radiographic status and survival. RESULTS: High-grade glioma patients who underwent a surgical resection of their tumor had transient increase of both YKL-40 and MMP-9 serum levels in the postoperative period. Glioblastoma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients, 50 samples) had a significantly lower level of YKL-40 and MMP-9 than patients with active tumor (n = 66 patients, 209 samples; P = 0.0003 and 0.0002, respectively). Anaplastic glioma patients with no radiographic evidence of disease (n = 32 patients, 107 samples) also had a significantly lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199 samples; P = 0.04). There was a significant inverse association between YKL-40 and survival in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard ratio, 2.2; P = 0.05). CONCLUSIONS: YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients. YKL-40 can be used as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger patient population are needed to confirm these findings.
PURPOSE: We previously reported a series of patients treated with high-dose methotrexate (MTX) -based chemotherapy, with or without whole brain radiotherapy. The purpose of this report is to update the initial results and provide long-term data regarding overall survival, patterns of relapse, and the risk of treatment-related neurotoxicity. PATIENTS AND METHODS: Fifty-seven patients with an average age of 65 and median Karnofsky performance score of 70 were treated; all patients have been observed longitudinally with serial magnetic resonance imaging scans and neurologic examinations. RESULTS: The overall median survival was 51 months with a median follow-up of 115 months for surviving patients. Twenty-five patients relapsed or developed progressive disease; median progression-free survival was 129 months. Seventeen patients developed treatment-related neurotoxicity; all but one had received whole brain radiotherapy as a component of treatment. Seventy-four percent of patients younger than 60 years who received both MTX-based chemotherapy and whole brain radiotherapy were alive at last follow-up. Median survival for patients older than 60 years was 29 months regardless of whether or not they received whole brain radiotherapy. CONCLUSION: Long-term follow-up of our initial cohort confirms the observation of excellent overall survival, particularly for those patients younger than age 60 at diagnosis. For older patients, it appears to be reasonable to defer whole brain radiotherapy in an effort to minimize treatment-related neurotoxicity.
BACKGROUND: Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM). OBJECTIVES: To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM. PATIENTS AND METHODS: Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200 mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%. RESULTS: Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32-84); median Karnofsky performance status was 80% (range 60-100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I. 10-20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome. CONCLUSION: This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.
PURPOSE: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. EXPERIMENTAL DESIGN: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. RESULTS: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. CONCLUSIONS: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.
PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG). PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety. RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups. CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.
BACKGROUND: The role of radiotherapy and chemotherapy in the treatment of low-grade gliomas (LGG) is controversial regarding their effect on survival and the development of neurotoxicity. The few published studies examining adverse treatment effects on cognition revealed conflicting results. OBJECTIVE: To assess cognitive functioning in LGG patients who received conformal radiation therapy (RT), chemotherapy, or no treatment. DESIGN: 40 LGG patients participated in the study; 16 patients had RT +/- chemotherapy, and 24 patients had no treatment. All patients underwent a neuropsychological evaluation. APOE genotype was obtained in 36 patients who were classified in two groups based on the presence or absence of at least one apolipoprotein E small je, Ukrainian-4 (APOE small je, Ukrainian-4) allele. RESULTS: Treated LGG patients had lower scores than untreated patients on several cognitive domains; patients who completed treatment at intervals greater than 3 years and had long disease duration had significantly lower scores on the Non-Verbal Memory domain. Antiepileptic polytherapy, treatment history, and disease duration jointly contributed to low Psychomotor domain scores. 62% of treated patients showed white matter confluence on MRI, whereas only 9% of the untreated patients had such changes. Preliminary comparisons between APOE small je, Ukrainian-4 carriers (n = 9) and non-carriers (n = 27) on cognitive domain scores revealed no statistically significant differences, but APOE small je, Ukrainian-4 carriers had lower mean scores on the Verbal Memory domain than did non-small je, Ukrainian-4 carriers. CONCLUSIONS: RT +/- chemotherapy, disease duration, and antiepileptic treatment contributed to mild cognitive difficulties in LGG patients.
The authors report eight patients with primary dural lymphoma (PDL). All patients had extra-axial masses on MRI that diffusely enhanced after gadolinium. Pathology revealed low-grade non-Hodgkin lymphoma (marginal zone lymphoma of MALT [mucosa-associated lymphoid tissue] type) in all patients. All patients underwent radiation therapy, and three received chemotherapy. Complete response was achieved in 100% of patients, but three developed systemic relapse.
We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18-67) and a median KPS of 100 (range, 70-100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44-142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.
BACKGROUND: Radiation-induced glioblastoma multiforme (GBM) is particularly resistant to treatment and therapeutic options are limited. We report a patient with a radiation-induced GBM who had a complete response to carmustine and survived for 44 months. PATIENTS AND METHODS: Case report of a 38-year-old man with a radiation-induced GBM that responded to carmustine. RESULTS: Our patient developed a left occipital GBM 35 years after a left cerebellar astrocytoma was treated with surgery and radiation therapy (4500 rad). The GBM was treated with subtotal resection followed by four cycles of carmustine; a complete response was achieved. He relapsed 34 months after diagnosis and with further surgery survived 44 months from his diagnosis of GBM. CONCLUSION: GBMs may be a late complication of radiation treatment for pediatric brain tumors. If further radiotherapy is not a therapeutic option, chemotherapy may result in prolonged survival.
Cancer patients are at increased risk for stroke from direct and indirect effects of their malignancy. Some tumors are at high risk for cerebrovascular complications. Certain stroke mechanisms are specific to cancer, such as compression and occlusion of cerebral vessels by tumor, coagulopathy predisposing to hemorrhage and thrombosis, and treatment-related atherosclerosis. Special consideration for these mechanisms needs to be made when evaluating cancer patients, and treatment aimed at secondary prevention needs to incorporate overall prognosis and goals of care.
The most important recent advance in treatment of primary central nervous system lymphoma has been the introduction of high-dose methotrexate-based chemotherapy. Convincing data demonstrate that the regimens of such chemotherapy improve survival compared with historical controls treated with radiotherapy alone. However, the optical treatment approach is still unclear and therapy can be associated with long-term neurotoxicity. Current research focuses on maximizing survival while minimizing neurologic sequelae.
OBJECTIVE: To study risk factors for the development of postoperative neurological deficits after brain tumor resection and to define prognostic factors for recovery. METHODS: We prospectively studied 82 brain tumor patients undergoing tumor resection. Pre- and postoperative neurological examination, functional and performance status, cancer treatment, cardiovascular risk factors, seizure history, and blood pressure and oxygen saturation were recorded perioperatively. Postoperative magnetic resonance imaging scans were obtained within 72 hours of surgery, and the radiologist was blinded to the patient's status. Abnormalities on magnetic resonance diffusion weighted images were classified as new if they extended beyond the tumor cavity margins and were absent before surgery. RESULTS: Of the 80 assessable patients, 24 had a new or increased postoperative deficit by at least one point on the National Institutes of Health Stroke Scale. Presence of preoperative neurological deficits predicted development of postoperative deficits, whereas a new diffusion weighted imaging lesion after craniotomy predicted incomplete recovery of a new postoperative deficit. CONCLUSION: Postoperative diffusion magnetic resonance imaging is useful in predicting early functional recovery from new deficits after brain tumor surgery.
BACKGROUND: The age-adjusted incidence of primary central nervous system lymphoma (PCNSL) has increased since the 1970s, and treatment for this disease has evolved considerably. The objective of this study was to examine time trends in overall survival and disease-specific mortality in a population-based cohort of patients with PCNSL. METHODS: We identified patients diagnosed with PCNSL from 1975-1999 in the Surveillance, Epidemiology, and End Results (SEER) cancer registries. To assess time trends, year of diagnosis was classified in 5-year intervals: 1975-1980, 1981-1985, 1986-1990, 1991-1995, and 1996-1999. Overall survival distributions were estimated via Kaplan-Meier methodology and a competing risk analysis was used to assess PCNSL-specific mortality. We used information on underlying cause of death to distinguish likely immunocompetent patients from those whose PCNSL was related to human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). We also examined survival stratified by age at diagnosis. RESULTS: From 1975-1999, 2462 patients were diagnosed with PCNSL in SEER. Median survival was 4 months (95% CI 4, 5) for the entire cohort and 9 months (95% CI 8, 11) for the immunocompetent cohort (n = 1565). In the immunocompetent cohort, 965 of 1323 (73%) deaths were attributed to PCNSL. No significant time trend was observed in either overall or PCNSL-specific survival. CONCLUSIONS: Overall survival for patients with PCNSL has not improved consistently in the past three decades despite important therapeutic advances during this time. Although results from clinical trials suggest progress in the treatment of PCNSL, survival improvements are not reflected in this population-based cohort.
PURPOSE: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. EXPERIMENTAL DESIGN: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre-erlotinib/gefitinib-exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. RESULTS: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. CONCLUSIONS: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.
Standardized guidelines for the baseline evaluation and response assessment of primary CNS lymphoma (PCNSL) are critical to ensure comparability among clinical trials for newly diagnosed patients. The relative rarity of this tumor precludes rapid completion of large-scale phase III trials and, therefore, our reliance on the results of well-designed phase II trials is critical. To formulate this recommendation, an international group of experts representing hematologic oncology, medical oncology, neuro-oncology, neurology, radiation oncology, neurosurgery, and ophthalmology met to review current standards of reporting and to formulate a consensus opinion regarding minimum baseline evaluation and common standards for assessing response to therapy. The response guidelines were based on the results of neuroimaging, corticosteroid use, ophthalmologic examination, and CSF cytology. A critical issue that requires additional study is the optimal method to assess the neurocognitive impact of therapy and address the quality of life of PCNSL survivors. We hope that these guidelines will improve communication among investigators and comparability among clinical trials in a way that will allow us to develop better therapies for patients.
The authors reviewed 37 patients with leptomeningeal metastasis (LM) who required a ventriculoperitoneal shunt (VP shunt) for management of intracranial hypertension. Improvement was seen in 27 (77%) patients; subdural hematoma developed in one and shunt malfunction in three. Median overall survival was 2 months (range 2 days to 3.6 years) after VP shunt placement, but there was no procedure-related mortality. The prognosis of LM remained poor, but VP shunt can be an effective palliative tool when required.