Correlations between perfusion MR imaging cerebral blood volume, microvessel quantification, and clinical outcome using stereotactic analysis in recurrent high-grade glioma.

BACKGROUND AND PURPOSE: Quantifying MVA rather than MVD provides better correlation with survival in HGG. This is attributed to a specific "glomeruloid" vascular pattern, which is better characterized by vessel area than number. Despite its prognostic value, MVA quantification is laborious and clinically impractical. The DSC-MR imaging measure of rCBV offers the advantages of speed and convenience to overcome these limitations; however, clinical use of this technique depends on establishing accurate correlations between rCBV, MVA, and MVD, particularly in the setting of heterogeneous vascular size inherent to human HGG. MATERIALS AND METHODS: We obtained preoperative 3T DSC-MR imaging in patients with HGG before stereotactic surgery. We histologically quantified MVA, MVD, and vascular size heterogeneity from CD34-stained 10-µm sections of stereotactic biopsies, and we coregistered biopsy locations with localized rCBV measurements. We statistically correlated rCBV, MVA, and MVD under conditions of high and low vascular-size heterogeneity and among tumor grades. We correlated all parameters with OS by using Cox regression. RESULTS: We analyzed 38 biopsies from 24 subjects. rCBV correlated strongly with MVA (r = 0.83, P < .0001) but weakly with MVD (r = 0.32, P = .05), due to microvessel size heterogeneity. Among samples with more homogeneous vessel size, rCBV correlation with MVD improved (r = 0.56, P = .01). OS correlated with both rCBV (P = .02) and MVA (P = .01) but not with MVD (P = .17). CONCLUSIONS: rCBV provides a reliable estimation of tumor MVA as a biomarker of glioma outcome. rCBV poorly estimates MVD in the presence of vessel size heterogeneity inherent to human HGG.

Season of birth and risk of brain tumors in adults.

BACKGROUND: Recent studies demonstrated an excess of winter births in children with brain tumors and in adults with various neurologic or psychiatric diseases relative to the general population. OBJECTIVE: To investigate a possible association between month of birth and risk of brain tumors in adults using data from a large, hospital-based case-control study. METHODS: Cases were patients with incident glioma (n = 489) or meningioma (n = 197) diagnosed at hospitals in Boston, MA, Phoenix, AZ, and Pittsburgh, PA. Controls (n = 799) were patients hospitalized for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race/ethnicity, and distance of residence from hospital. Odds ratios (ORs) were calculated using multivariate unconditional logistic regression allowing for cyclic variation in risk with month of birth. RESULTS: A relationship between month of birth and risk of adult glioma and meningioma was found, best described by a 12-month periodic function with peaks in February and January and troughs in August and July. The association between month of birth and risk of glioma differed significantly by handedness, with left-handed and ambidextrous subjects born during late fall through early spring being at particularly high risk of adult glioma as compared with those born at other times of the year. CONCLUSION: These findings suggest the importance of seasonally varying exposures during the pre- or postnatal period in the development of brain tumors in adults.

Occupation and the risk of adult glioma in the United States.

OBJECTIVE: Previous studies have observed increased glioma incidence associated with employment in the petroleum and electrical industries, and in farming. Several other occupations have also been associated with increased risk, but with inconsistent results. We evaluated associations between occupational title and glioma incidence in adults. METHODS: Cases were 489 patients with glioma diagnosed from 1994 to 1998 at three United States hospitals. Controls were 799 patients admitted to the same hospitals for non-malignant conditions. An experienced industrial hygienist grouped occupations that were expected to have similar tasks and exposures. The risk of adult glioma was evaluated for those subjects who ever worked in an occupational group for at least six months, those who worked longer than five years in the occupation, and those with more than ten years latency since starting work in the occupation. RESULTS: Several occupational groups were associated with increased glioma incidence for having ever worked in the occupation, including butchers and meat cutters (odds ratio [OR] = 2.4; 95% confidence limits [CL]: 1.0, 6.0), computer programmers and analysts (OR = 2.0; 95% CL: 1.0, 3.8), electricians (OR = 1.8; 95% CL: 0.8, 4.1), general farmers and farmworkers (OR = 2.5; 95% CL: 1.4, 4.7), inspectors, checkers, examiners, graders, and testers (OR = 1.5; 95% CL: 0.8, 2.7), investigators, examiners, adjustors, and appraisers (OR = 1.7; 95% CL: 0.8, 3.7), physicians and physician assistants (OR = 2.4; 95% CL: 0.8, 7.2), and store managers (OR = 1.6; 95% CL: 0.8, 3.1), whereas occupation as a childcare worker was associated with decreased glioma incidence (OR = 0.4; 95% CL: 0.2, 0.9). These associations generally persisted when the subjects worked longer than five years in the occupation, and for those with more than ten years latency since starting to work in the occupation. CONCLUSIONS: This is our first analysis of occupation and will guide future exposure-specific assessments.

Intra-arterial cisplatin plus oral etoposide for the treatment of recurrent malignant glioma: a phase II study.

Twenty-five adults with recurrent malignant glioma were enrolled into a phase II clinical study. All patients had undergone surgical resection and had failed radiotherapy and first-line treatment with nitrosourea-based chemotherapy; five had failed second-line chemotherapy. Our objective was to test the efficacy of combining intra-arterially (i.a.) infused cisplatin and oral etoposide. Using conventional angiographic technique to access anterior/posterior cerebral circulation, cisplatin 60 mg/m2 was administered by i.a. infusion on day 1 of treatment. Oral etoposide 50 mg/m2/day was given days 1-21, with a 7 day rest interval between courses. Response to treatment was evaluated in 20 patients. Two patients with anaplastic astrocytoma had partial responses (PR) and six patients experienced stable disease (SD) for an overall response rate (PR +/- SD) of 40%. The median time to disease progression (MTP) following treatment for the responder subgroup was 18 weeks. The median survival time from treatment (MST) for the responders (n = 8) and non-responders (n = 12) was 56.5 weeks and 11 weeks, respectively. Combined i.a. cisplatin and oral etoposide was well-tolerated, but produced an objective response in only a minority of patients. Those considered responders (PR + SD) experienced significant survival advantage when compared to the non-responders. Nonetheless, i.a. delivery of chemotherapy is an expensive and technologically burdensome treatment for most patients to access, requiring proximity to a major center with neuro-oncological and neuroradiological clinical services. This is of special concern for patients suffering recurrent disease with progressive neurological symptoms at a time in their course when quality of life must be safeguarded and palliation of symptoms should be the therapeutic goal. Despite the efforts of previous investigators to use this combination of agents to treat recurrent malignant glioma, we cannot recommend the use of i.a. chemotherapy for salvage treatment of this disease.

Cellular-telephone use and brain tumors.

BACKGROUND: Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. METHODS: We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. RESULTS: As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. CONCLUSIONS: These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.

Current therapy for brain tumors: back to the future.

In the last 30 years, while considerable progress has been made in laboratory research of malignant gliomas, fewer clinical breakthroughs can be highlighted. Laboratory research has improved our understanding of the biology, and especially the molecular genetics of this disease. Unfortunately, these successes highlight the difficulties in translating laboratory results into substantive clinical improvements. In part, these difficulties stem from a schizophrenic view of the development and evolution of brain tumors. We believe either that (1) brain tumors are local and therefore the most important research should have as its goal local control, or (2) brain tumors are diffuse, which is to say that the cells rapidly grow beyond their initial locus, and our research goal is the prevention or treatment of the advancing tumor front. Clearly both hypotheses have merit and, in fact, almost certainly, both are true. The question becomes, should we devote our research energies to one hypothesis at the exclusion of the other?

Biology and treatment of malignant glioma.

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.

Results of a randomized trial comparing intra-arterial cisplatin and intravenous PCNU for the treatment of primary brain tumors in adults: Brain Tumor Cooperative Group trial 8420A.

PURPOSE: To test the efficacy of intra-arterial (IA) cisplatin versus intravenous (IV) PCNU for treating primary brain tumors, in a randomized trial (Brain Tumor Cooperative Group [BTCG] Trial 8420A). METHODS: 311 adult patients (ages 19-79 years; median 45) with supratentorial tumors (confirmed histologically) were randomized by nine participating institutions. Patients were required to have completed radiotherapy (4500-6020 cGy to the tumor bed) before randomization. Patients were stratified as either nonprogressive (clinically and radiologically stable) or progressive. Results were analyzed for the 311 patients in the randomized population (RP), and for the 281 patients in the Valid Study Group (VSG) meeting protocol eligibility requirements. 56% of patients in the VSG had glioblastoma multiforme, 33% had other malignant glioma, and 11% had low-grade glioma. 64% were stratified as progressive. 12% had received prior chemotherapy. RESULTS: The group randomized to PCNU had the longer survival (p = 0.06 for the RP, p = 0.07 for the VSG). In the VSG, median survival was 10 months for the cisplatin group, 13 months for the PCNU group. The difference between treatment groups was significant (p < or = 0.02) when adjusted for important prognostic factors. PCNU lead to greater hematotoxicity; cisplatin lead to greater renal toxicity and some ototoxicity. Some cisplatin patients experienced complications associated with IA administration, including six cases of encephalopathy. CONCLUSION: The trial showed a survival advantage to the group randomized to PCNU, although the difference was modest. Coupled with previous BTCG results, these trails suggest that PCNU is an active drug for brain tumors.

Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the Brain Tumor Study Group.

PURPOSE: A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment of de novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies. METHODS: During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75-100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6-8 weeks. All patients who had not received 'full dose' radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review. RESULTS: Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p = 0.01) and the VSG (p = 0.02). Life-table analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p = 0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.

Chromosome number and carmustine sensitivity in human gliomas.

BACKGROUND: Although some patients with malignant gliomas respond to treatment with chemotherapeutic agents like BCNU, tumor recurrence inevitably occurs, heralding the development of chemoresistance. Treating and/or preventing chemoresistance requires distinguishing newly developed resistance from the presence of intrinsically resistant cells in the primary tumor population. This study relates the chromosomal complements of freshly resected astrocytomas to the cells' chemosensitivity and ultimately to the patients' response to treatment. METHODS: The authors dissociated 31 freshly resected human gliomas (5 astrocytomas, 10 anaplastic astrocytomas, 16 glioblastomas multiforme) into single cells, and performed cytogenetic analysis and BCNU sensitivity testing using the colony-forming assay (CFA) on first division cells from these tumors. RESULTS: The major cytogenetic abnormalities involved the loss of a sex chromosome in all three classes of gliomas and the gain of chromosome 7 in anaplastic astrocytoma and glioblastoma multiforme; clonal marker chromosomes were observed in only anaplastic astrocytoma and glioblastoma multiforme with no common rearrangement observed among the tumors. The five astrocytomas were near-diploid (2n+/-, 35-57 chromosomes/cell), and all were resistant to BCNU. Seven of ten anaplastic astrocytomas were composed primarily of 2n+/- cells and were BCNU resistant. Three other anaplastic astrocytomas had a 39% or greater representation of 4n+/- cells (88-101 chromosomes/cell), and these tumors were sensitive to BCNU. Ten of 16 glioblastomas multiforme were composed predominantly of 2n+/- cells and were resistant to carmustine. Six other glioblastomas multiforme had at least 41% 3n+/- (58-87 chromosomes/metaphase) and 4n+/- cell populations and were sensitive to carmustine. Thus, gliomas demonstrating BCNU sensitivity were more than 60% hyperdiploid (60 or more chromosomes/metaphase) with 1 to 8 clonal marker chromosomes and multiple clonal populations involving complex karyotypic deviations. In contrast, all 22 resistant tumors were composed primarily of near-diploid cells. Only 4 of 22 tumors had a clonal marker, and the chromosome ploidy changes were less extensive. CONCLUSIONS: In freshly resected untreated human gliomas, BCNU is most effective against hyperdiploid cells that have extensive ploidy changes and chromosome rearrangement, whereas resistance to carmustine is characteristic of near-diploid populations with few ploidy changes and rearranged chromosomes. This observation was consistent for all three classes of gliomas.

BCNU-sensitivity in parental cells and clones from four freshly resected near-diploid human gliomas: an astrocytoma, an anaplastic astrocytoma and two glioblastomas multiforme.

We compared the BCNU sensitivity of 4 freshly resected tumors (astrocytoma WM, and malignant gliomas MK, MB, and AM) and their clones to their karyology. The majority of primary cells in all 4 tumors had near-diploid chromosome numbers (2n +/-) and all were resistant to concentrations of BCNU exceeding 10 micrograms/ml. Following in vitro cultivation, the cells from tumors WM and MB retained their 2n +/- modal chromosome number with little change in the complexity of the karyotype. In contrast, tumors MK and AM demonstrated a more unstable genome. The modal chromosome number of MK shifted from 45 to 86 and that of tumor AM from 45 to 90. Karyotyping demonstrated additional ploidy changes and new marker chromosomes in both tumors. The colony forming assay (CFA) performed on the in vitro cultivated cells demonstrated little change in the sensitivity to BCNU in tumors WM and MB, while tumors MK and AM exhibited greater than a one log cell kill at 10.0 micrograms/ml and 15.0 micrograms/ml BCNU, respectively. The modal chromosome number and BCNU sensitivity followed a similar pattern in the 30 clones that were isolated; 21 clones with near-diploid and pseudodiploid chromosome numbers were all resistant to BCNU doses at or greater than 10 micrograms/ml. In contrast, 9 clones isolated from the 3 malignant gliomas with 3n +/- and 4n +/- modal chromosome numbers were sensitive to this concentration of BCNU. The karyotypes of the hyperdiploid clones were more complex; they contained 5 or more ploidy changes and/or had marker chromosomes. These studies confirm the association of diploidy and BCNU-resistance in freshly resected malignant gliomas.

A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma.

This Phase III trial tested the efficacy and safety of intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of newly resected malignant glioma, comparing intra-arterial BCNU and intravenous BCNU (200 mg/sq m every 8 weeks), each regimen without or with intravenous 5-fluorouracil (1 gm/sq m three times daily given 2 weeks after BCNU). All patients also received radiation therapy. A total of 505 patients were randomly assigned within the study. Fifty-seven patients were excluded, primarily because of neuropathology error, and the remaining 448 patients constituted the Valid Study Group. Of the total 505 patients, 190 patients could not receive intra-arterial BCNU and 315 patients were randomly assigned to receive intra-arterial (167 patients) and intravenous (148 patients) BCNU. Actuarial analysis (log-rank) demonstrated reduced survival for the intra-arterial group (p = 0.03). Serious toxicity was observed in the intra-arterial group; 16 patients (9.5%) developed irreversible encephalopathy with computerized tomography evidence of cerebral edema, and 26 patients (15.5%) developed visual loss ipsilateral to the infused carotid artery. Administration of 5-fluorouracil did not influence survival. The survival rate between the intravenous and the intra-arterial BCNU patients with glioblastoma multiforme did not differ, but was worse for intra-arterial BCNU patients with anaplastic astrocytoma than for those receiving intravenous BCNU (p = 0.002). Neuropathologically, intra-arterial BCNU produced white matter necrosis. It is concluded that intra-arterial BCNU is neither safe nor effective in prolonging survival when administered by the methods used in this study of newly diagnosed patients with malignant glioma.