PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme.

BACKGROUND: Survival of patients with anaplastic astrocytoma is highly variable. Prognostic markers would thus be useful to identify clinical subsets of such patients. Because specific genetic alterations have been associated with glioblastoma, we investigated whether similar genetic alterations could be detected in patients with anaplastic astrocytoma and used to identify those with particularly aggressive disease. METHODS: Tissue specimens were collected from 174 patients enrolled in Mayo Clinic Cancer Center and North Central Cancer Treatment Group clinical trials for newly diagnosed gliomas, including 63 with anaplastic astrocytoma and 111 with glioblastoma multiforme. Alterations of the EGFR, PTEN, and p53 genes and of chromosomes 7 and 10 were examined by fluorescence in situ hybridization, semiquantitative polymerase chain reaction, and DNA sequencing. All statistical tests were two-sided. RESULTS: Mutation of PTEN, amplification of EGFR, and loss of the q arm of chromosome 10 were statistically significantly less common in anaplastic astrocytoma than in glioblastoma multiforme (P =.033, P =.001, and P<.001, respectively), and mutation of p53 was statistically significantly more common (P<.001). Univariate survival analyses of patients with anaplastic astrocytoma identified PTEN (P =.002) and p53 (P =.012) mutations as statistically significantly associated with reduced and prolonged survival, respectively. Multivariate Cox analysis of patients with anaplastic astrocytoma showed that PTEN mutation remained a powerful prognostic factor after adjusting for patient age, on-study performance score, and extent of tumor resection (hazard ratio = 4.34; 95% confidence interval = 1.82 to 10.34). Multivariate classification and regression-tree analysis of all 174 patients identified EGFR amplification as an independent predictor of prolonged survival in patients with glioblastoma multiforme who were older than 60 years of age. CONCLUSION: PTEN mutation and EGFR amplification are important prognostic factors in patients with anaplastic astrocytoma and in older patients with glioblastoma multiforme, respectively.

A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.

BACKGROUND: The current study was conducted to determine whether the addition of interferon-alpha (IFN-alpha) to treatment with radiation therapy and carmustine (BCNU) improves time to disease progression or overall survival in patients with high-grade glioma. METHODS: Patients with anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma multiforme, or gliosarcoma received radiation therapy plus BCNU as initial therapy. Subsequently, patients without tumor progression at the completion of radiation therapy were stratified by age, extent of surgery, tumor grade and histology, Eastern Cooperative Oncology Group performance status, and treating institution, and then were randomly assigned to receive either BCNU alone (200 mg/m(2) on Day 1) or BCNU (150 mg/m(2) on Day 3) plus IFN--alpha (12 million U/m(2) on Days 1-3, Weeks 1, 3, and 5) every 7 weeks for a maximum of 6 cycles. RESULTS: Of the 383 patients enrolled in the study, 275 eligible patients were randomized. There was no significant difference with regard to time to disease progression or overall survival between the two groups. Patients receiving IFN-alpha experienced more fever, chills, myalgias, and neurocortical symptoms including somnolence, confusion, and exacerbation of neurologic deficits. Cox multivariate regression models confirmed known favorable prognostic variables including younger age, Grade 3 tumor (according to World Health Organization criteria), and greater extent of surgery. Cox and classification and regression tree analysis models also demonstrated that a normal baseline Folstein mini-mental status examination (MMSE) score was associated with better prognosis. CONCLUSIONS: IFN-alpha does not appear to improve time to disease progression or overall survival in patients with high-grade glioma and appears to add significantly to toxicity. The baseline MMSE score may serve as an independent prognostic factor and warrants further investigation.

Efficacy of neuroradiological imaging, neurological examination, and symptom status in follow-up assessment of patients with high-grade gliomas.

OBJECT: It is standard practice for the oncological follow-up of patients with brain tumors (especially in the setting of clinical trials) to include neurological examination and neuroradiological studies such as computerized tomography (CT) or magnetic resonance (MR) imaging in addition to evaluation of the patients' symptomatology and performance score. The validity of this practice and its impact on the welfare of patients with high-grade gliomas has not been adequately assessed. The purpose of this study is to provide such an assessment. METHODS: The authors studied 231 similarly treated patients who were participating in three prospective North Central Cancer Treatment Group or Mayo Clinic trials who developed progressive disease during follow up. According to the protocol, the symptom status, performance score, results of neurological examination, and CT or MR status were recorded prospectively in each patient at each evaluation (every 6-8 weeks). At progression, 177 (77%) of 231 patients experienced worsening of their baseline symptoms or they developed new ones. In the remaining 54 asymptomatic patients (23%), neuroradiological imaging revealed the progression. Asymptomatic progression was more likely to be detected on MR imaging compared with CT studies (p < 0.01). In no asymptomatic patient was progression detected on neurological examination alone. The median survival time after tumor recurrence was 13.3 weeks in symptomatic patients compared with 41.7 weeks in the asymptomatic group (p < 0.0001). Asymptomatic patients were more aggressively treated, with surgery (p < 0.0001) and second-line chemotherapy (p < 0.0002). Multivariate analysis of survival time following first progression by using both classification and regression trees and Cox models showed that treatment at recurrence was the most important prognostic variable. CONCLUSIONS: Symptoms are the most frequent indicators of progression in patients with high-grade gliomas (77%). All asymptomatic progressions were detected on neuroradiological studies; MR imaging was more likely than CT scanning to reveal asymptomatic recurrences. Survival after disease progression was significantly longer in asymptomatic patients and could be related both to treatment following progression and to other favorable prognostic factors such as performance score.

Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas.

Inactivation of the p53 gene is a common early event of astrocytoma tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes have been implicated in malignant progression, detection of losses or amplifications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diffuse gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and CEN12/CDK4 were performed and revealed expected frequencies of abnormalities, except for p53 losses, which were low (7%). The latter supports the concept that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation and were univariately associated with decreased patient survival. However, only patient age and histologic classification retained statistical significance on multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotype. Thus, their detection by fluorescence in situ hybridization may have diagnostic usefulness in cases with equivocal morphologic features. Although our numbers are small, we find no additional prognostic significance to these genetic abnormalities one age, grade, and oligodendroglial histology are taken into account.

Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors. An analysis of DNA content (ploidy), cellular proliferation, and p53 expression.

BACKGROUND: The biologic behavior of anaplastic (World Health Organization Grade III) astrocytomas and oligoastrocytomas is highly variable, ranging from rapid progression to prolonged survival. It is difficult to predict the outcome of an individual patient based on morphology alone. METHODS: To determine the prognostic value of commonly used clinicopathologic markers, we reviewed our experience with 85 similarly treated patients enrolled in 3 North Central Cancer Treatment Group high grade glioma protocols. The pathology was comprised exclusively of primary anaplastic astrocytic tumors (66 astrocytomas and 19 oligoastrocytomas). Variables examined included patient age, morphologic type, preoperative performance score, extent of surgery, solitary versus multiple mitoses, DNA flow cytometric and image morphometric parameters, and expression of proliferating cell nuclear antigen, MIB-1, and p53 expression. RESULTS: The study was comprised of 48 men and 37 women ranging in age from 14-79 years (median age, 47 years). Overall survival ranged from <1 month to >12 years (median, 21.6 months). Statistical analyses revealed that age accounted for the majority of this extensive variability in survival. The median survival times were 65. 5 months, 22.1 months, and 4.4 months, respectively, for the groups <40 years, 40-59 years, and >/=60 years, respectively (P < 0.0001). On univariate analyses, aneuploidy by flow cytometry and a low performance score also predicted a better survival (P values of 0.04 and 0.009, respectively). Statistical trends predicting a better survival were observed for patients with a solitary mitosis and p53 immunopositivity. However, only patient age remained significant in multivariate models. CONCLUSIONS: In a small but relatively uniformly treated cohort of patients with anaplastic astrocytomas and oligoastrocytomas, patient age was associated strongly and inversely with overall survival. Once patient age was taken into account, the clinical and pathologic markers tested appeared to be of limited prognostic value.

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Phase II North Central Cancer Treatment Group study of 2-cholorodeoxyadenosine in patients with recurrent glioma.

There is no standard treatment for patients with recurrent gliomas, and their prognosis remains poor. 2-Chlorodeoxyadenosine is a purine analogue that has significant activity in many low-grade lymphoproliferative disorders. The authors conducted a phase II study to determine the efficacy of 2-chlorodeoxyadenosine in patients with recurrent gliomas. Patients with a histologically confirmed primary brain tumor with evidence of progression after radiation therapy were eligible. Protocol treatment consisted of 2-chlorodeoxyadenosine 7.0 mg/m2 intravenously on days 1 through 5 every 28 days. For those with a history of prior nitrosourea therapy, the dose of 2-chlorodeoxyadenosine was reduced to 5.6 mg/m2 on days 1 through 5. Treatment was continued until progression or a maximum of 12 cycles. Fifteen patients with recurrent astrocytomas or oligoastrocytomas of all grades were entered in the study. Treatment was well tolerated. Major toxicities were myelosuppression and neurotoxicity. No responses were seen. The authors conclude that although 2-chlorodeoxyadenosine is well tolerated, no demonstrable activity in patients with recurrent gliomas was established.

Primary central nervous system non-Hodgkin's lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52.

PURPOSE: We herein report updated survival and toxicity data on the entire cohort of 53 eligible patients treated on North Central Cancer Treatment Group (NCCTG) protocol 86-72-52, which is now closed. METHODS AND MATERIALS: An initial report was published in this journal in 1995. No substantive changes in the conclusions of that report were identified in this analysis. Median survival was 9.6 months for the entire cohort; median survival for the 20 patients who completed the prescribed protocol treatment was 20.7 months. The hematologic and non-hematologic toxicity distributions are virtually the same as those reported in the original paper. RESULTS: Results are given for the entire group and for subsets defined by age < or = 60 versus > 60 years, and < 70 versus > or = 70 years of age. CONCLUSIONS: No significant differences were observed in any of the outcome variables by age group. There was, however, a nonsignificant suggestion of poorer outcome in those who were > 60 years of age.

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Increasing the proportion of women in academic medicine: one institution's response.

OBJECTIVE: To increase gender diversity among the physician consulting staff (PCS) at a major medical center. DESIGN: Because the proportion of female PCS at academic medical centers in the United States has not increased commensurately with increases in the proportion of female graduates from American medical schools, a modeling and graphing technique was developed to analyze this problem and recommend solutions for one large academic medical center. MATERIAL AND METHODS: Personnel data, by gender and year from 1980 through 1994, were collected for all PCS at Mayo Clinic Rochester (MCR). These data were compared with similar data from other US academic medical centers and were used to develop models to predict the proportion of female PCS at MCR yearly until 2005, assuming various hiring and resignation patterns. Novel techniques were developed to illustrate and compare the models. Model-based predictions were compared with national projections, and a realistic target proportion of female PCS was defined on the basis of assumptions about the proportion of female graduates from medical school and internship programs during the next 10 years as well as probable hiring, retention, and resignation rates at MCR. To identify issues critical to recruitment, retention, and professional growth of female PCS at MCR, we used factor analysis to assess responses to a confidential questionnaire sent to all female faculty members. RESULTS: In 1994 and 1995, the proportion of female PCS was 25% at US academic medical centers but only 15% at MCR, and the rate at which this proportion increased from 1980 through 1994 at MCR was also lower than the national rate. Model-based predictions demonstrated that gradually (1.5% per year) increasing the female percentage of new recruits from 26% in 1995 to 40% in 2005 would achieve the targeted 25% female PCS in 13 years. Questionnaire responses from 119 (68%) of the 175 female PCS at MCR identified 6 important recommendations for recruitment and retention of female PCS: survey resignees and candidates who decline positions; appoint more qualified women to policy-making committees; require sensitivity and diversity training for all staff (especially leaders); develop explicit, gender-sensitive criteria for selecting department and division chairs; compare Mayo gender and diversity data with national data at the department or division level; and develop mechanisms for mentoring junior female staff members. CONCLUSION: We developed useful methods for analyzing the PCS gender distribution, defined feasible hiring strategies, and identified specific recommendations to enhance the professional experience of female PCS. These methods can provide a model for other institutions seeking to optimize gender diversity among their staff.

Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations.

Although common among adult intracranial neoplasms, pediatric malignant astrocytomas (PMAs) comprise a relatively small proportion of the brain tumors that occur in children. The scarcity of such cases generally requires that molecular analyses of PMAs are based on the utilization of paraffin-embedded material, and here we have used 39 such specimens to examine the incidence and prognostic significance of oncogene and tumor suppressor gene alterations (including amplifications of EGFR, CDK4, and MDM2 as well as inactivating mutations of CDKN2A, TP53, and PTEN) in these tumors. In general, the frequency of alteration for the genes we have studied fell within ranges that have been reported for adult astrocytomas. However, EGFR amplification, which is usually observed in approximately 40% and 15% of adult grade 4 and grade 3 astrocytomas, respectively, was not detected in any member of this series. With regard to prognosis, PTEN mutations were significantly associated with decreased survival among grade 3 and grade 4 PMA patients, a potentially important observation because neither patient age nor tumor malignancy grade was correlated with outcome for these individuals. In total, our data suggest at least one significant distinction between the genetic etiology of pediatric and adult astrocytomas and additionally reveal that analysis of PTEN mutations in PMA patients may be useful in the differential diagnosis of these tumors.

The consequences of treatment and disease in patients with primary CNS non-Hodgkin's lymphoma: cognitive function and performance status. North Central Cancer Treatment Group.

Per protocol, patients with primary CNS non-Hodgkin's lymphoma in an intergroup phase II trial conducted by the North Central Cancer Treatment Group and the Eastern Cooperative Oncology Group had their cognitive functions measured using the Folstein and Folstein Mini-Mental Status Examination (MMSE) and their physical functions measured using the Eastern Cooperative Oncology Group Performance Score (PS) at study entry, at each treatment evaluation, and at quarterly intervals thereafter until disease progression or death. Of the 53 eligible participants who began therapy, 46 (87%) had baseline MMSE scores recorded, 36 (68%) had at least one follow-up MMSE, and 32 (60%) had both, while 52 (98%) had baseline PS, 49 (92%) had at least one follow-up PS, and 48 (91%) had both. Patterns of MMSE and PS values over time were studied in each individual, in the group as a whole, in the 20 patients who completed the study regimen, in the 23 who survived more than a year, and in patients who were classified as nonprogressors at each key evaluation. For each patient, all recorded values were plotted versus time, with dates of disease progression and death included, to look for signs of decline in cognitive or physical function preceding adverse events. Long-term declines in scores of both cognitive and physical function were observed in many treated patients with primary CNS non-Hodgkin's lymphoma. Nearly all patients who were alive more than 52 weeks after study entry had a demonstrable decline in cognitive and physical functionality. Such declines may occur before disease progression is documented; they may also occur in some patients who have long-term follow-up without evidence of disease progression. Declining MMSE and PS was a poor predictor of disease progression. There was no association of PS and toxicity. The data from this study demonstrated the considerable difficulties we encountered conducting an ancillary study such as this within a multicenter clinical trial. Firstly, the test instruments written into the protocol were unable to tell if the declines seen were due to disease, treatment, co-morbidity, or other factors. Secondly, the missing data created difficulties in interpreting outcome.

Randomized comparison of four tools measuring overall quality of life in patients with advanced cancer.

PURPOSE: We report on a clinical trial developed to compare four different instruments that provide overall quality-of-life (QOL) scores, ranging from a simple, one-item instrument to more detailed instruments. Two issues addressed were (1) Will QOL tools suffer from missing data when used in a community-based cooperative group setting?, and (2) Are there additional data generated by a more detailed multiitem instrument over that provided by a single-item global QOL question? MATERIALS AND METHODS: A four-arm randomized trial was designed to compare four instruments that provide overall QOL scores in patients with advanced colorectal cancer. Patients and physicians completed the single-item Spitzer Uniscale (UNISCALE) at baseline and monthly. Patients were randomly assigned to complete, in addition, either the 22-item Functional Living Index-Cancer (FLIC), the five-item Spitzer QOL index (QLI), a picture-face scale (PICT), or nothing else. RESULTS: A total of 128 patients were randomized. Greater than 90% complete QOL data were obtained. There was strong correlation, concordance, and criterion-related validity among all four patient-completed tools. The UNISCALE had a greater decrease over time than did the FLIC (P=.005), which suggests a greater sensitivity; the UNISCALE was similar to the QLI and the PICT in this regard. Physicians provided lower UNISCALE scores than patients. Results supported the hypothesis that QOL is prognostic for survival. CONCLUSION: Patients can effectively complete QOL tools in a cooperative group setting with proper education of health care providers and patients. A simple single-item tool (UNISCALE) appears to be appropriate to obtain a measure of overall QOL.

Neuroimaging and treatment implications of patients with multiple epidural spinal metastases.

BACKGROUND: Although multiple spinal epidural metastases (MEMs) commonly occur in cancer patients, their clinical significance remains uncertain. The authors attempted to ascertain the incidence of MEMs and their association with the completeness of spinal imaging by magnetic resonance (MR) scanning versus myelography to determine how often they are missed because of incomplete spinal imaging and to assess their prognostic and treatment implications. METHODS: A review of 337 epidural spinal cord compression (ESCC) cases seen at the Mayo Clinic between 1985 and 1993 was conducted. RESULTS: ESCC patients undergoing myelography only were significantly more likely to undergo complete spinal imaging (CSI)than patients undergoing either MR scan only or both imaging modalities (P < 0.0001). MEMs were detected in 32% of patients undergoing CSI and 18% of patients with incomplete spinal imaging (P=0.02). Failure to image the cervical spine in patients with symptomatic thoracic or lumbar epidural lesions would have missed secondary epidural lesions in only 1% of patients; however, this figure increased to 21% for failure to image either the thoracic or lumbosacral spine when symptomatic disease was located elsewhere. Radiation oncologists included secondary epidural deposits in treatment ports in 93% of MEM cases. In a multivariate model, the presence of MEMs was an independent prognostic factor for poorer survival. CONCLUSION: The incidence of MEMs in patients with ESCC is approximately 30%, and their presence frequently alters treatment plans. It appears safe to forgo cervical spine MR scanning in patients with radiographically verified thoracic or lumbar ESCC; however, careful imaging of the thoracic and lumbar spine should be considered in all ESCC patients to detect MEMs.

Clinical outcome of gliosarcoma compared with glioblastoma multiforme: North Central Cancer Treatment Group results.

OBJECT: Gliosarcoma, a rare malignancy of the central nervous system, consists of gliomatous and sarcomatous elements. There are conflicting reports regarding its aggressiveness and cell line of origin compared with those of glioblastoma multiforme (GBM). The goal of this study was to compare clinicopathological features such as disease-free survival time and actual survival time in patients with gliosarcoma with a matched group of patients with GBM as well as with the entire group of patients with GBM. METHODS: The authors report on 18 cases of gliosarcoma derived from a series of 748 Grade 4 astrocytoma cases that were part of four consecutive randomized Phase III trials conducted between 1979 and 1996. In this series the gliosarcoma group represented only 2.4% of all GBMs and included 11 men and seven women with a median age of 61.5 years (range 31-81 years). The median tumor size was 5 cm (range 2-8 cm). The locations, all supratentorial, included temporal in 44%, parietal in 28%, frontal in 17%, and occipital in 11%. The 18 patients with gliosarcomas, all Grade 4 (World Health Organization classification), were compared with the entire group of 730 patients with GBM and a control group of 18 patients with GBM matched for known prognostic factors including patient age, randomization date, performance status, extent of resection, and protocol number. Patients in all treatment groups received radiation and nitrosourea-based chemotherapy. The median time to progression and the median survival times for the patients with gliosarcoma were 28.0 and 35.1 weeks as compared with 24.7 and 41.6 weeks for the entire group of patients with GBM (log rank test, p = 0.94 and 0.27, respectively) and 16.7 and 34.4 weeks in the control group (p = 0.20 and 0.84, respectively). In previous molecular cytogenetic analyses of gliosarcoma these authors have shown similar genetic changes in the gliomatous and sarcomatous components. CONCLUSIONS: The data obtained in this study support the conclusion that gliosarcoma shares significant clinical and genetic similarities with GBM and that the same principles should be applied for patient enrollment in research protocols and treatment for these two kinds of tumor.

Effects of radiation and chemotherapy on cognitive function in patients with high-grade glioma.

PURPOSE: The effect of radiotherapy on the long-term cognitive performance of patients treated for intracranial neoplasm is a major concern to clinicians and patients, particularly as long-term survival or cure is possible for a small minority of patients. To assess the effects of cranial radiotherapy and chemotherapy on the cognitive performance of high-grade glioma patients, we analyzed cognitive performance data collected in a series of prospective clinical trials. METHODS: We studied 701 high-grade brain tumor patients entered onto two consecutive North Central Cancer Treatment Group (NCCTG) randomized treatment trials designed to compare radiotherapy and carmustine (BCNU) versus radiotherapy and 1-(2-chloroethyl)-3(2,6 dioxo-l-piperidyl)-1-nitrosource a (PCNU) (first trial) and radiotherapy and BCNU and interferon alfa (IFN) versus radiotherapy and BCNU (second trial). Folstein Mini-Mental Status Exam (MMSE) score and Eastern Cooperative Oncology Group (ECOG) performance score (PS) recorded at baseline and 6, 12, 18, and 24 months were analyzed to assess cognitive and physical function over time. Patients who did not demonstrate tumor progression within 60 days of the assessment time were considered nonprogressors at that evaluation. A loss of greater than 3 points on the MMSE was considered significant deterioration. RESULTS: The number of patients who experienced a greater than 3-point decrease in MMSE from baseline was 13 of 119 nonprogressors (10.9%; 95% confidence interval [CI], 6.3% to 18.9%) at 6 months, three of 54 nonprogressors (5.5%; 95% CI, 0.5% to 12.8%) at 12 months, three of 30 nonprogressors (10%; 95% CI, 2.1% to 26.5%) at 18 months, and four of 22 nonprogressors (18.2%; 95% CI, 5.2% to 40.3%) at 24 months. The CIs at all times overlapped, which indicates no statistically significant increase in the percentage of patients who experienced a significant decrease in their MMSE score. Patients who demonstrated a significant decrease in their MMSE score were significantly older than those who did not (P = .0017) at 6 months and remained so throughout follow-up; moreover, they had a significantly shorter time to progression and death. ECOG PS was strongly negatively correlated with MMSE score throughout the study, and MMSE score at all time intervals was correlated with baseline PS. CONCLUSION: In this population of glioma patients who received radiotherapy, there is no clear trend to cognitive worsening. Factors such as older age, poorer PS, and subclinical tumor progression may be more significant factors in those patients who did demonstrate a significant cognitive decline.

Phase II trial of recombinant interferon-alpha-2a and eflornithine in patients with recurrent glioma.

Interferons alpha and beta have been reported to cause tumor regression in a small proportion of patients with recurrent glioma. Eflornithine, an irreversible inhibitor of ornithine decarboxylase, reduces cellular polyamine levels and has also been reported to cause tumor regression in patients with recurrent anaplastic astrocytoma and glioblastoma multiforme. In vitro evidence suggests that interferon and eflornithine are synergistic. In this phase II trial, we investigated the combination of recombinant alpha interferon (36 x 10(6) units/m2 subcutaneously days 3 to 7) and eflornithine (2.25 g/m2 QID PO days 1 to 7) repeated every 28 days. All 29 patients entered in the study were evaluable for toxicity and efficacy. Toxicity consisted primarily of fever, chills, myalgia, weakness and fatigue as well as cortical dysfunction including somnolence, confusion, and exacerbation of underlying neurologic deficits. One patient died from cerebral herniation attributable to interferon. None of the patients experienced objective tumor regression. Seven patients (24%) were stable for more than six months, but the disease stability could also be explained by indolent underlying disease or inability to distinguish recurrent tumor from delayed radiation effects. Intermittent high-dose recombinant interferon alpha plus eflornithine demonstrated no definite antitumor effects in this trial.

Randomized trial of radiation therapy (RT) plus dibromodulcitol (DBD) versus RT plus BCNU in high grade astrocytoma.

PURPOSE: We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and DBD with RT and BCNU in patients with high-grade astrocytoma. METHODS: A total of 238 patients with supratentorial grade 3 and grade 4 astrocytoma were studied. Patients were stratified by age, extent of surgery, tumor grade, and performance score and randomly assigned to receive RT 55-60 Gy and either DBD, 200 mg/m2 orally on Days 1-10 every five weeks or BCNU, 200 mg/m2 intravenously every seven weeks. Median age was 60 years; 62% were 55 years or older. Eighty-three percent had subtotal resection, 58% had grade 4 tumors, and 83% had performance scores of 0-2. RESULTS: Survival distributions for all patients in the two arms were similar, with median survival of 41 weeks in each arm. Time to progression distributions were virtually identical, with medians of 22 weeks. BCNU produced significantly greater hematologic toxicity; median leukocyte and platelet nadirs on the first cycle were 3.6 vs. 4.7 (P = 0.0001) and 117 vs. 162 (P < 0.0001), and overall platelet nadirs were 80.5 vs. 114 (P = 0.0019). Non-hematologic toxicities were also significantly greater with BCNU, including nausea (57% vs. 31%; P < 0.0001) and vomiting (45% vs. 17%; P < 0.0001). CONCLUSION: This trial found no evidence of differences in treatment efficacy when either DBD or BCNU is combined with radiation therapy for patients with high-grade astrocytoma.

An evaluation of postoperative follow-up tests in colon cancer patients treated for cure.

BACKGROUND: Currently patients with colon cancer who are potentially cured by surgery are followed periodically with physical examinations, blood tests and imaging studies to detect tumor recurrence early, on the presumption that intervention can effect outcome. There is little information to indicate whether frequent visits to the doctor's office or frequent testing improves survival or quality of life. METHODS: Ninety-eight patients with resected stage B2, B3 or C (modified Astler-Coller) colon cancer who developed recurrent disease while enrolled in prospective adjuvant trials at Mayo Clinic sponsored by the North Central Cancer Treatment Group were studied to evaluate the utility of follow-up tests to detect the first recurrence of colon cancer and the outcome following various interventions for these recurrences. These patients had a history, physical examination, complete blood count, chemistry panel and chest x-ray approximately every 3-4 months in the 1st year and then every 6-12 months thereafter for a total of 5 years. Bowel evaluation was done at 6 months, 12 months and annually thereafter. In addition, a minority of patients had carcinoembryonic antigen (CEA) testing, and radioisotope liver scans at various intervals. RESULTS: Symptoms signaled the diagnosis of recurrent disease in 55 patients, physical examination in 4 patients, and abnormalities in chest x-ray in 18 patients. An elevated CEA was the initial abnormal test in 5 patients, abnormal liver scans in 5 patients, elevated liver function tests in 6 patients and laparotomy for other reasons in 2 patients. Hemoglobin, barium enema, and fecal blood testing were useful in 1 patient each. Thirty-one percent of recurrences were diagnosed between scheduled visits. In our series, histories, physical examinations, and chest x-rays led to the detection of 79% of the recurrences while liver function tests, liver scans and CEAs led to the detection of 16% of recurrences. Sixteen patients underwent resection for cure for their first recurrence; the diagnosis of recurrence was signaled by symptoms in 6 patients, chest x-ray in 6 patients and abnormal liver function tests, CEA, hemoglobin, and laparotomy for colostomy closure in 1 patient each. CONCLUSIONS: The majority of tumor recurrences were detected by symptoms, physical examinations and chest x-rays. Testing for asymptomatic tumor recurrences during the 1st follow-up year is likely to be much less fruitful for detecting resectable recurrences than testing patients in the 2nd through 4th follow-up years. Patients who had a disease recurrence in the 1st postoperative year were less likely to be candidates for curative intent surgery. Lower tumor grade at initial diagnosis correlated both with likelihood of undergoing secondary surgical resection and the chance of doing well following this. These data may be helpful for defining more appropriate follow-up test for detection of tumor recurrence in patients with resected colon cancer.

Supratentorial gliomas: a comparative study by grade and histologic type.

PURPOSE: To try and identify biologic differences based on tumor grade and histologic type between the major classes of glial tumors, including low-grade diffuse fibrillary and pilocytic astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas and high-grade diffuse fibrillary astrocytomas, oligodendrogliomas and mixed oligo-astrocytomas. METHODS: Utilizing the St. Anne-Mayo (SAM) grading system, the incidence, patient characteristics, and survivals of 196 patients with low-grade (SAM grade 1 + 2) and 318 patients with high-grade (SAM 3 + 4) supratentorial tumors were compared. RESULTS: Among low-grade tumors, most favorable were 5- and 10-year survival rates for patients with pilocytic astrocytomas, which were 85% and 79%, respectively. Median survival and 5- and 10-year survival rates for the other low-grade tumors were lower, and were proportionately improved by the presence of an oligodendroglial component: diffuse fibrillary astrocytomas-4.7 years, 46%, and 17%, oligodendroglioma-9.8 years, 73%, and 49%; and mixed oligo-astrocytoma-7.1 years, 63%, and 33%, respectively. For high-grade tumors, patients with either oligodendrogliomas or mixed oligo-astrocytomas had comparable favorable survivals in comparison to diffuse fibrillary astrocytomas. Median survivals and 5- and 10-year survival rates were 4.5 years, 45%, and 15% for the oligodendrogliomas and mixed oligo-astrocytomas versus 0.8 years, 3%, and 0% for the diffuse fibrillary astrocytomas, respectively. CONCLUSION: These survival data suggest that both low-grade and high-grade supratentorial gliomas have outcomes which are highly dependent upon histologic type.