Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis.

Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3-4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7-10.2); oligoastrocytoma, 4.4 years (95% CI 3.5-5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2-4, 2.1 years) (95% CI 1.7-2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5-1.1 vs. 0.6 years, CI: 0.5-1.0 vs. 1.4 years, 95% CI: 1.1-2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.

Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Phase II evaluation of carboplatin in advanced endometrial carcinoma.

Carboplatin was administered by iv bolus every 28 days to 26 patients who had extensive metastatic or recurrent endometrial adenocarcinoma and no prior chemotherapy exposure. The dose level was 400 mg/m2 in 5 patients with and 4 patients without prior irradiation and 300 mg/m2 in 16 patients with prior pelvic irradiation. Partial disease regressions were seen in 28% of patients (95% confidence interval, 12%-50%), with a median response duration of 129 days. Median survival of all patients was 215 days; median time to disease progression for all patients was 117 days. We conclude that carboplatin is an active agent in advanced endometrial carcinoma and is worthy of further investigation in single-agent and combination chemotherapy.

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.

Phase I study of difluoromethylornithine in combination with recombinant alpha 2a-interferon.

24 patients with advanced, histologically proven cancer were treated with difluoromethylornithine 2.25 g/m2 orally every 6 h for the first 7 days of each 4-week treatment cycle. These patients also received daily i.m. doses of recombinant human alpha 2a-interferon (IFN) on Days 3 through 7 of each cycle. IFN doses of 3, 6, 12, 24, 36, and 48 X 10(6) units/m2 have been studied utilizing three patients at each daily dose level. Three additional patients have been observed at each of the two highest doses for better toxicity definition. This combination produced slight transient declines in leukocyte and platelet counts and transient rises in serum aspartate aminotransferase; however, these changes were no more pronounced at the higher IFN doses than at daily doses of 6 X 10(6) units/m2. Mild nausea and vomiting occurred in most patients and mild diarrhea also was common at all IFN dose levels. Chills, fever, myalgia, lethargy and fatigue, and anorexia were also observed at all IFN doses; however, lethargy and fatigue (lassitude) seemed to be the major factor which limited patient tolerance of IFN to 48 X 10(6) units/m2 daily. No ototoxicity was identified clinically or audiometrically and no life-threatening toxicity has occurred. Initial Phase II studies in melanoma are currently in progress.

QOL and Survival Comparisons by Race in Oncology Clinical Trials.

BACKGROUND: Significant efforts have been made to increase access and accrual to clinical trials for minority cancer patients (MP). This meta-analysis looked for differences in survival and baseline quality of life (QOL) between MP and non-minority cancer patients (NMP). MATERIALS AND METHODS: Baseline QOL and overall survival times from 47 clinical trials (6513 patients) conducted at Mayo Clinic Cancer Center/North Central Cancer Treatment Group were utilized. Assessments included Uniscale, Linear Analogue Self Assessment, Symptom Distress Scale (SDS), Profile of Mood States and Functional Assessment of Cancer Therapy - General, each transformed into a 0-100 scale with higher scores indicating better outcomes. This transformation involves subtracting the lowest possible value from the assessment, dividing by the range of the scale (the maximum minus the minimum), and multiplying by 100. Analyses included Fisher's Exact tests, linear regression, Kaplan-Meier curves, and Cox proportional hazards models. RESULTS: Eight percent of patients self-reported as MP (0.45% American Indian/Alaskan Native, 0.7% Asian, 5% Black/African American, 1.5% Hispanic, 0.1% Native Hawaiian and 0.3% Other). MP had no meaningful deficits relative to non-MP in overall QOL but were slightly worse on FACT-G total score, physical, social/family, functional, and SDS nausea severity. MP with lung, neurological or GI cancers had significantly worse mean scores in nausea (58 vs. 69), sleep problems (34 vs. 54); emotional (53 vs. 74); and social/family (60 vs. 67), respectively. Regression models confirmed these results. After adjusting for disease site, there were no significant differences in survival. CONCLUSION: MP on these clinical trials indicated small deficits in physical, social, and emotional subscales at baseline compared to NMP. Within cancer sites, MP experienced large deficits for selected QOL domains that bear further attention.

Effective chemotherapy for advanced CNS embryonal tumors in adults.

PURPOSE: Embryonal tumors of the CNS include, among others, medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors (PNETs). Almost all data on the treatment of embryonal CNS tumors are derived from the pediatric population, since these tumors are uncommon in adulthood. The purpose of this study was to examine the rate and duration of response to chemotherapy of advanced embryonal CNS tumors in adults. PATIENTS AND METHODS: We retrospectively studied all adult (> 18 years of age) patients with advanced embryonal tumors of the CNS who received chemotherapy at our institution between 1976 and 1994. Seventeen consecutive patients were treated with regimens that contained either nitrosourea or cisplatin or both sequentially, with no patients having received the combination of nitrosourea and cisplatin concurrently. RESULTS: In patients who received cisplatin-based chemotherapy, responses were observed in 84.5% (26% complete response [CR] rate), 10.5% remained stable, and 5% progressed. The median time to progression was 18 months for patients who had a CR, 6 months for those with partial response (PR), and 10 months for stable patients. Among patients who received nitrosourea-based chemotherapy, PR was observed in 27%, 36.5% remained stable, and 36.5% progress. The median time to progression was 6 months for patients who had a PR and 6.5 months for stable patients. CONCLUSION: In adults with advanced embryonal CNS tumors, conventional-dose intravenous cisplatin-based chemotherapy regimens are able to produce responses in the majority of the patients (84.5%), even as second- or third-line regimens. Nitrosourea-based regimens less frequently produce responses (27%).

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 III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma.

PURPOSE: We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and PCNU with those of RT and carmustine (BCNU) in patients with malignant glioma. PATIENTS AND METHODS: A total of 346 patients with histologically verified supratentorial grade 3 and grade 4 astrocytoma were studied. After surgery, patients were randomly assigned to receive RT 60 Gy in 30 fractions and either PCNU 100 mg/m2 or BCNU 200 mg/m2 every 7 weeks for 1 year and every 10 weeks for the second year. RT and chemotherapy were started within 72 hours of randomization and usually on the same day. Of 334 assessable patients, 72% had partial or radical resection and 71% had grade 4 tumors. Median age was 59 years, and 85% had performance scores of 0 to 2 (Eastern Cooperative Oncology Group [ECOG]). The follow-up duration of 51 living patients ranged from 10.3 to 63.2 months, with a median of 36.2 months. RESULTS: The median survival duration in each group was 47 weeks, and median time to progression was 28 weeks. PCNU produced significantly more leukopenia and thrombocytopenia, whereas BCNU produced significantly more nausea, vomiting, and irritation. CONCLUSION: PCNU has no therapeutic advantage at this dose and schedule and does not warrant further study as a single agent for patients with high-grade glioma.

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.

Phase II trial of nitrogen mustard, vincristine, and procarbazine in patients with recurrent glioma: North Central Cancer Treatment Group results.

PURPOSE: Previous investigators have reported responses in 52% of patients treated with mechlorethamine (nitrogen mustard), vincristine, and procarbazine (MOP) for recurrent glioma. To confirm these promising results, we conducted a phase II prospective study. PATIENTS AND METHODS: Sixty-three patients with histologic confirmation of recurrent glioma were treated with the MOP regimen. Patients with or without prior chemotherapy received nitrogen mustard 3 mg/m2 or 6 mg/m2, respectively, intravenously on days 1 and 8 plus vincristine 2 mg/m2 intravenously on days 1 and 8, and procarbazine 100 mg/m2 orally on days 1 to 14. Cycles were repeated every 28 days. RESULTS: Of 61 patients assessable for response, eight responded (13%), with one complete response (CR). Responses were as follows: low-grade gliomas, 19%; anaplastic astrocytomas, 11%; anaplastic oligodendrogliomas or oligoastrocytomas, 25%; and glioblastomas, 4.3%. The most common toxicity was myelosuppression with leukocyte nadirs less than 1,000/microL in 23% and platelet nadirs less than 25,000/microL in 13% of patients. Two patients died of infection in the setting of neutropenia. Nonhematologic toxicity included neurosensory changes in 21% of patients (severe in 3%) and severe dermatologic reactions in 8%. In multivariate analysis, Eastern Cooperative Oncology group (ECOG) performance status (PS) was the best predictor for response to chemotherapy (P=.01) and time to progression (P=.008), while PS and grade were the most important predictors of survival (P=.002 and .05, respectively). CONCLUSION: This study did not confirm the high response rate previously reported in recurrent gliomas. Patients with recurrent anaplastic oligodendrogliomas or oligoastrocytomas and recurrent low-grade gliomas had the highest response rates (25% and 19%, respectively). In multivariate analysis, ECOG PS was the best predictor of response, while PS and tumor grade were the most important predictors of survival.

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.

Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer.

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1-2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Prevalence of mental health and substance use disorders among homeless and low-income housed mothers.

OBJECTIVE: This study compared the prevalence of DSM-III-R disorders among homeless and low-income housed mothers with the prevalence of these disorders among all women in the National Comorbidity Survey. METHOD: The authors used an unmatched case-control design for assessing 220 homeless and 216 housed mothers receiving public assistance. RESULTS: Homeless and housed mothers had similar rates of psychiatric and substance use disorders. Both groups had higher lifetime and current rates of major depression and substance abuse than did all women in the National Comorbidity Survey. Both groups also had high rates of posttraumatic stress disorder and two or more lifetime conditions. CONCLUSIONS: The prevalence of trauma-related disorders among poor women was higher than that among women in the general population. Programs and policies designed for low-income mothers must respond to the high prevalence of DSM-III-R disorders.

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma.

PURPOSE: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done. METHODS AND MATERIALS: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily x 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m2 days 1-3, cisplatin 30 mg/m2 days 1-3 and 29-31, and etoposide 50 mg orally days 1-14 and 29-42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m2 every 8 weeks x 4 cycles was given after radiation therapy. RESULTS: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3-4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m2 days 1-3, cisplatin 20 mg/m2 days 1-3 and 29-31, and oral etoposide 50 mg days 1-21 and 29-49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m2 every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 microg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean +/- SD 2 hr and 6 hr plasma concentrations were 0.92 +/- 0.43 microg/ml and 0.36 +/- 0.12 microg/ml, respectively. Estimated duration of exposure to >0.1 microg/ml etoposide was 10-17 hr. CONCLUSIONS: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.

Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma.

PURPOSE: A Phase I study to determine the safety, toxicity, and maximum tolerated dose (MTD) of carmustine (BCNU) and interferon alpha-2a (IFN-a) when combined with radiation as initial therapy in high-grade glioma. METHODS AND MATERIALS: Patients with newly diagnosed Grade 3 or 4 astrocytoma, oligoastrocytoma, or gliosarcoma were enrolled after surgery. All received radiation therapy to the brain (64.8 Gy/36 fractions), combined with a single dose of BCNU (200 mg/m2) at the start of radiation. Chemotherapy after completing radiation consisted of BCNU 150 mg/m2 once every 7 weeks, and IFN-a 12 x 10(6) units/m2 subcutaneously Days 1-3 each week of a 7-week cycle. Subsequent dose modification was based on constitutional symptoms for IFN-a and on myelosuppression for BCNU. RESULTS: Fifteen patients were entered on the study. Four were excluded because they did not receive IFN-a (3 refused treatment and 1 patient left the study due to multiple medical problems). Eleven were evaluable for toxicity and efficacy. Nonhematological toxicity, mainly lethargy and flu-like symptoms, were dose-limiting for IFN-a. After the first 6 patients were treated per the initial protocol, the frequency of IFN-a administration was decreased to Days 1-3 on weeks 1, 3, and 5 of the 7-week cycle for 5 additional patients. Lethargy, fever, chills, myalgias, alopecia, and anorexia occurred in all patients. Other toxicities included nausea and vomiting (91%), central-nervous-system depression or mood changes (64%), headaches (55%), and elevation of liver enzymes (36%). Grade 3-4 leukopenia occurred in 4 (45%) of 11 patients, and Grade 3-4 thrombocytopenia in 3 (27%) of 11 patients. Due to myelosuppressive effects, BCNU dose was not escalated. Median survival of the cohort was 44 months. Objective responses occurred in 5 (56%) of 9 patients and median duration of response was 33 months. The MTD of this combination after radiation therapy is IFN-a 12 x 10(6) units/m2 Days 1-3, on Weeks 1, 3, and 5 of a 7-week cycle and BCNU 150 mg/m2 Day 1, every 7 weeks. CONCLUSIONS: Treatment with radiation, IFN-a, and BCNU is feasible and effective in patients with high-grade gliomas, although constitutional symptoms from IFN-a are substantial.

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Brain metastatic lesions.

OBJECTIVE: To describe current concepts in the diagnosis and treatment of brain metastases. RESULTS: More than 25% of all autopsy-proven brain metastases have a pulmonary source. Most brain metastases manifest with a combination of focal and generalized symptoms and signs. Typically, patients have subacute, progressive symptoms. In most situations, a computed tomographic scan of the head provides sufficient neuroimaging and allows one to monitor the effects of therapy. Magnetic resonance imaging has become increasingly useful in the diagnosis and management of brain metastases. It can detect computed tomographic occult metastases, identify associated leptomeningeal disease, and reveal early therapeutic complications. CONCLUSION: Treatment options for patients with brain metastases include corticosteroids, whole-brain radiation therapy (WBRT), surgical intervention, stereotactic radiosurgical techniques, and chemotherapy. Corticosteroids produce prompt improvement in most patients; however, prolonged use is associated with considerable risks. For most patients, WBRT is the preferred treatment. Nonetheless, it has associated nonneurologic and neurologic complications, some of which are serious. In patients with a single metastasis, surgical removal should be considered. Recent studies have suggested that resection of a single metastatic lesion followed by radiation therapy offers better survival than does radiation therapy alone. The subsequent administration of WBRT after radiosurgical treatment has become standard practice. The role of chemotherapy is uncertain.

Thromboembolism in patients with high-grade glioma.

OBJECTIVE: To identify factors related to increased or decreased risk of thromboembolism (TE) in patients with high-grade glioma. DESIGN: We performed a retrospective analysis of 64 patients enrolled in two prospective clinical trials of chemotherapy and radiation therapy for newly diagnosed high-grade glioma. MATERIAL AND METHODS: The 64 patients were 18 years of age or older and had histologically confirmed grade 3 or 4 astrocytoma, mixed astrocytoma-oligodendroglioma, or gliosarcoma. The diagnosis of TE was confirmed by impedance plethysmography, venography, duplex ultrasonography, ventilation-perfusion lung scanning, or pulmonary angiography. For statistical analysis, the study group was divided into those with and those without TE. RESULTS: TE developed in 18 of the 64 patients (28%). Of the 18 patients, 11 had deep venous thrombosis of a lower extremity, 5 had pulmonary emboli, and 2 had superficial thrombophlebitis. A paretic arm (P = 0.017), a paretic leg (P = 0.026), or a history of TE before the diagnosis of glioma (P = 0.076) was more common in patients with TE than in those without TE. Ten patients in the group without TE were using aspirin preoperatively in comparison with no patient in the TE group (P = 0.05). No significant differences were noted in duration of survival (median, 39.4 weeks and 46 weeks for the TE and non-TE groups, respectively). One patient with apparently excessive anticoagulation had a fatal intracerebral hemorrhage. CONCLUSION: This study suggests that TE in patients with newly diagnosed high-grade glioma might be associated with a history of TE or with a paretic extremity; however, no evidence of worse survival was noted in the TE group. Treatment with heparin followed by warfarin sodium was associated with infrequent bleeding complications. An intriguing finding was that the use of aspirin before operation was associated with a decreased risk of TE. Thus, a prospective study with use of aspirin in patients with high-grade glioma at risk for TE would be reasonable.