Evaluating glioma therapies: modeling treatments and predicting outcomes.

BACKGROUND: Intra-arterial chemotherapy with carmustine (BCNU) and interstitial radiation therapy with the use of stereotactically placed 125I sources are aggressive local therapies for malignant glioma. These therapies emerged in the 1980s and both appeared promising in phase II studies but yielded disappointing results in subsequent randomized controlled trials by the Brain Tumor Cooperative Group (BTCG). Florell and colleagues had prepared us for the possibility that brachytherapy would have less impact on survival than anticipated from the phase II experience by demonstrating that patients who were judged eligible for interstitial radiation, but treated conventionally, lived significantly longer than those who were ineligible and had better than average outcomes. PURPOSE: To further examine the impact of patient selection on outcome, we used the database of Florell et al. to assess the survival of patients with malignant glioma who were eligible or ineligible for chemotherapy by three intra-arterial methods, one of which was similar to that employed by the BTCG in its randomized, controlled trial evaluating intra-arterial BCNU. METHODS: The medical records and computed tomography (CT) scans of 102 consecutive patients with malignant glioma receiving standard treatment (i.e., maximum feasible surgical resection, external-beam radiotherapy, and often adjuvant systemic chemotherapy) at a single cancer center in Canada during the calendar years 1988 and 1989 were used for this analysis. Based on CT imaging and blind to outcome, an interventional neuroradiologist decided which patients were eligible or ineligible for intra-arterial chemotherapy via injection of two major arteries, via injection of one major artery, or via selective middle-cerebral artery injection. A Karnofsky performance score of greater than or equal to 60 was required. The percent of eligible patients, the median survival time, and the distribution of prognostic factors were analyzed for each group of eligible and ineligible patients. Median survival times were compared with the use of the generalized Wilcoxon (Breslow) test. All P values were based on two-tailed tests. RESULTS: For two-vessel treatment, 72.5% of the patients (74 of 102) were eligible; the eligible patients on average lived longer than the ineligible patients (14.8 versus 3.5 months; P < .00001). For one-vessel treatment, 48% of the patients (49 of 102) were eligible; again, the eligible patients lived longer than the ineligible patients (18.4 versus 5.1 months; P < .00001). For middle-cerebral artery treatment, 30% of the patients (31 of 102) were eligible, and these eligible patients did live somewhat longer than the ineligible patients, but this result did not reach statistical significance (13.6 versus 9.9 months; P = .1304). Trends were similar for patients with glioblastoma multiforme and anaplastic glioma. The median duration of survival was 11.4 months for all patients. CONCLUSIONS: Patients who were eligible for intra-arterial chemotherapy lived significantly longer or somewhat longer (depending on the selection criteria used) than patients who were ineligible and had better than expected outcomes. Patients who were judged eligible for intra-arterial chemotherapy by the two-vessel method and the control group in the BTCG phase III trial of intra-arterial chemotherapy had similar median survival times (14.8 versus 14.0 months). IMPLICATIONS: Modeling treatments with the use of a comprehensive clinical and imaging database of unselected, conventionally treated patients may help investigators decide if new therapies warrant definitive evaluation in randomized trials by measuring the degree to which patient selection may have enhanced phase II study outcomes.

Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To examine the rate and duration of response of anaplastic oligodendrogliomas to a dose-escalated combination chemotherapy regimen consisting of procarbazine, lomustine (CCNU), and vincristine (PCV) and to evaluate the side effects of this treatment. METHODS: In this single-arm multicentered phase II study, patients with measurable, newly diagnosed or recurrent, contrast-enhancing anaplastic oligodendrogliomas were treated with up to six cycles of PCV. Central pathology and radiology review were mandatory, and rigorous response criteria based on imaging were used. RESULTS: Thirty-three patients entered the trial; nine were excluded subsequently, seven due to ineligible pathology. Eighteen of 24 eligible patients (75%) responded, nine completely (38%), four had stable disease (SD), and two progressed during the first cycle of PCV. Responses were observed in nine of 10 patients (90%) with a preexisting low-grade oligodendroglioma and 10 of 15 (67%) with necrotic tumors, called glioblastoma multiforme by some. Previously irradiated patients were as likely to respond to PCV as those newly diagnosed (11 of 15 [73%] v seven of nine [78%]). The median time to progression will be at least 25.2 months for complete responders, and was 14.2 months for partial responders and 6.8 months for stable patients. Four ineligible patients also responded to PCV; all had gliomas with oligodendroglial differentiation. All responders, eligible or ineligible, were stable or improved neurologically, but nine of 22 (41%) experienced a decline in Eastern Cooperative Oncology Group (ECOG) performance status of one grade while on PCV. Adverse events on treatment included a death from Pneumocystis pneumonia, a severe reversible encephalopathy due to procarbazine, an intratumoral hemorrhage, and a subdural hematoma. All other acute toxicities were anticipated and manageable. CONCLUSION: Anaplastic oligodendrogliomas are chemosensitive brain cancers. Patients with these tumors respond predictably, durably, and often completely to PCV, and many tolerate a dose-escalated formulation. Cooperative group and randomized trials will be necessary to explore fully the role of chemotherapy in the treatment of aggressive oligodendrogliomas.

Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea.

O6-Alkylguanine-DNA alkyltransferase (AT) is a cellular protein that protects cells from the cytotoxic effects of nitrosoureas by repairing alkyl lesions at the O6 position of guanine. We have studied the ability of O6-benzylguanine to deplete AT activity in brain tumor xenografts and thereby increase the sensitivity of these tumors to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In toxicity studies, pretreatment of athymic mice with O6-benzylguanine increased the toxicity of BCNU significantly. After i.p. injection of O6-benzylguanine into athymic mice carrying subcutaneous (s.c.) D341MED, a human medulloblastoma xenograft with a high AT activity, the AT activity of the tumors became undetectable within 1 h and remained depleted until 36 h. In s.c. xenografts to D341MED, treatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly greater growth delay (14.8 days) than was seen with BCNU alone (2.3 days). A lower pretreatment dose of O6-benzylguanine produced a significantly smaller therapeutic effect. Delaying the administration of BCNU until 36 h after O6-benzylguanine resulted in a growth delay (1.2 days) that was not significantly different from that produced by the control or BCNU alone. In athymic mice with intracranial (i.c.) xenografts of D341MED, pretreatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly increased survival as compared with that of the control, BCNU alone, O6-benzylguanine alone, and O6-benzylguanine followed 36 h later by BCNU. In experiments with s.c. xenografts of D245MG, a human glioma xenograft with undetectable AT activity, pretreatment with O6-benzylguanine 1 h prior to BCNU produced a significantly greater effect than was seen with BCNU treatment alone. The combination regimen, however, was not as effective as an equitoxic dose of BCNU alone. These studies suggest that O6-benzylguanine may be a useful adjuvant to nitrosourea therapy in human malignancies that exhibit a range of AT activities and that dose and timing are important variables in achieving therapeutic success. These data also indicate that therapeutic potentiation of BCNU by O6-benzylguanine can be achieved in i.c. tumors. As a result, this approach may be useful in the treatment of neoplasms of the central nervous system.

Intensive 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma.

Intensive monochemotherapy with carmustine (BCNU) (either 1,050, 1,200, or 1,350 mg/m2) and cryopreserved autologous marrow transplantation was administered to 36 patients with malignant glioma: 27 with progressive disease and nine without progression (adjuvant therapy group). Twelve (44%) of the patients with progressive disease responded; two remain disease free 84 and 60 months after BCNU treatment. In the adjuvant therapy group, three patients remain progression free at 70, 48, and 27 months after BCNU therapy. Tumor progression posttransplantation occurred in 25 patients; six others died of therapy-induced complications. In addition, late neurologic deterioration of unknown cause has developed in two surviving patients. Results from this and other series using intensive BCNU monochemotherapy and autologous marrow transplantation for progressive malignant glioma indicate that prolonged progression-free survival can be produced in an occasional patient, an extremely unusual result with conventional chemotherapy. Although intensive BCNU and autologous marrow transplant regimens are toxic, these results are encouraging. The treatment of patients in an adjuvant fashion with BCNU and other active agents may produce improved results.

Experience using two CT-guided stereotactic biopsy methods.

15 patients had intracranial CT-guided stereotactic biopsies. Biopsies were performed either with a Riechert-Mundinger stereotactic frame modified for use in the CT or by using the CT scan to establish the relationship of the intracranial lesion to identifiable bony landmarks, and subsequently performing the biopsy in a standard stereotactic frame. Both systems provided safe and accurate methods for obtaining intracranial tissue.

Cerebral mucormycosis: an unusual case.

A 36-year-old obese woman with hyperglycemia and immunosuppression died of bilateral internal carotid artery occlusion associated with mucormycosis. This report describes a rare case in which cerebral mucormycosis occurred without the usual preceding clinical evidence of nasal and orbital infection.

Cerebral hemorrhage from a mycotic aneurysm developing during appropriate antibiotic therapy.

A patient with bacterial endocarditis had headaches, cerebrospinal fluid pleocytosis and normal cerebral angiograms. Fifteen days later, while on appropriate antibiotic therapy, he developed an intracerebral hematoma due to a mycotic aneurysm. Mycotic aneurysm is an infrequent but serious complication of bacterial endocarditis. An aneurysm should be considered whenever a patient with bacterial endocarditis has neurologic symptoms even when the patient is receiving antibiotics.

Origin of seizures in elderly patients.

Among 50 previously well patients, aged 69 years or older, who had a first seizure, a cause could be identified in only 25 (50%). Cerebrovascular disease accounted for the seizures in 30% of the total group. Only one tumor was found. Treatable causes were found in 20%. In 25 patients (50%), a cause could not be identified. A total of 56% of the patients had focal motor seizures, and in 44%, the seizures were generalized. A definite cause could be established in 57% of those with focal seizure and in 41% of those with generalized seizures. These results are compared with previous surveys of adult-onset epilepsy and indicate a somewhat different etiologic distribution in elderly patients.