A controlled, prospective, randomized study evaluated the use of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or radiotherapy in the treatment of patients who were operated on and had histological confirmation of anaplastic glioma. A total of 303 patients were randomized into this study, of whom 222 (73%) were within the Valid Study Group (VSG), having met the protocol criteria of neuropathology, corticosteroid control, and therapeutic approach. Patients were divided into four random groups, and received BCNU (80 mg/sq m/day on 3 successive days every 6 to 8 weeks), and/or radiotherapy (5000 to 6000 rads to the whole brain through bilateral opposing ports), or best conventional care but no chemotherapy or radiotherapy. Analysis was performed on all patients who received any amount of therapy (VSG) and on the Adequately Treated Group (ATG), who had received 5000 or more rads radiotherapy, two or more courses of chemotherapy, and had a minimum survival of 8 or more weeks (the interval that would have been required to have received either the radiotherapy or chemotherapy). Median survival of patients in the VSG was, best conventional care: 14 weeks (ATG: 17.0 weeks); BCNU: 18.5 weeks (ATG: 25.0 weeks); radiotherapy: 35 weeks (ATG: 37.5 weeks); and BCNU plus radiotherapy: 34.5 weeks (ATG: 40.5 weeks). All therapeutic modalities showed some statistical superiority compared to best conventional care. There was no significant difference between the four groups in relation to age distribution, sex, location of tumor, diagnosis, tumor characteristics, signs or symptoms, or the amount of corticosteroid used. An analysis of prognostic factors indicates that the initial performance status (Karnofsky rating), age, the use of only a surgical biopsy, parietal location, the presence of seizures, or the involvement of cranial nerves II, III, IV, and VI are all of significance. Toxicity included acceptable, reversible thrombocytopenia and leukopenia.
Within three weeks of definitive surgical intervention, 467 patients with histologically proved malignant glioma were randomized to receive one of four treatment regimens: semustine (MeCCNU), radiotherapy, carmustine (BCNU) plus radiotherapy, or semustine plus radiotherapy. We analyzed the data for the total randomized population and for the 358 patients in whom the initial protocol specifications were met (the valid study group). Observed toxicity included acceptable skin reactions secondary to radiotherapy and reversible leukopenia and thrombocytopenia due to chemotherapy. Radiotherapy used alone or in combination with a nitrosourea significantly improved survival in comparison with semustine alone. The group receiving carmustine plus radiotherapy had the best survival, but the difference in survival between the groups receiving carmustine plus radiotherapy and semustine plus radiotherapy was not statistically significant. The combination of carmustine plus radiotherapy produced a modest benefit in long-term (18-month) survival as compared with radiotherapy alone, although the difference between survival curves was not significiant at the 0.05 level. This study suggests that it is best to use radiotherapy in the post-surgical treatment of malignant glioma and to continue the search for an effective chemotherapeutic regimen to use in addition to radiotherapy.
Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.
Within 3 weeks of definitive surgery, 571 adult patients with histologically confirmed, supratentorial malignant gliomas were randomly assigned to receive one of three chemotherapy regimens: BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) alone, alternating courses (every 8 weeks) of BCNU and procarbazine, or BCNU plus hydroxyurea alternating with procarbazine plus VM-26 (epipodophyllotoxin). Patients accrued in 1980 and 1981 were to receive 6020 rads of whole-brain radiotherapy concurrent with the first course of chemotherapy. Patients accrued in 1982 and 1983 were randomly assigned to receive either whole-brain irradiation as above, or 4300 rads of whole-brain radiotherapy plus 1720 rads coned down to to the tumor volume. The data were analyzed for the total randomized population and separately for the 510 patients, termed the "Valid Study Group (VSG)," who met protocol eligibility specifications (including central pathology review), 80% of whom had glioblastoma multiforme. The median survival times from time of randomization for the three chemotherapy groups of the VSG ranged from 11.3 to 13.8 months, and 29% to 37% of the patients survived for 18 months (life-table estimate); the differences between these groups were not statistically significant. Survival differences between the radiotherapy groups were small and not statistically significant. It is concluded that, for malignant glioma, giving part of the radiotherapy by coned-down boost is as effective as full whole-brain irradiation, and that multiple-drug chemotherapy as outlined in this protocol conferred no significant survival advantage over BCNU alone.
An excellent response by participating institutions was realized in this survey of patterns of care for patients with primary brain tumors. Since the histopathology of the tumor is such a strong predictor of outcome and influences care so greatly, most analyses were performed not only on the overall series of patients but also by World Health Organization histological classification. Several factors that influence outcome were identified: tumor type, patient age, patient Karnofsky rating, tumor location, and therapy. Very few cases were coded as regards the American Joint Committee on Cancer clinical stage, and few potentially eligible cases were placed in investigative protocols. It behooves those centers providing investigative protocol opportunities to develop liaisons with practicing physicians nearby as well as at some distance and to provide an organizational framework that will make participation in these protocols practical for a larger segment of our brain-tumor patient population. Between 1980 and 1985, the increased use of magnetic resonance imaging in neuroradiology is apparent as well as the increased use of stereotactic biopsy and interstitial radiotherapy. Complications of therapy seem acceptably low. Five-year survival for benign brain tumor is high, while that for the most common primary tumor, glioblastoma multiforme, is only 5.5%. Some of the findings in this survey confirm those from the literature while others, particularly the pattern of care, represent new data.
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