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BACKGROUND. Efforts to improve local control and survival by increasing the dose of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant gliomas have as yet been unsuccessful. Hyperfractionated radiation therapy (HF) should allow for delivery of a higher total dose without increasing normal tissue late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may minimize tumor repopulation by shortening overall treatment time. The Radiation Therapy Oncology Group (RTOG) conducted a randomized Phase I/II study of escalating doses of HF and AHF with carmustine (bis-chloroethyl nitrosourea [BCNU]) for adults with supratentorial glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and chronic treatment-related toxicity. METHODS. From 1983 to 1989, 786 patients with supratentorial gliomas (81% with GBM and 19% with AA) were stratified by histology, age, and performance status and randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All patients received carmustine. The distribution of prognostic factors was similar in all arms. RESULTS. There were 747 eligible and analyzable patients among 786 enrolled patients (95%). Two patients had a Grade 5 and 65 patients had a Grade 4 chemotherapy toxicity. Two patients in the 81.6 Gy arm experienced late Grade 4 radiation toxicity and there was 1 late radiation-associated death in the 54.4 Gy arm. The rate of Grade 3 or worse radiation toxicity at 5 years, calculated by the delivered dose level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8 and 81.6 Gy) (P = 0.54). Survival rates at 2 and 5 years were: 21% and 11%, respectively, for all patients; 62% and 41%, respectively, for AA patients; and 10% and 4%, respectively, for GBM patients. There were no significant differences between the treatment arms with regard to median survival time (MST), when analyzed by the originally assigned dose. The MST for all patients varied between 10.8 months and 12.7 months (P = 0.59); between 9.6 months and 11 months for patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose received rather than by dose assigned revealed a 14% 5-year survival rate for the lower HF doses (64.8 and 72 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 54.4 Gy)(P = 0.1). The subgroup of AA patients had a better MST (49.9 months) in the lower received HF doses than in the higher HF doses (34.6 months)(P = 0.35). In contrast, GBM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST of 11.6 months and 10.2 months, respectively; P = 0.04). CONCLUSIONS. The use of HF with BCNU and dose escalation up to 81.6 Gy is both feasible and tolerable, although late toxicity increases slightly with increasing dose. The best MST with the least toxicity were observed for AA in the lower received HF doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the investigational arm of a completed Phase III trial (RTOG 90-06).

Background. The third and final randomization of Radiation Therapy Oncology Group (RTOG) 83–02 was performed to identify the maximal tolerated dose and potential efficacy of accelerated hyperfractionated radiation therapy (AHRT) in 1.6 Gy twice-daily fractions for adult malignant glioma. Methods. From December 1987 to July 1989, 304 patients with malignant glioma were stratified by age, performance status, and histologic findings and randomized to receive total AHRT doses of 48.0 or 54.4 Gy, with 80 mg/m2 of bis-chlorethyl nitrosourea (BCNU) for 3 days every 8 weeks. Distribution of other prognostic factors, including neurologic function, extent of surgery, tumor size, and sex, was comparable in each treatment arm. Results. One Grade 5 radiation therapy (RT)-related toxic effect was reported (in the 54.4-Gy treatment arm), and the incidence of late Grade 3–5 RT-related toxic effects at 18 months was 1% at 48.0 Gy and 4% at 54.4 Gy. The median survival times (MST) for the 48.0 Gy and 54.4 Gy treatment arms were 11.7 and 10.8 months, respectively, comparable to the MST in prior RTOG trials with a similar proportion of patients with glioblastoma multi-forme (79%). For the 123 patients who were 60 years of age or older, the MST for the 48.0 Gy and 54.4 Gy treatment arms were 8.9 and 10.4 months, respectively, and compare favorably with the MST of 6.0 months reported with standard RT and BCNU treatment used for 101 patients who were 60 years of age or older in two prior RTOG malignant glioma trials (74–01 and 79–18). Although these results differ significantly (P < 0.0015), this contrast is not significant when adjusted by performance status. Conclusions. The maximum tolerated dose of AHRT has yet to be identified, and pursuit of this information may most benefit patients with malignant glioma who are 60 years of age or older.

BACKGROUND Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. PURPOSE This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. METHODS We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. RESULTS The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. CONCLUSIONS This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. IMPLICATIONS The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

Between January 1983 and November 1987, the Radiation Therapy Oncology Group conducted a prospective, randomized, multi-institutional, dose searching Phase I/II trial to evaluate hyperfractionated radiation therapy in the treatment of supratentorial malignant glioma. Patients with anaplastic astrocytoma, or glioblastoma multiforme, age 18-70 years with a Karnofsky performance status of 40-100 were stratified according to age, Karnofsky performance status, and histology, and were randomized. Initially randomization was to one of three arms: 64.8 Gy, 72.0 Gy, and 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week, with intervals of 4 to 8 hr. All patients received bis-chlorethyl nitrosourea (BCNU) 80 mg/m2 on days 3, 4, 5 of radiation therapy and then every 8 weeks for 1 year. After acceptable rates of acute and late effects were found, the randomization was changed to 81.6 Gy and 72.0 Gy with a weighting of 2:1. Out of 466 patients randomized, 435 were analyzed. The distribution of prognostic factors was comparable among the 76.8 Gy arm, 81.6 Gy arm, and the final randomization of the 72 Gy arm. The 64.8 Gy arm and the initial randomization of the 72 Gy arm had somewhat worse prognostic variables. Late radiation toxicity occurred in 1.3-6.8% of the patients, with a modest increase with increasing radiation dose. The best survival occurred in those patients treated with 72 Gy (median survival of 12.8 months overall, and 14 months for the final 72 Gy randomization). The Cox proportional hazards model confirmed the prognostic variables of age, histology and Karnofsky performance status. In addition, the longer interval of 4.5-8 hr was associated with a worse prognosis than the 4-4.4 hr interval (p = 0.0011). The difference in survival between the 81.6 Gy arm and the lower three arms approached significance (p = 0.078) with inferior survival observed in the 81.6 Gy arm. When therapy was evaluated by radiation therapy dose received (60-74.4 Gy compared with 74.5-84.0 Gy), the p value was 0.062 in favor of the lower dose range. Patients with anaplastic astrocytoma treated with 72 Gy by hyperfractionation + BCNU had at least as good a survival as those treated with 60 Gy by conventional fractionation + BCNU on Radiation Therapy Oncology Group protocols 7401 and 7918. This suggests that 72 Gy delivered by 1.2 Gy twice daily is no more toxic than 60 Gy delivered by conventional fractionation.

Fifty-four patients with Grade III or IV malignant glioma were treated with the hypoxic-cell radiosensitizer misonidazole, and radiation therapy (RT) in a Phase II trial of the Radiation Therapy Oncology Group (RTOG). The median survival was 39 weeks. Toxicity was acceptable. Almost all toxicities were reversible and self-limited. The were no significant changes in hematologic, hepatic or renal parameters. The median survival obtained is similar to the results with conventional radiotberapy. A Phase III trial is under way comparing standard radiation and BCNU chemotherapy (1,3-bis (2-chloroethyl)-1-nitrosourea) with sensitized radiation and chemotherapy (RT + misonidazole + BCNU). Additive toxicity between misonidazole and BCNU was not observed in a pilot group.

A randomized prospective study was performed to evaluate misonidazole radiosensitized radiation therapy in the treatment of malignant glioma. The control arm, Group A, consisted of conventional radiation therapy (6000 cGy/6-7 weeks) to the whole brain plus BCNU (80 mg/m2 on day 3, 4, 5, and then repeated q 8 weeks for 2 years). The BCNU schedule was identical in both arms. In the experimental arm, Group B, misonidazole 2.5 gm/m2 was given once a week for six weeks, to a total dose of 15 gm/m2. It was given orally four hours prior to 400 cGy on Mondays. On Tuesdays, Thursdays and Fridays, 150 cGy was delivered to a total of 5100 cGy/6 weeks. An additional 900 cGy/5F/1 week was given without misonidazole. Patients were stratified according to the prognostic factors of age, performance status, and histology. Distribution of these characteristics among the treatment groups was comparable. As of March 1, 1982, 245 patients were randomized with follow-up information available on 202 patients. The median follow-up is 12 months (range 3-39 months). There is no significant difference in the survival of the two groups. The median survival for Group A was 12.6, and for Group B, 10.7 months. Misonidazole toxicity included an 11% peripheral neuropathy and a 3% central nervous system toxicity. BCNU toxicity included severe hematologic toxicity in 25%, including one death, and significant pulmonary toxicity in 6 out of 55 patients who received a minimum total dose of 960 mg/m2 of BCNU.