FINAL REPORT OF A PHASE I II TRIAL OF HYPERFRACTIONATED AND ACCELERATED HYPERFRACTIONATED RADIATION-THERAPY WITH CARMUSTINE FOR ADULTS WITHSUPRATENTORIAL MALIGNANT GLIOMAS - RADIATION-THERAPY ONCOLOGY GROUP-STUDY 83-02/

BACKGROUND, Efforts to improve local control and survival by increasin g the dose of once-daily radiation therapy beyond 70 Gray (Gy) for pat ients with malignant gliomas have as yet been unsuccessful. Hyperfract ionated radiation therapy (HF) should allow for delivery of a higher t otal dose without increasing normal tissue late effects, whereas accel erated hyperfractionated radiation therapy (AHF) may minimize tumor re population by shortening overall treatment time. The Radiation therapy Oncology Group (RTOG) conducted a randomized Phase I/II study of esca lating doses of HF and AHF with carmustine (bis-chloroethyl nitrosoure a [BCNU]) for adults with supratentorial glioblastoma multiforme (GEM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and chronic treatment-related toxicity. METHODS, Fr om 1983 to 1989, 786 patients with supratentorial gliomas (81% with GE M 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 re ceived carmustine. The distribution of prog nostic 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 la te 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 do se 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 do se 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%, respe ctively, for AA patients; and 10% and 4%, respectively, for GEM patien ts. There were no significant differences between the treatment arms w ith regard to median survival time (MST), when analyzed by the origina lly 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 pati ents with GEM (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 pa tients 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 th e higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 5 4.4 Gy)(P = 0.1). The subgroup of AA patients had a better MST (49.9 m onths) in the lower received HF doses than in the higher HF doses (34. 6 months)(P = 0.35), In contrast, GEM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST o f 11.6 months and 10.2 months, respectively; P = 0.04). CONCLUSIONS, T he use of HF with BCNU and dose escalation up to 81.6 Gy is both feasi ble and tolerable, although late toxicity increases slightly with incr easing 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 i n two 1.2 Gy fractions was used as the investigational arm of a comple ted Phase III trial (RTOG 90-06). In contrast, for GEM patients, longe r survival times were noted in the higher received HF doses (76.8 and 81.6 Gy), suggesting the role for further dose escalation. The low tox icity rate with AHF arms suggest that further dose escalation is possi ble and is currently occurring in RTOG 94-11. (C) 1996 American Cancer Society.