Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme

Purpose: To report the results of a prospective Phase III trial for patient s with newly diagnosed glioblastoma multiforme (GBM), treated with either a ccelerated hyperfractionated irradiation with or without difluromethylornit hine (DFMO) or standard fractionated irradiation with or without DFMO. Methods and Materials: Adult patients with newly diagnosed GEM were registe red and randomized following surgery to one of 4 treatment arms: Arm A, acc elerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a to tal dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before r adiation until the last fraction was given; Arm C, single-fraction irradiat ion of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DEMO given as in Arm B, Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibil ity required histologically proven GEM, age greater than or equal to 18, Ka rnofsky performance status (KPS) greater than or equal to 60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this pr otocol. Results: A total of 231 eligible patients were enrolled, There were 95 men and 136 women with a median age of 57 years, and median KPS of 90, Extent o f resection was total in 23, subtotal in 152, and biopsy only in 56 patient s. The 4 arms were balanced with respect to age, KPS, and extent of resecti on, Times to event measurements are from date of diagnosis. Median OS and P FS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 wee ks for Arm C; and 34 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.3 2 for PFS), Comparison of the 2 arms treated with DFMO to the 2 arms withou t DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PF S and thus no benefit to the use of DEMO, Comparison of the 2 standard frac tionation arms to the 2 accelerated hyperfractionation arms also resulted i n no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. Conclusions: In this prospective Phase III study, no survival or PFS benefi t was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor w as any benefit seen with DEMO as a radiosensitizer. Standard fractionated i rradiation to 59.4 Gy remains the treatment of choice for newly diagnosed p atients with glioblastoma multiforme, (C) 2001 Elsevier Science Inc.