There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: Results ofa pediatric oncology group phase III trial comparing conventional vs. hyperfractionated radiotherapy

Purpose: In June 1992, FOG began accrual to a phase III study, POG-9239, de signed to compare the time to disease progression, overall survival, and to xicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m(2) of infusional cisplatin and randomized to either conventio nal vs. hyperfractionated radiotherapy. Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pens. Hist ologic confirmation of diagnosis was not mandatory, provided that the clini cal and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiothera py with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose esca lation levels of POG-8495) (arm 2). Because of previously reported poor res ults with conventional radiotherapy alone, cisplatin was included as a pote ntial radiosensitizer in an attempt to improve progression-free and ultimat e survival rates. Based on results of the phase 1 cisplatin dose escalation trial, POG-9139, 100 mg/m(2) was chosen for this trial and was delivered b y continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligibl e patients were treated on protocol, 66 on arm 1 and 64 on arm 2. Results: The results we report are from time of diagnosis through October 1 997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2-15 months) and the med ian time to death 8.5 months (range 3-24 months); survival at 1 year was 30 .9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1-12 months) and 8 months (range 1-23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluati on of response by MRI at 4 or 8 wks post treatment was available in 108 pat ients and revealed a complete response in 1 patient of each Rx arm, a parti al response (> 50% decrease in size) in 18 patients of arm 1 and 15 patient s of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 p atients of arm 2. The pattern of failure was local in all patients. Morbidi ty of treatment was similar in both Rx arms, with no significant toxicity ( including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases. Conclusion: The major conclusion from this trial is that the hyperfractiona ted method of Rx 2 did not improve event-free survival (p = 0.96) nor did i t improve survival (p = 0.65) over that of the conventional fractionation r egimen of Rx 1, and that both treatments are associated with a poor disease -free and survival outcome. (C) 1999 Elsevier Science Inc.