A Randomized Trial of Short-Course Versus Conventional Radiotherapy With Concomitant and Adjuvant Temozolomide in Patients 18 to 70 Years of Age With Glioblastoma

Abstract

<h3>Purpose/Objective(s)</h3> Patients 70 years old or younger with good performance status with glioblastoma often are treated with radiotherapy (RT) over 6 weeks with concurrent and adjuvant temozolomide. Whether short-course hypofractionated RT using the same total dose over a shorter time has similar clinical efficacy without increased toxicity is presently not known. Primary objective was to compare outcomes between conventional and short-course RT regimens. <h3>Materials/Methods</h3> We conducted a randomized noninferiority trial for patients aged 18-70 years with histologically confirmed, newly diagnosed glioblastoma and ECOG 0-2. Patients were randomized in a 1:1 ratio, stratified by extent of surgical resection, to conventional RT of 60 Gy in 30 fractions over 6 weeks or short-course RT of 60 Gy in 20 fractions over 4 weeks, with concomitant and maintenance temozolomide in both arms. Primary endpoint was overall survival defined as time from randomization until death. Secondary endpoints included acute and late toxicity graded according to NCI CTCAE version 4.0, and patient-reported quality of life assessed by EORTC QLQ-C30 and QLQ-BN20 questionnaires. Survival outcomes were analyzed by intention to treat. Noninferiority margin was 14.5% (hazard ratio, < 1.57). <h3>Results</h3> One hundred thirty-three patients were randomized to short-course arm (n = 68) or conventional arm (n = 65). Median age was 58 years (range 24-70); 69% male; 91% had ECOG 0-1; 88% had resection. In prospective molecular analysis of suitable specimens, IDH1 mutation was seen in 13/131 patients (9.9%) and MGMT promotor methylation in 68/126 patients (54.0%). Age (< 60 vs. ≥60 years), ECOG (0-1 vs. 2), extent of resection (resection vs. biopsy), IDH1 status (wildtype vs. mutated), MGMT status (methylated vs. unmethylated), and extent of disease (unifocal vs. multifocal) were not different between two arms. Median overall survival was 14.4 months (95% CI 12.7 – 16.1 months) in the short-course arm; 11.0 months (95% CI 9.2 – 12.8 months) in the conventional arm (HR 0.94, 95% CI 0.64 – 1.38, <i>P</i>-value for superiority = 0.751, <i>P</i>-value for non-inferiority < 0.01). In 97 patients without multifocal disease, median overall survival was 15.3 months (95% CI 13.0 - 17.7 months) in the short-course arm; 11.8 months (95% CI 9.4 -14.2 months) in the conventional arm (HR 0.95, 95% CI 0.62 – 1.46, <i>P</i> = 0.816). With median follow-up time of 18.7 months, no significant differences were detected between arms for any grade ≥2 toxicity. No patients had reoperation for radionecrosis in the short-course arm. In the conventional arm, one patient had reoperation for radionecrosis. Quality of life between both arms at the end of RT, and at 12 weeks and 16 weeks post-RT was not different. <h3>Conclusion</h3> The short-course RT regimen used in this trial was not inferior to conventional RT and was not associated with increased toxicity or reduced quality of life. Short-course RT is more convenient for patients and may be recommended as a treatment option for patients 70 years old or younger with newly diagnosed glioblastoma.