The evidence supporting the use of this protocol comes from the phase III trials by Perry et al. (2017), Malmstrom et al. (2012), Wick et al. (2012) and Roa et al. (2015) and the Canadian phase II RCT by Roa et al. (2004).rrrrr These studies demonstrate equivalent or improved overall survival when using hypofractionated RT.
There has been considerable uncertainty around the management of older patients with glioblastoma due to length of standard treatment schedules and the shorter overall survival expected in these patients. Hypofractionation schedules have shown similar median survival rates and quality of life in the elderly and those patients with borderline performance status with high grade glioma (HGG) when compared to the conventional 60Gy six week course.rrr
Hypofractionated RT vs conventional fractionation RT vs temozolomide alone
The Nordic phase III RCT by Malmstrom et al. (2012) enrolled 342 patients, of whom 291 were randomised to one of three treatment groups to receive either 6 cycles of temozolomide (TMZ) (n=93), hypofrationated RT (34Gy in 10#, n=98) or standard RT (60Gy in 30#, n=100) and 51 of whom were randomised across only two groups to receive either TMZ alone or hypofractionated RT.r
With the three-group randomisation, in comparison with standard RT, median overall survival was significantly longer with TMZ (8.3 months [95%CI: 7.1-9.5]; n=93) versus standard RT (6.0 months [95% CI: 5.1-6.8]; n=100), hazard ratio (HR) 0.70; (95% CI: 0.52-0.93, p=0·01). Overall median survival was not significantly longer with TMZ versus hypofractionated RT (7.5 months [95% CI: 6.5-8.6]; n=98), HR 0.85 [95% CI: 0.64-1.12] (p=0.24). Overall survival was similar for all patients who received TMZ or hypofractionated RT (n=242), 8.4 months ([95% CI: 7.3-9.4]; n=119) versus 7.4 months ([95% CI: 6.4-8.4]; n=123); HR 0.82, (95% CI: 0.63-1.06; p=0.12) respectively.
For patients aged older than 70 years, survival was better in both the TMZ and hypofractionated RT arms than in the standard RT arm; HR for TMZ versus standard RT 0.35 (95% CI: 0.21-0.56, p<0.0001), and HR for hypofractionated RT versus standard RT 0.59 (95% CI: 0.37-0.93, p=0.02).
Malmstrom et al. (2012) concluded that standard RT was associated with poor outcomes, especially in patients older than 70 years, and furthermore that both TMZ and hypofractionated RT should be considered as viable treatment options in elderly patients with glioblastoma.r
In contrast, the NOA-8 study randomised 373 patients older than 65 years, with anaplastic astrocytoma or glioblastoma, and Karnofsky performance score ≥60 to either 100mg/m2 TMZ (1 week on/1 week off schedule), or RT (60Gy in standard daily fractionation).r Median survival was 8.6 months (95% CI: 7.3-10.2) in the TMZ group versus 9.6 months (95% CI: 8.2-10.8) in the RT group (HR 1.09, [95% CI: 0.84-1.42], non-inferiority=0·033). Event free survival (EFS) was longer in patients with MGMT promoter methylation who received TMZ than in those who underwent RT (8.4 months vs 4.6 months). Patients with no methylation of the MGMT promoter had longer EFS with RT alone than in those who received TMZ (4.6 months vs 3.3 months).
Hypofractionated RT + temozolomide vs hypofractionated RT alone
The evidence supporting the addition of concurrent and adjuvant TMZ to hypofractionated RT comes from a multicentre, randomised, phase III trial in patients who had a newly diagnosed histologically confirmed glioblastoma (WHO grade IV).r In this trial, 562 patients aged 65 years or older, with an ECOG performance status of 2 or less, who were deemed not suitable for conventional combined chemoradiotherapy were randomised to RT alone (40.05Gy in 15#) or the same dose of RT with concurrent TMZ at a dose of 75 mg/m2/day for 21 consecutive days from the first day of radiation. This was followed by up to 12 cycles of adjuvant TMZ at 150-200 mg/m2/day on days 1 to 5 every 28 days.r The primary end point was overall survival with a secondary end point of progression free survival.
Median overall survival was longer in the RT plus TMZ group than in the RT alone group (9.3 months versus 7.6 months, HR for risk of death 0.67, (95% CI: 0.56-0.80, P<0.001). Progression free survival was longer in the RT plus TMZ group compared to RT alone (5.3 months versus 3.9 months, HR for disease progression or death 0.50, (95% CI: 0.41-0.60, P<0.001). The benefit of RT plus TMZ was seen in both methylated and unmethylated MGMT status patients. MGMT methylated status patients had a median survival of 13.5 months in the RT plus TMZ group, versus 7.7 months with RT alone (HR 0.53, [95% CI: 0.38-0.73], P<0.001). Unmethylated MGMT status patients had a clinically meaningful overall survival advantage which did not reach statistical significance in the RT plus TMZ group with a median survival of 10 months versus 7.9 months with RT alone (HR 0.75, [95% CI: 0.56-1.01], P=0.055).r
Figure 1: Overall survivalr