Efficacy
The evidence supporting the use of this protocol comes from the phase III trials by Perry et al., Malmstrom et al., and Roa et al. and the Canadian phase II RCT by Roa et al.rrrr These studies demonstrate equivalent or improved overall survival when using hypofractionated radiation therapy.
Fractionation schedules
There has been considerable uncertainty around the optimal management of older patients with glioblastoma due to the length of standard treatment schedules and the shorter overall survival expected in these patients. Hypofractionated 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 when compared to the conventional 60 Gy six week course.rrr
Conventionally fractionated radiation therapy versus hypofractionated radiation therapy
Prospective validated hypofractionated radiation therapy regimens were derived from the following studies:
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IAEA phase III RCTr
- Between 2010 and 2018, 98 patients defined as being frail and/or elderly (age >50 years with KPS 50-70; or age >65 years with KPS 60+) were randomised to 40 Gy in 15 fractions (n = 50) versus 25 Gy in 5 fractions (n = 48).
- There were no differences in overall survival between arms 40 Gy (median = 6.4 months) and 25 Gy (median = 7.9 months) (p = 0.988), and no differences in the median progression free survival (4.2 months versus 4.2 months, p = 0.716).
- This 1 week fractionation schedule may be considered in patients who are unable to tolerate 2-3 weeks of hypofractionated radiation therapy.
- Nordic phase III trialr
- Between 2000 and 2009, 291 patients aged >60 years were randomised to temozolomide (TMZ) alone (200 mg/m2 day 1-5, every 28 days for up to 6 cycles) (n = 93) versus 34 Gy in 10 fractions over 2 weeks (n = 98) versus standard 60 Gy in 30 fractions (n = 100).
- Overall, there were no significant differences in the median overall survival between the two radiation therapy arms (6.0 months in 60 Gy arm versus 7.5 months in 34 Gy arm, p = 0.24).
- In the patient subgroup aged >70 years, 34 Gy was associated with improved overall survival compared to 60 Gy (7.0 months versus 5.2 months, HR = 0.59, 95%CI:0.37-0.93, p = 0.02)
- Canadian phase II RCTr
- Between 1996 and 2001, 100 patients aged >60 years with Karnofsky performancce status (KPS) >50 were randomised to 60 Gy in 30 fractions (n = 47) versus 40 Gy in 15 fractions (n = 48).
- There were no differences in overall survival between arms 60 Gy (median = 5.1 months) and 40 Gy (median = 5.6 months) (p = 0.57), no differences in the KPS scores, and less corticosteroid requirement in those treated with a hypofractionated course (23% versus 49%; p = 0.02).
Hypofractionated radiation therapy alone versus temozolomide alone
Hypofractionated radiation therapy was also compared with TMZ monotherapy in the Nordic phase III trial.r Median overall survival was significantly longer in the TMZ arm compared to 60 Gy arm (8.3 months versus 6.0 months, p = 0.01), but not when compared to 34 Gy arm (7.5 months, p = 0.24). TMZ monotherapy also resulted in similar median overall survival when compared with conventionally fractionated 60 Gy in 30 fractions radiation therapy alone (8.6 months versus 9.6 months, p = 0.033) in 373 patients aged >65 years in the NOA-08 phase III trial.r
In both randomised control trials, MGMT promotor methylation status was predictive of treatment response. In the Nordic trial, TMZ was associated with longer overall survival benefit in patients with MGMT promoter-methylated tumours compared to those with non-methylated tumours (9.7 months versus 6.8 months, p = 0.02).r In the NOA-08 trial, TMZ was associated with longer event-free survival compared to radiation therapy alone in those with MGMT promotor methylation (8.4 versus 4.6 months), and vice versa in those without methylation (4.6 months in RT arm versus 3.3 months in TMZ arm).r
These findings may be taken into account when monotherapy is considered in those who are not able to tolerate multi-modality therapies.
Hypofractionated radiation therapy alone versus hypofractionated radiation therapy plus concurrent/adjuvant temozolomide
The addition of TMZ to hypofractionated radiation was supported by the CCTG/ EORTC phase III randomised control trial.r
- Between 2007 and 2013, 562 patients aged >65 years with ECOG ≤2 were randomised to 40.05 Gy in 15 fractions plus concurrent and adjuvant TMZ (concurrent dose: 75 mg/m2/day for 21 consecutive days from day 1 of radiation; adjuvant dose: 150-200 mg/m2/day on day 1-5, every 28 days for up to 12 cycles) (n = 281) versus 40.05 Gy in 15 fractions alone (n = 281).
- The addition of TMZ was associated with improved overall survival (median 9.3 months versus 7.6 months, HR = 0.67, 95%CI:0.56-0.80, p<0.001) and progression-free survival (median 5.3 months versus 3.9 months, HR = 0.50, 95%CI:0.41-0.60, p<0.001). Quality of life was similar.
- The survival benefit was more pronounced in those with MGMT-methylated tumours (13.5 months versus 7.7 months, p<0.001). The benefit neared statistical significance in those with MGMT-unmethylated tumours (10 months versus 7.9 months, p = 0.055).
To date, there has been no direct comparison in the elderly population (aged >65 years) between hypofractionated radiation therapy of 40 Gy in 15 fractions with concurrent and adjuvant TMZ, versus standard radiation therapy of 60 Gy in 30 fractions with concurrent and adjuvant TMZ.
Figure 1: Overall survival
© N Engl J Med 2017r