Glioblastoma (GBM) is the most common malignant primary brain tumour. It disproportionately
affects the older segment of the population, as approximately half of the patients
with GBM are above 65 years [1,2]. Moreover, the aging of the baby boom generation
foreshadows a ‘silver tsunami’ of GBM .
Overlapping problems complicate management decisions for elderly patients, whether
or not they have GBM. These may include multiple comorbidities and poor physiologic
reserves, polypharmacy, limited mobility, cognitive decline, and social and financial
vulnerability . In addition, survival among elderly patients with GBM has been
consistently shorter than among younger patients, with a population based median survival
of approximately 6 months (m) . It is unclear if this is due to more aggressive
tumor biology , the use of less intense treatment approaches  or increased susceptibility
to treatment toxicities .
The standard of care for GBM management for patients below 70 years of age, has been
defined by the EORTC 26981/22981 NCIC-CE3 trial , fondly referred to as the ‘Stupp
regimen’. This international, randomized controlled trial compared concurrent and
adjuvant temozolomide (TMZ) with conventionally fractionated radiation therapy (RT;
60 Gy/30 fractions) to RT alone (60 Gy/30 fractions). The combined modality therapy
(CMT) group had improved overall survival (OS) compared with the RT alone group (hazard
ratio [HR]: 0.63 95%; CI: 0.52–0.75; p < 0.001). The 2-year OS were 27 and 10%, respectively.
The presence of O(6)-methylguanine-DNA methyltransferase (MGMT) methylation greatly
accentuated the survival benefit with TMZ. The 5-year analysis  was published in
2009 and investigated if the benefit of TMZ was seen in older patients. Patients between
60 and 70 years of age comprised 30% of the participants. The median survival for
this subgroup was lower with CMT (10.9 vs 11.8 m). An unplanned subgroup analysis
showed that survival differences for the 65–70-years old cohort failed to reach statistical
significance (HR: 0.78; 95% CI: 0.5–1.24; p = 0.29) . This suggested that older
patients derived less benefit from CMT, although it had to be interpreted with caution
due to the small patient numbers.
Many elderly patients with GBM seen in daily clinical practice do not qualify for
the ‘Stupp regimen’ because of their age. Unfortunately, elderly patients have been
excluded from many randomized clinical trials, and hence there is a lack of consensus
on how this group should be managed – especially with regard to CMT.
Across various cancer types [9–11], hypofractionated radiotherapy regimens have been
increasingly adopted. Hypofractionated regimens reduce resource utilization for the
healthcare system, potentially reduce costs and reduce the time spent by the patient
commuting to and at the hospital. For instance, for a patient with an expected survival
of 7 m, a regimen that is 3 weeks shorter would free up 10% of their remaining lifetime
spent with hospital visits. Roa et al.  demonstrated the noninferiority of 40
Gy/15 fractions compared with 60 Gy/30 fractions for patients with GBM aged 60 years
and over with Karnofsky Performance status (KPS) ≥50. Standard fractionation and hypofractionation
provided OS of 5.1 and 5.6 m, respectively (p = 0.57). Moreover, fewer patients in
the hypofractionated arm stopped treatment prematurely (10 vs 25%), suggesting better
tolerability. However, widespread adoption was blunted as the reported survival was
shorter than expected, and many felt the included patients were not representative
of everyday practice. More recently, shorter regimens such as 25 Gy/5 fractions 
and 34 Gy/10 fractions  have shown to be equally effective in elderly and/or frail
patients. However, it has to be noted that the definition of elderly has varied among
these trials from above 60 , 65  and 70 years .
Compared with the ‘Stupp regimen’, hypofractionated RT regimens have been largely
regarded as ‘palliative’ treatments. Hence, the aim of such treatments is to provide
reasonable longevity as well as palliation without increasing treatment-related toxicity.
To that end, many favored single-modality therapy as an approach with less toxicity.
For example, the Nordic trial  compared three single modality treatments (60 Gy/30
fractions RT alone, TMZ alone [200 mg/m2 for 5 days every 28 days] and 34 Gy/10 fractions
hypofractionated RT alone) in elderly patients with GBM. In this trial, patients with
TMZ alone or hypofractionated RT alone had better outcomes than those treated with
In addition, regimens with fraction sizes larger than 2 Gy are seldom combined with
concurrent chemotherapy for the same concerns of worse acute and late toxicities.
However, late neurological toxicity is unlikely to clinically manifest in this group
of patients with a short lifespan. Cao et al.  performed a retrospective study
where patients >60 years (n = 112) were treated with hypofractionated RT (40 Gy/15
fractions) with concurrent TMZ. Although a survival benefit was not demonstrable (median
OS 6.9 vs 9.3 months for RT alone), only 9% of patients (from the combined modality
arm) reported grade 3 or 4 hematological toxicity. Minniti et al.  conducted a
prospective Phase II trial involving 71 patients >70 years who were treated with hypofractionated
RT (40 Gy/15 fractions) with concurrent TMZ and adjuvant TMZ (12 cycles). Patients
from this cohort achieved a median survival of 12.4 months with a progression-free
survival of 6 months. This study showed that this regimen is well-tolerated with only
8% of patients having treatment interruption. Grade 3–4 toxicities occurred in 22%
of patients, most of which were hematological.
Given the controversy over optimal treatment of elderly patients, Perry et al. are
to be commended for designing and completing this international, randomized controlled
trial (NCIC-CE6/EORTC 26062–22061) . From 2007 to 2013, 562 patients aged 65 years
and above, with Eastern Cooperative Oncology Group (ECOG) performance status ≥2 were
randomized to hypofractionated RT 40 Gy/15 fractions with concurrent and adjuvant
TMZ (12 cycles) versus RT alone (40 Gy/15 fractions). The arms were equally balanced
in number and baseline characteristics. The median age was 73 years (range: 65–90
years), with two-thirds aged over 70 years. It has to be stressed that only patients
deemed unsuitable for ‘Stupp regimen’ therapy were eligible for this study. Overall,
68.3% of patients underwent a partial or complete resection, and the remainder had
biopsies only. The median OS was longer in the CMT arm (9.3 vs 7.6 months; HR: 0.67;
95% CI: 0.56–0.80; p < 0.001). The median PFS was also longer (5.3 vs 3.9 months;
HR: 0.50; 95% CI: 0.41–0.60; p < 0.001).
MGMT status was available in 62.9% of participants, and promoter methylation was found
in 46.6%. Among these patients, median OS was much improved with CMT (13.5 vs 7.7
months; HR: 0.53; 95% CI: 0.38–0.73; p < 0.001). An exploratory analysis suggested
that combined modality in the MGMT methylated subgroup was associated with a persistent
survival advantage at 24 months. In the unmethylated subgroup, median OS improvement
was still clinically meaningful but just short of statistical significance (10.0 vs
7.9 months; HR: 0.75; 95% CI: 0.56–1.01; p = 0.055). More importantly, although toxicity
(mostly hematological and gastrointestinal) was worse in the CMT group, quality-of-life
scores (measured through QLQ-C30 and QLQ-BN20) were similar in both arms. Treatment
tolerability and adherence were high in both arms. More than 97% of patients completed
radiotherapy and the median number of adjuvant TMZ cycles was five.
Patients were stratified at randomization according to their age groups: 65–70 years,
71–75 years, 75 years and above. It was surprising that the treatment effect was more
pronounced in the older age groups, although this failed to reach statistical significance
(p = 0.06 for interaction). This may be due to a selection bias, as only patients,
including the 65–70 years subgroups, who were deemed unsuitable for ‘Stupp regimen’
were eligible for this study. As such, this group may have inherently worse outcomes
from the outset.
40% of the patients received some type of systemic therapy on progression, and the
proportion was equal across the arms. More patients received salvage TMZ from the
RT only arm. Patients from the CMT arm received agents other than TMZ, such as lomustine
or bevacizumab. It is nearly impossible to determine whether these treatments were
associated with longer survival, or whether the longer survival provided more opportunity
for these patients to receive salvage systemic therapy.
It is clear that this study will change our practice for management of elderly patients
with GBM. The treatment regimen used in this study is effective and tolerable and
offers a meaningful benefit to older patients. However, there are still many unanswered
How does 40 Gy/15 fractions and TMZ compare to 60 Gy/30 fractions + TMZ?
As in the ‘Stupp regimen’, we are still unsure if most of the benefit comes from the
concurrent portion of TMZ or the adjuvant portion of TMZ – clarifying this may guide
us in choosing the ‘minimum required treatment’ for patients unable to tolerate both
concurrent and adjuvant phases;
Can we do away with RT altogether for patients with MGMT methylation? [14,15]
Can we combine TMZ with other hypofractionated regimens such as 34 Gy/10 or 25 Gy/5
Undoubtedly, further trials will be needed to answer these questions and guide our
Last, age is just a number and can be regarded as a ‘soft’ factor when deciding therapy.
Age has been emphasized in clinical trials, and is included in many prognostic scoring
systems, due to its objectivity and ubiquity. Tumor molecular profiling, physiological
age and performance status, may be more important to determine which patients may
benefit from more aggressive treatment.