Front-line Systemic Therapy for Glioblastoma

Combined chemoradiation is currently standard of care for glioblastoma patients age 70 years with good PS.

Temozolomide

Benefits of combined chemoradiation with temozolomide were demonstrated in a large phase III, randomised trial. Stupp et al assessed temozolomide in 573 glioblastoma patients age 70 years with a WHO PS 2, and showed that RT with concurrent and adjuvant temozolomide improved median (14.6 vs 12.1 months), 2-year (26.5% vs 10.4%) and 5-year (10% vs 2%) survivals when compared with RT alone.10, 11Significant improvement in survival outcome did not adversely affect health-related quality of life (HRQOL).14Temozolomide is administered at 75 mg/m2 daily concurrent with RT, followed by 150 to200 mg/m2 for 5 days every 28 days for 6 cycles post-RT.10 11Alternate dose-dense regime showed no improvement in survival outcomes. 15A local cohort study of 50 adult patients with glioblastoma treated with adjuvant temozolomide demonstrated similar median (13.6 months) and 2-year (24.4%) survival rates as the large European Multicentre Study.16It supports the use of temozolomide in our local population. Of note, there were no grade IV haematological or gastrointestinal toxicity in the patient cohort. Nevertheless, we recommend monitoring of blood count during chemoradiation therapy. Prophylaxis against Pneumocystis jiroveci pneumonia is advised when temozolomide is administered concurrent with RT due to risk of lymphopenia and subsequent opportunistic infection.

Special PopulationElderly Patients (Age >65 Years)

The first randomised trial examining the effectiveness of an abbreviated RT course (40 Gy in 15 fractions over 3 weeks) in older patients (age 60 years) with glioblastoma showed no significant difference in OS compared to those who received standard RT (60 Gy in 30 fractions over 6 weeks).17 Patients in the abbreviated RT arm also had similar KPS and reduced increment in corticosteroid requirements. The Nordic randomised phase III trial assessed treatment in 342 glioblastoma patients age >60 years with WHO PS 2.18After 4 years of recruitment, in light of positive results from the EORTC 26981 trial, age cutoff was raised to >65 years. Better median survival was demonstrated in patients >70 years who received temozolomide (200 mg/m2 on days 1 to 5 of every 28 days for up to 6 cycles) or hypofractionated RT (34.0 Gy administered in 3.4 Gy fractions over 2 weeks) than those who received standard RT (60.0 Gy administered in 2.0 Gy fractions over 6 weeks) (9.0 vs 7.0 vs 5.2 months). Survival did not differ between treatments for patients aged 60 to 70 years. The NOA-08 randomised phase III trial assessed treatment in 373 high-grade glioma (malignant astrocytoma or glioblastoma) patients age >65 years with KPS 60,19and demonstrated that dose-dense temozolomide (100 mg/m2 on days 1 to 7 of every 14 days) alone was non-inferior to RT (60.0 Gy administered in 1.8-2.0 Gy fractions over 6 to 7 weeks) (median OS 8.6 vs 9.6 months). There was no significant difference in HRQOL between the 2 treatment groups. Event-free survival (EFS) was longer in patients with MGMT promoter methylation (see below) who received temozolomide than in those who underwent RT (8.4 [95% CI, 5.5 to 11.7] vs 4.6 months [95% CI, 4.2 to 5.0]), whereas for patients with no methylation of the MGMT promoter, EFS was longer for those who received RT (3.3 [95% CI, 3.0 to 3.5] vs 4.6 months [95% CI, 3.7 to 6.3]). A meta-analysis of 5 studies, including the Nordic and NOA-08 trials, showed a marginally significant reduction in mortality in elderly GBM patients receiving temozolomide monotherapy compared to RT.20This borderline significance was lost after sensitivity analysis. The role of early RT and temozolomide will be better defined with results from the ongoing EORTC and National Cancer Institute of Canada (NCIC) Clinical Trial Group elderly trial (NCT00482677).

O-6-methylguanine-DNA Methyltransferase (MGMT)

MGMT is a DNA repair enzyme that can adversely affect tumour response to DNA-alkylating agents. Methylation of MGMT gene promoter results in gene-silencing and has been shown to improve median OS in glioblastoma patients age 70 years with a WHO PS 2 (18.2 vs 12.2 months).21Among high-grade glioma patients age >65 years, those with MGMT promoter methylation also demonstrated longer median OS compared to those without methylation (11.9 vs 8.2 months; HR = 0.62; 95% CI, 0.42 to 0.91; P = 0.014).19Its predictive role in treatment response to temozolomide alone was suggested in the NOA-08 trial as discussed above. Similarly, the Nordic trial demonstrated a non-significant improvement in median OS in glioblastoma patients with MGMT promoter methylation compared to those without methylation (9.7 vs 6.8 months; HR = 0.97; P = 0.81).18This improvement in survival was not seen in patients treated with RT only. Overall, MGMT methylation status remains at best a prognostic marker. Its predictive role in response to therapy requires validation in future prospective studies.

Bevacizumab

Bevacizumab was thought to be able to improve outcomes in patients with newly diagnosed glioblastoma by potentiating the therapeutic effects of both RT and chemotherapy. This was supported by 2 phase II studies that showed favourable OS and PFS compared to historical controls respectively.22, 23 However, 2 subsequent randomised, placebo-controlled phase III trials of standard chemoradiation (concurrent temozolomide and RT followed by adjuvant temozolomide) with or without bevacizumab in newly diagnosed glioblastoma patients failed to demonstrate any survival benefits in patients treated with bevacizumab compared to placebo.24,25Although both trials showed similar adverse effects of bevacizumab, AVAglio24demonstrated maintenance of HRQOL, while RTOG 082526reported increased symptom burden, worse HRQOL and decline in neurocognitive function.

Nimotuzumab

Nimotuzumab is a humanised monoclonal antibody that binds to epidermal growth factor receptor (EGFR) and alters cell division. A randomised, double-blind phase II trial conducted in patients with high-grade glioma and KPS 60 demonstrated improved median OS when treated with nimotuzumab and RT compared to RT alone (17.8 vs 12.6 months; HR = 0.64; P = 0.032).26Of note, majority of the patients in this trial have anaplastic astrocytoma (41 anaplastic astrocytoma and 29 glioblastoma multiforme), hence results from this study cannot be generalised to patients with glioblastoma. A German phase III trial also showed no significant PFS or OS difference in glioblastoma patients treated with standard chemoradiation (temozolomide and RT) with or without nimotuzumab; EGFR amplification status did not predict treatment response.27In both studies, there was a trend towards improved efficacy in MGMT non-methylated glioblastoma patients. This efficacy stratified by MGMT methylation status remains to be validated.

Cost-effectiveness

Alongside the landmark trial by Stupp et al,10economic data were collected prospectively for a subgroup of 219 (38%) patients, and analysed from the perspective of the public healthcare system in the Netherlands, Switzerland and Canada.28The incremental cost-effectiveness ratio (ICER) was estimated at USD $40,716 per life-year gained, comparable to accepted first-line chemotherapy in cancer patients. In England, an economic evaluation of treatment with temozolomide in the adjuvant and concomitant phase revealed an additional cost of around USD $11,971 for an additional 0.217 quality-adjusted life year (QALY) per patient, translating to a base-case ICER of USD $55,254/ QALY.29Similarly, in China, the addition oftemozolomide increased the cost and QALY relative to RT alone by USD $25,328 and 0.29 respectively, giving rise to an ICER of USD $87,940/QALY. 30Authors in both of these latter studies concluded that temozolomide is not a cost-effective option for glioblastoma patients but suggested an improved cost-effectiveness with selection and treatment of patients with more favourable prognostic factors. There is currently no local cost-effectiveness study available.