A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme

Abstract

The effect of temozolomide (TMZ) and radiotherapy (RT) in the treatment of glioblastoma multiforme (GBM) has been well documented in randomized controlled trials. Here we present our findings on the effect of TMZ added to RT at a population level. The Cancer Registry of Norway was searched for patients with a GBM diagnosis from January 1, 2000 to December 31, 2007. Subsequently, the prescriptions registered to these patients were obtained from the Norwegian Prescription Database. The data were analyzed according to era (pre-TMZ introduction or post-TMZ introduction) and according to treatment received. Furthermore, a matching procedure was utilized to reduce the bias between the RT + TMZ and RT alone treatments so that the effect of TMZ could be better scrutinized. We identified 1157 GBM patients. The median overall survival (OS), in months, was 8.3 (95% confidence interval: 7.6-9.0) and 10.1 (95% confidence interval: 9.1-11.0) in the pre-TMZ and TMZ eras, respectively (P < .001). By treatment, we found median OS for the control, RT alone, and RT + TMZ groups to be 2.5, 9.0, and 16.2 months, respectively (P < .001). Two-year survival was 0%, 4%, and 25%, respectively. The effect of age on TMZ effect was insignificant. In the matched group analysis, TMZ provided a 7.6-month OS benefit. Our population data reproduce the beneficial effect of TMZ from randomized controlled trials with a median OS of 16.2 months and 25% 2-year survival.

Fig. 1.

Kaplan–Meier analyses of OS for histologically proven GBM in Norway between January 1, 2000 and December 31, 2007. (A) The entire GBM population stratified by era, demonstrating increased OS after TMZ was introduced (P < .001). (B) We excluded the patients who received TMZ and saw that the OS was reduced in the post-TMZ era (P < .001). (C) We analyzed the subset not receiving radiotherapy or TMZ and demonstrated that the OS for this population is similar (P = .08).

Fig. 2.

Kaplan–Meier analyses of OS according to adjuvant therapy for (A) all ages, (B) patients aged 18–70 years, and (C) patients aged >70 years. There is a significant effect of TMZ + RT vs RT alone in both (A), (B), and (C) (P < .001). Furthermore, there is a significant effect of RT vs no adjuvant therapy (P < .001).

Fig. 3.

Kaplan–Meier plot of effect on time of first TMZ prescription after diagnosis. We defined concomitant as ≤60 days of diagnosis and adjuvant as >60 days from time of diagnosis. There is no significant difference between adjuvant and concomitant administration (P = .18).

Fig. 4.

Plot demonstrating the CEM procedure. Before matching, the RT alone and the RT+ TMZ groups were poorly matched. After matching, none of the variables had absolute standardized differences, including interactions between terms and squared terms, of more than 0.21. The 2 groups were matched on the following available variables: sex, radiation dose, age, and time until start of RT.