Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis

Abstract

Translation of survival benefits observed in glioblastoma clinical trials to populations and to longerterm survival remains uncertain. We aimed to assess if ≥ 2-year survival has changed in relation to the trial of radiotherapy plus concomitant and adjuvant temozolomide published in 2005. We searched MEDLINE and Embase for population-based studies with ≥ 50 patients published after 2002 reporting survival at ≥ 2 years following glioblastoma diagnosis. Primary endpoints were survival at 2-, 3-and 5-years stratified by recruitment period. We meta-analysed survival estimates using a random effects model stratified according to whether recruitment ended before 2005 (earlier) or started during or after 2005 (later). PROSPERO registration number CRD42019130035. Twentythree populations from 63 potentially eligible studies contributed to the meta-analyses. Pooled 2-year overall survival estimates for the earlier and later study periods were 9% (95% confidence interval [CI] 6-12%; n/N = 1,488/17,507) and 18% (95% CI 14-22%; n/N = 5,670/32,390), respectively. Similarly, pooled 3-year survival estimates increased from 4% (95% CI 2-6%; n/N = 325/10,556) to 11% (95% CI 9-14%; n/N = 1900/16,397). One study with a within-population comparison showed similar improvement in survival among the older population. Pooled 5-year survival estimates were 3% (95% CI 1-5%; n/N = 401/14,919) and 4% (95% CI 2-5%; n/N = 1,291/28,748) for the earlier and later periods, respectively. Meta-analyses of real-world data suggested a doubling of 2-and 3-year survival in glioblastoma patients since 2005. However, 5-year survival remains poor with no apparent improvement. Detailed clinically annotated population-based data and further molecular characterization of longer-term survivors may explain the unchanged survival beyond 5 years. Glioblastoma multiforme is the most common primary malignant brain tumour in adults with an incidence rate of 3.7 per 100,000 person-years, though geographical variation exists 1. Despite an increasing understanding of the underlying pathophysiology, glioblastoma remains an incurable disease with high mortality 2. A landmark clinical trial in 2005 demonstrated that the addition of concomitant and adjuvant temozolomide to radiotherapy provided an additional survival benefit to patients diagnosed with glioblastoma 3. Multiple clinical trials had investigated novel therapies that showed promise in pre-clinical and early phase studies, but to date there have been no major additions to the treatment armamentarium for newly diagnosed patients since 2005. The median survival in the intervention arm of the 2005 trial was 14.6 months 3 , but there is uncertainty about whether survival benefit from clinical trials is translated to the population 4,5. Clinical trial participation itself is associated with better survival 6 , which may be caused by the preferential inclusion and exclusion criteria into clinical trials. In clinical practice not all patients are eligible for the trial standard of care involving maximal surgical debul...

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