Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma
Adding the oral chemotherapy temozolomide during and after radiotherapy extended median survival in glioblastoma by about two and a half months and more than doubled the number of patients alive at two years; twenty years later it is still the standard.
Open-label phase 3 trial (EORTC 26981/NCIC CE.3) of 573 patients aged 18-70 with newly diagnosed glioblastoma randomised to radiotherapy alone (60 Gy) or radiotherapy with concomitant daily temozolomide followed by six cycles of adjuvant temozolomide. Primary endpoint was overall survival.
Median OS was 14.6 vs 12.1 months (HR 0.63) and 2-year OS 26.5% vs 10.4%. The companion paper by Hegi showed that MGMT promoter methylation predicted benefit. The 'Stupp protocol' became the global standard for glioblastoma and remains so, with only tumour-treating fields added since; the trial also illustrates how little progress has been made against this tumour.
- Median overall survival 14.6 vs 12.1 months; HR 0.63 (95% CI 0.52-0.75).
- 2-year overall survival 26.5% vs 10.4%.
- Five-year follow-up (Lancet Oncology 2009): 5-year OS 9.8% vs 1.9%.
- MGMT promoter methylation (Hegi, NEJM 2005) identified patients with the greatest benefit: median OS 21.7 months with temozolomide in methylated tumours vs 12.7 months in unmethylated.
- Grade 3-4 haematological toxicity in about 7% during concomitant treatment and 14% during adjuvant treatment.
Patients with newly diagnosed glioblastoma who are fit and under about 70 receive six weeks of radiotherapy with daily temozolomide followed by six monthly cycles of temozolomide; this is still the backbone of treatment two decades later. Testing MGMT methylation identifies who benefits most and guides decisions in older patients. Median survival with the regimen remains only around 15-20 months, and no drug since has clearly improved on it, which is why glioblastoma is a priority for new approaches.
- Excluded patients over 70 and with poor performance status; later trials (e.g. Perry 2017) addressed short-course radiotherapy with temozolomide in the elderly.
- The benefit in MGMT-unmethylated tumours is small, yet temozolomide is still usually given for lack of alternatives.
- Open-label design; no quality-of-life data in the primary report.
- Two decades of subsequent negative trials (bevacizumab, nivolumab, vaccines) make this the standard by default rather than by continued advance.