Clinical trialPhase 3Brain tumours

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

N Engl J Med · 2005573 patients

Stupp R, Mason WP, van den Bent MJ, et al. N Engl J Med. 2005. 352:987-996

A newer report of this study has been published: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (2009)

Study type: Clinical trial
Study name: EORTC 26981-22981 / NCIC CE.3 (Stupp)
Phase: Phase 3
Design: Randomised, open-label, international multicentre trial (EORTC and NCIC Canada); 85 centres
Sample size: 573 patients
Source: N Engl J Med · 2005
Trial registration: NCT00006353

In plain words

Glioblastoma is the most common and most aggressive primary brain tumour in adults. This large study showed that if, after surgery, temozolomide chemotherapy tablets are taken together with 6 weeks of radiotherapy and continued for 6 more cycles after radiotherapy ends, patients live longer on average and the chance of being alive at 2 and 5 years is several times higher. Serious blood side effects were seen in a small percentage of patients and are monitored with regular blood tests. Since 2005 this approach has been known as the "Stupp protocol" and is the standard treatment for glioblastoma.

Key results

14.6 vs 12.1 months

Median overall survival

HR for death 0.63 (95% CI 0.52 to 0.75); P<0.001; median follow-up 28 months

26.5% vs 10.4%

2-year survival

Original NEJM 2005 paper

9.8% vs 1.9%

5-year survival (final analysis)

Stupp et al., Lancet Oncol 2009 (PMID 19269895); HR 0.6 (95% CI 0.5 to 0.7)

Drugs in this study:Temozolomide (Temodal)

Dose and schedule cards

Stupp protocol: radiotherapy + concurrent and maintenance temozolomide (EORTC-NCIC)

Newly diagnosed glioblastoma after maximal safe resection or biopsy; patients younger than 70 years with good performance statusOn the page “Brain tumours” · Newly diagnosed glioblastoma: after surgery

Newly diagnosed glioblastoma after maximal safe resection or biopsy; patients younger than 70 years with good performance status

Drug	Dose	Route	Schedule
Concurrent phase (6 weeks)
Focal radiotherapy	60 Gy in 30 fractions (2 Gy per day)	External beam radiotherapy	5 days a week for 6 weeks
Temozolomide	75 mg/m² once daily	Oral	Daily from the first to the last day of radiotherapy (42 to 49 days)
Maintenance: 6 cycles, starting 4 weeks after the end of radiotherapy
Temozolomide (cycle 1)	150 mg/m² once daily	Oral	Days 1 to 5
Temozolomide (cycles 2 to 6)	200 mg/m² once daily if tolerated	Oral	Days 1 to 5

Cycle length: Concurrent phase daily; maintenance every 28 days
Duration: 6 weeks of chemoradiotherapy, a 4-week break, then 6 maintenance cycles

The greatest benefit was seen in tumours with MGMT promoter methylation. Temozolomide monitoring and dose modification as in the “Common safety considerations” above. Dose source:.

On the page “Brain tumours” · Newly diagnosed glioblastoma: after surgery

Stupp

Newly diagnosed glioblastomaOn the page “The Stupp regimen: temozolomide with radiotherapy in glioblastoma”

Newly diagnosed glioblastoma

Drug	Dose	Route	Schedule
Concomitant phase
Temozolomide	75 mg/m²	Oral	Daily during radiotherapy (60 Gy in 30 fractions)
Adjuvant phase
Temozolomide	150 mg/m² in cycle 1, then 200 if tolerated	Oral, fasting	Days 1 to 5

Cycle length: Adjuvant phase every 28 days, starting 4 weeks after the end of radiotherapy
Duration: 6 adjuvant cycles

As in Stupp and colleagues.

Dose source:.

On the page “The Stupp regimen: temozolomide with radiotherapy in glioblastoma”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Radiotherapy + temozolomide (concurrent and adjuvant)

Focal radiotherapy 60 Gy: 2 Gy daily, 5 days a week, for 6 weeks (30 fractions).

Concurrent temozolomide: 75 mg/m² orally per day, 7 days a week, from the first to the last day of radiotherapy; then 6 cycles of adjuvant temozolomide 150 to 200 mg/m² for 5 days in each 28-day cycle.

Per the FDA label: Pneumocystis pneumonia prophylaxis during the concurrent phase; each dose started only with neutrophils at least 1.5 × 10⁹ and platelets at least 100 × 10⁹ per litre; weekly blood counts during the concurrent phase and on day 22 of each maintenance cycle; maintenance cycle 1 at 150 and escalation to 200 mg/m² from cycle 2 if no interruption or discontinuation was needed in cycle 1; after an interruption, the next cycle reduced by 50 mg/m², and permanent discontinuation if 100 mg/m² is not tolerated.

2Radiotherapy alone (control group)

Fractionated focal radiotherapy 60 Gy (2 Gy per day, 5 days a week, 6 weeks).

Source of the regimen details: Radiotherapy and temozolomide doses (concurrent and adjuvant) from the published abstract of the NEJM 2005 paper (PubMed 15758009); PCP prophylaxis, blood count criteria, dose escalation and reduction from the FDA label for temozolomide (TEMODAR, DailyMed).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with histologically confirmed newly diagnosed glioblastoma after surgery (resection or biopsy). Median age was 56 years and 84% of patients had debulking surgery.

Endpoints

Primary endpoint: overall survival (OS).

Secondary endpoints: progression-free survival, safety and quality of life.

Safety and side effects

During the concurrent radiotherapy and temozolomide phase, grade 3 or 4 haematological toxicity occurred in 7% of patients (per the abstract of the paper). The authors considered the addition of temozolomide to be associated with "minimal additional toxicity". Full details of adverse events in the adjuvant phase are given in the full text of the paper.

Clinical significance and place in guidelines

This trial made the "Stupp" regimen (radiotherapy 60 Gy in 30 fractions + concurrent temozolomide followed by 6 cycles of adjuvant temozolomide) the global standard of care for newly diagnosed glioblastoma. The EANO 2021 guideline regards this regimen as the standard of care at the highest level (C: I; L: A) for patients under 70 years with KPS above 70. The concurrent analysis by Hegi et al. (NEJM 2005) showed that the greatest benefit is seen in tumours with MGMT promoter methylation. The 5-year analysis (Lancet Oncol 2009) confirmed that the survival benefit is sustained.

Limitations

Open-label design (no placebo). MGMT status was determined only retrospectively and in a subset of patients (206 in the 5-year analysis). Patients over 70 years were not enrolled; the current WHO classification (2021, IDH-based) did not yet exist, and some patients probably had IDH-mutant tumours.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.