Clinical trialPhase 3Brain tumours

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

The Lancet Oncology · 2009573 patients

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. The Lancet Oncology. 2009. 10:459-466

Study type: Clinical trial
Study name: EORTC 26981/22981–NCIC CE.3
Phase: Phase 3
Design: Randomised phase 3 trial (final analysis with median follow-up of more than 5 years; intention-to-treat analysis)
Sample size: 573 patients
Source: The Lancet Oncology · 2009
Trial registration: NCT00006353

In plain words

In this study, patients with glioblastoma (a type of malignant brain tumour) who received the chemotherapy drug temozolomide during and after radiotherapy lived longer over 5 years of follow-up. Five years after treatment, about 9.8% of these patients were alive, compared with 1.9% of patients in the radiotherapy-alone group. Patients whose tumour had a methylated MGMT gene benefited most from this drug.

Key results

27.2% vs 10.9%

2-year overall survival

Temozolomide + radiotherapy vs radiotherapy alone; 95% CI for the temozolomide group 22.2 to 32.5

16.0% vs 4.4%

3-year overall survival

95% CI for the temozolomide group 12.0 to 20.6

12.1% vs 3.0%

4-year overall survival

95% CI for the temozolomide group 8.5 to 16.4

9.8% vs 1.9%

5-year overall survival

95% CI for the temozolomide group 6.4 to 14.0

0.6

Hazard ratio (HR) for overall survival

95% CI 0.5 to 0.7; P<0.0001

89% (254 of 287) vs 97% (278 of 286)

Deaths during 5 years of follow-up

Combined treatment group vs radiotherapy alone

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 alone

Focal radiotherapy 60 Gy: 2 Gy daily, 5 days a week, for 6 weeks (30 fractions) (286 patients).

2Radiotherapy plus temozolomide

The same radiotherapy (287 patients): 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, after a 4-week break, 6 cycles of adjuvant temozolomide 150 to 200 mg/m² for 5 days in each 28-day cycle.

Source of the regimen details: Original paper of this trial (Stupp et al., NEJM 2005, PubMed 15758009; doses in the abstract) and the FDA label for temozolomide (4-week break before maintenance)

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

Adult patients with newly diagnosed glioblastoma. MGMT methylation status was determined retrospectively in the tumour tissue of 206 patients.

Endpoints

Primary endpoint: overall survival. Analyses were by intention to treat. The predictive role of MGMT methylation status was also assessed.

Safety and side effects

Safety data are not reported in the abstract of this paper.

Clinical significance and place in guidelines

This final analysis showed that the benefit of adding temozolomide to radiotherapy in newly diagnosed glioblastoma is sustained over 5 years of follow-up and is seen in all clinical prognostic subgroups, including patients aged 60 to 70 years. MGMT methylation status can identify the patients most likely to benefit from temozolomide. The current status of clinical guideline recommendations should be checked separately.

Limitations

MGMT methylation status was determined retrospectively and only in 206 of the 573 patients. Safety data are not reported in the abstract.

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.