Clinical trialPhase 3Brain tumours

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma

N Engl J Med · 2017562 patients (281 in each group)

Perry JR, Laperriere N, O'Callaghan CJ, et al. N Engl J Med. 2017. 376:1027-1037

Study type: Clinical trial
Study name: NCIC CE.6 / EORTC 26062-22061 / TROG 08.02 (Perry)
Phase: Phase 3
Design: International randomised trial (NCIC Canada in collaboration with EORTC and TROG), 1:1 randomisation
Sample size: 562 patients (281 in each group)
Source: N Engl J Med · 2017
Trial registration: NCT00482677

In plain words

In older people with glioblastoma, a shorter course of radiotherapy of about 3 weeks is usually used instead of 6 weeks. This study showed that adding temozolomide tablets to this short radiotherapy helps people live longer without making quality of life worse. The greatest benefit was seen in patients whose tumour had a feature called "MGMT methylation" (median survival about 6 months longer), which is why MGMT testing on the tumour sample helps in choosing treatment.

Key results

9.3 vs 7.6 months

Median overall survival

HR for death 0.67 (95% CI: 0.56 to 0.80); P<0.001

5.3 vs 3.9 months

Median progression-free survival

HR 0.50 (95% CI: 0.41 to 0.60); P<0.001

13.5 vs 7.7 months

Overall survival with methylated MGMT (165 patients)

HR 0.53 (95% CI: 0.38 to 0.73); P<0.001

10.0 vs 7.9 months

Overall survival with unmethylated MGMT (189 patients)

HR 0.75 (95% CI: 0.56 to 1.01); P=0.055; P for interaction=0.08

Drugs in this study:Temozolomide (Temodal)

Dose and schedule cards

Short-course radiotherapy + temozolomide in older adults (CCTG CE.6/EORTC 26062)

Newly diagnosed glioblastoma in patients aged 65 years or older who are not candidates for 60 Gy in 30 fractions with temozolomide; ECOG 0 to 2; greatest benefit in MGMT-methylated tumoursOn the page “Brain tumours” · Newly diagnosed glioblastoma: after surgery

Newly diagnosed glioblastoma in patients aged 65 years or older who are not candidates for 60 Gy in 30 fractions with temozolomide; ECOG 0 to 2; greatest benefit in MGMT-methylated tumours

Drug	Dose	Route	Schedule
Concurrent phase (3 weeks)
Radiotherapy	40 Gy in 15 fractions	External beam radiotherapy	About 3 weeks
Temozolomide	75 mg/m² once daily	Oral	Daily from the first to the last day of radiotherapy (up to 28 days)
Adjuvant: up to 12 cycles
Temozolomide	150 mg/m²; from cycle 2, up to 200 mg/m² if tolerated	Oral	First 5 days of each cycle

Cycle length: The adjuvant cycle length is not stated in the registered protocol; in the maintenance phase of the temozolomide label, cycles are 28 days
Duration: Radiotherapy for 3 weeks, then up to 12 cycles of temozolomide

The trial required granulocytes of at least 1500/mm³ and platelets of at least 100,000/mm³, creatinine and bilirubin no more than 1.5 times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Temozolomide monitoring as in the “Common safety considerations”. Dose source: protocol NCT00482677.

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

Older people: short-course radiotherapy + temozolomide

Glioblastoma at age 65 or overCycle length: —On the page “Temozolomide (Temodal)” · Dose and schedule (FDA label and key trials)

Glioblastoma at age 65 or over

Drug	Dose	Route	Schedule
Radiotherapy	40 Gy in 15 fractions	—	—
Temozolomide	Concomitant and adjuvant (dose details in the full paper)	Oral	—

Cycle length: —
Duration: —

Trial by Perry and colleagues.

On the page “Temozolomide (Temodal)” · Dose and schedule (FDA label and key trials)

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

1Short-course radiotherapy + temozolomide

Radiotherapy 40 Gy in 15 fractions (about 3 weeks).

Concurrent temozolomide: 75 mg/m² orally daily from the first to the last day of radiotherapy (maximum 28 days); then adjuvant temozolomide for up to 12 cycles: 150 mg/m² on the first 5 days of each (28-day) cycle, with possible escalation to 200 mg/m² from cycle 2 if tolerated.

2Short-course radiotherapy alone

Radiotherapy 40 Gy in 15 fractions.

Source of the regimen details: Radiotherapy 40 Gy in 15 fractions from the published abstract of the NEJM 2017 paper; concurrent temozolomide dose (75 mg/m² daily) and adjuvant dose (up to 12 cycles, 150 escalated to 200 mg/m², 5 days per cycle) from the interventions section of ClinicalTrials.gov NCT00482677. Grade 3-4 toxicity figures are in the full text of the paper and were not reviewed.

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 aged 65 and over with newly diagnosed glioblastoma who were not candidates for the standard regimen of 60 Gy in 30 fractions with temozolomide; ECOG zero to 2; surgery or diagnostic biopsy within the past 4 weeks (ClinicalTrials.gov). Median age 73 years (65 to 90).

Endpoints

Primary endpoint: overall survival (OS).

Secondary endpoints: progression-free survival, quality of life and analysis by MGMT methylation status.

Safety and side effects

According to the abstract, quality of life was similar in the two groups. Adding temozolomide was associated with more haematological toxicity (especially grade 3 or 4 lymphopenia, thrombocytopenia and neutropenia); exact figures are in the full text of the paper.

Clinical significance and place in guidelines

Radiotherapy 40 Gy in 15 fractions with concurrent and adjuvant temozolomide became a standard option for older patients (aged 65 and over) with good performance status. The EANO 2021 guideline suggests, for patients older than 65 to 70 years, chemoradiotherapy with temozolomide or temozolomide alone when MGMT is methylated, and short-course radiotherapy (40 Gy in 2.67 Gy fractions) when MGMT is unmethylated, and recommends determining MGMT status in older patients (C: I; L: B).

Limitations

Open-label design. MGMT status was available for only some patients (354). The benefit in the MGMT-unmethylated group was statistically borderline. Patients with poor performance status (ECOG 3 and 4) were not enrolled.

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.