Results of the search
For the updated review, the search found 70 publications on CENTRAL, 278 on MEDLINE and 193 on EMBASE.
Three RCTs met the inclusion criteria. Two were included in the first Cochrane review in 2008 (Quon 2008). Several updates with analysis of biomarkers were published for both studies. The third study was published after the first review was developed.
The RTOG trial 9402 was a multicentre RCT (1994 to 2002) that included 289 participants older than 18 years of age with AO or AOA (Cairncross 2006). Since the first publication in 2006, three published updates have addressed the outcomes that we are evaluating, and the median follow-up is now 11.3 years. Anaplasia was identified based on five features (tumour cellularity, nuclear pleomorphism, mitotic activity, endothelial proliferation and necrosis). Anaplastic tumours had to contain two of five features, one of which was high mitotic activity or endothelial proliferation. An oligoastrocytoma had to have at least 25% oligodendroglioma component. Participants had a Karnofsky Performance Scale (KPS) score of at least 60 and were randomized within eight weeks of surgery and received up to four cycles of PCV followed by RT (147 participants) versus RT alone (142 participants). RT was identical in both treatment arms and was given to a total dose of 59.4 Gy in 33 fractions. Unplanned analysis of codeletion of chromosomes 1p and 19q by fluorescence in situ hybridization (FISH) analysis, and of IDH-1 and -2 mutations by immunohistochemistry and sequencing, started after the initiation of the trial as the importance of these markers was not known until after participant accrual had begun. The codeletion of chromosomes 1p and 19q status was obtained for 91% of the participants in the update of the study, as compared with only 70% in the original. The IDH-1 and -2 status was obtained in 72% of the participants. The primary endpoint was OS and secondary endpoints included PFS, frequency of severe (grade 3 or greater) treatment toxicities, cognition and QoL.
The EORTC trial 26951 was a multicentre RCT (1996 to 2002) that included 368 participants aged 16 to 70 years with newly diagnosed AO or AOA (van den Bent 2006). Since the first publication in 2006, eight published updates have addressed the outcomes that we are evaluating, and the median follow-up is now 11.7 years. In contrast to RTOG 9402, anaplastic tumours were defined as having at least three of five anaplastic features (high cellularity, mitosis, nuclear abnormalities, endothelial proliferation and necrosis). An oligoastrocytoma had to have at least 25% oligodendroglioma component. Participants with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible and randomized after surgery to either RT (59.4 Gy in 33 fractions) followed by up to 6 cycles of PCV (185 participants) versus RT alone (183 participants). As with the RTOG trial, assessment of codeletion of chromosomes 1p and 19q by FISH analysis was not started until the trial had begun and was available for 85.9% of participants. The assessment of MGMT methylation by semi-quantitative methylation-specific multiplex ligation-dependent probe amplification and of IDH-1 and -2 mutations by bidirectional cycle sequencing of polymerase chain reaction (PCR)-amplified fragments was done after the conclusion of enrolment for the study. Information on the MGMT methylation and on IDH-1 and -2 was found for 49.7% and 48.6% of participants, respectively. Primary endpoints were OS and PFS, and secondary endpoints included QoL and toxicity.
The Neuro-Oncology Working Group (NOA) of the German Cancer Society 04 was a multicentre RCT (1999 to 2005) that included 274 participants aged 18 years and over with newly diagnosed AO, AOA or AA who were followed for a maximum of 4.5 years (NOA-04 2009). Similarly to the EORTC study, at least three criteria of anaplastic features were required for the tumours to be defined anaplastic. Participants had a KPS score of 70 or greater, and were randomized in a 2:1:1 fashion to 60 Gy in 30 to 33 fractions of RT (139 participants) versus 4 cycles of 8 weeks of PCV (68 participants) versus 8 cycles of 4 weeks of temozolomide (67 participants). In contrast to the RTOG and EORTC studies, molecular analyses was assessed at randomization. Assessment of codeletion of chromosomes 1p and 19q was carried out by a multiplex ligation-dependent probe assay and was available for 56.9% of participants. MGMT methylation status was determined in 63.5% of participants by methylation-specific PCR. IDH-1 and -2 mutations were evaluated by gene amplification, and results were available for 61.3% of participants. The primary endpoint was time from operation to treatment failure. Secondary endpoints included response rate, PFS, OS, time to treatment failure stratified for histology, codeletion of chromosomes 1p and 19q, MGMT promoter methylation status, IDH-1 mutation and toxicity.
These studies are summarized in Table 1.
Table 1. Summary of the studies
| || RTOG 9402|| EORTC 26951|| NOA-04|
| Histology||AO and AOA with at least 25% oligodendroglial elements||AO and AOA with at least 25% oligodendroglial elements||AO, AOA and AA|
| Pathological characteristics|
2 of 5: high cellularity, nuclear polymorphism, mitotic activity, endothelial proliferation and necrosis
At least 1 needs to be mitosis or endothelial proliferation
|3 of 5: high cellularity, mitosis, nuclear abnormalities, endothelial proliferation and necrosis|
3 of 4: high cellularity, mitotic activity, nuclear polymorphism and vascular proliferation
| Rate of codeletion of chromosomes 1p and 19q||47.9%||25.0%||40.9%|
| Number of participants randomly assigned||289||368||274|
| Randomization arms|
- RT + PCV intensive regimen 4 cycles prior to RT (n = 147)
- RT alone (n = 142)
- RT + PCV 6 cycles after RT (n = 185)
- RT alone (n = 183)
- RT first, chemotherapy at recurrence (n = 139)
- chemotherapy first, RT at recurrence (n = 135)
PCV 4 cycles (n = 68)
Temozolomide 8 cycles (n = 67)
| Rate of chemotherapy a time of recurrence in RT arms||79.0%||74.5%||48%|
| Median survival|
- 4.6 years for RT plus PCV
- 4.7 years for RT alone
- 3.5 years for RT plus PCV
- 2.6 years for RT alone
- 6.0 years for RT first
- 6.9 years for chemotherapy first
| Loss of heterozygosity||Prognostic and predictive for OS||Prognostic for OS||Prognostic for PFS|
| MGMT||NA||Not prognostic for OS||Prognostic for PFS|
| IDH-1 or -2||Prognostic and predictive for OS||Prognostic for OS||Prognostic for PFS|
| Author's clinical conclusion||For the subset of participants with 1p/19q codeleted or IDH-1 or -2 mutated AO/AOA, PCV plus RT may be an especially effective treatment||PCV plus RT increases both OS and PFS in AO/AOA. Codeleted tumours derive more benefit from adjuvant PCV compared with non-codeleted tumours||Initial RT or chemotherapy achieved comparable results in participants with anaplastic gliomas|
Limitations of studies
These three studies have significant differences worth mentioning.
First, there are noteworthy pathological characteristic distinctions in each study. The RTOG and EORTC studies included AOA and AO only. However, the number of anaplastic characteristics a tumour required to be defined anaplastic differed in each study. Two criteria were required in the RTOG study, as long as high mitotic activity or endothelial proliferation was present. The EORTC study based the diagnosis of anaplastic tumours on the WHO 1993 grading, requiring three criteria, including tumours with necrosis. The NOA-04 study included not only AO and AOA, but also AA. In this study, grading of tumours was based on the WHO 2000 grading, requiring three criteria of anaplasia excluding necrosis.
Second, assessment of chromosome 1p and 19q deletions and IDH-1 and -2 mutations were started after participant accrual had begun in the RTOG and EORTC studies. As a result, these studies assessed chromosome deletions and mutations in different proportions of their participant populations. As for MGMT methylation, it was not assessed in the RTOG study, and the EORTC group only began the analysis after the start of participant accrual. In contrast, all molecular analyses in the NOA-04 study were intended in the initial protocol.
Third, the treatments given were different. The RTOG and EORTC studies, although both comparing RT alone versus RT plus chemotherapy, had different sequences of treatment and doses of PCV in the experimental arms, with the RTOG 9402 study treating with up to four cycles of standard PCV prior to RT, and the EORTC 26951 trial delivering up to six cycles of standard PCV after RT. The chemotherapy arms of the NOA-04 included four cycles of higher dose PCV as well as eight cycles of temozolomide. The NOA-04 also standardized the treatments to be received at time of failure, with chemotherapy given to participants randomized to RT and vice-versa.
We screened 467 records and excluded 453 records (Figure 1):
401 were not RCTs;
41 were not restricted to grade III gliomas
four did not randomize participants to receive RT alone, chemotherapy alone or RT plus chemotherapy;
four included a paediatric population;
two did not address the outcomes of OS, PFS or toxicity of grade 3 or greater;
one was only in abstract form.