A systematic search of PubMed was undertaken between January, 1990, and June, 2010, with (combinations of) the key words: “low grade glioma”, “astrocytoma”, “oligodendroglioma”, “endpoints”, and “response criteria”. Only studies published in English language journals were considered. Additionally, all co-authors were asked to list all articles and book chapters that they considered essential for the Review.
ReviewResponse assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas
Introduction
Diffuse low-grade gliomas (LGG) are defined by WHO as diffuse infiltrative grade II glioma, and are histologically classified as astrocytoma, oligodendroglioma, or mixed oligoastrocytoma. LGG typically affect patients in their third and fourth decade of life. Radiographically, LGG are predominantly (>90%) non-contrast enhancing tumours that are best visualised on fluid attenuation inversion recovery (FLAIR) and T2-weighted MRI sequences. In almost all patients, despite an initial slow growth rate, the outcome is ultimately fatal, and LGG relapse as high-grade gliomas in most patients. Median survival in patients with astrocytoma was 5 years in recent phase 3 trials, with longer survival in low-grade oligodendroglioma.1, 2, 3 The prognosis is related to age, performance status, lesion size, midline involvement, and histology (pure astrocytic vs oligodendroglial elements).4, 5, 6 At present, clinical trials tend to distinguish between clinically defined high-risk and low-risk LGG.4, 5 In one study4 median survival was 7–8 years if fewer than three of five poor prognostic factors were present, but only 3–4 years when three or more factors were present. Findings from a smaller study showed almost 100% 5-year survival in patients with no or one risk factor, and only 56% in patients with three of four risk factors.5 As a result, patient selection is a substantial source for variability in trial outcome.
Because of the favourable outcome in young patients with LGG presenting with seizures only, recent phase 3 trials have limited accrual to intervention groups to so-called high-risk groups. Cognitive function as assessed by the Folstein mini mental state examination (MMSE) has also been related to outcome.7 Extent of resection is correlated with progression-free survival (PFS) and overall survival (OS), although irrefutable proof that surgery improves survival is unlikely to ever be available from a randomised phase 3 study.8, 9 Additionally, several molecular factors are of favourable prognostic significance, particularly the presence of 1p/19q co-deletion and IDH1 mutations.10, 11, 12, 13, 14 Although initial reports suggested a prognostic role of MGMT promoter methylation, current data suggest a tight correlation between MGMT promoter methylation and IDH1 mutational status, which questions the independent significance of MGMT status.15, 16
Notwithstanding the incurable nature of the disease, the need to preserve cognitive function and health-related quality of life (HRQoL) is a major focus of attention because of patients' relatively long survival. Several retrospective studies reported better cognitive function in patients treated later in the course of their disease with radiotherapy or surgery than in those who were treated at the time of diagnosis.17, 18, 19 A recent well designed, although retrospective, study of cognitive function confirmed the cognitive decline in patients with LGG many years after the end of radiotherapy.20 These results emphasise the importance of the preservation of cognition and quality of life (QoL) in patients with LGG.
Section snippets
Traditional primary endpoints in phase 3 LGG trials
Most recent phase 3 studies of LGG have used OS as the primary endpoint, but at least one ongoing study (EORTC 22023; NCT00182819) has PFS as its primary endpoint. Generally, OS is the most definitive and objective endpoint in oncology, but it is also subject to the effect of salvage treatments at recurrence (including cross-over treatments) that could dilute and obscure the efficacy of the initial investigational treatment.2 The relatively long life expectancy in LGG in particular provides
Imaging: diagnosis of progression and response
As a rule, the diagnosis of tumour progression in phase 3 LGG trials and of outcome to treatment in phase 2 trials in LGG is based on imaging. The two-dimensional Macdonald criteria are far from optimal for response evaluation in LGG, because they were designed mainly to assess high-grade gliomas and focus on changes in the contrast-enhancing area.21, 22 LGG, however, do not show significant contrast enhancement on CT or MRI (although some faint and patchy enhancement is present in about 10% of
Physiological and quantitative MRI
FLAIR sequences provide the clearest and most reproducible definition of WHO grade II glioma margins, although the exact relation between these sequences and the histological tumour margin has not been established.31, 32 Growth rates measured with linear metrics derived from three dimensions correlated negatively with OS in retrospective studies.24, 33 Volume and growth measurements based on semiautomated segmentation and subtraction of tumour margins are reproducible and sensitive to subtle
PET
Various radiotracers—including glucose, methionine, and tyrosine-related compounds—have been investigated for their potential in the diagnosis and follow-up of patients with gliomas. Glucose metabolism in LGG is decreased in relation to normal healthy brain. Therefore, 18F-fluorodeoxyglucose (18F-FDG) PET is of limited use in assessment of therapy in LGG. Radiolabelled aminoacids include 11C-methionine (11C-MET) and 18F-fluoroethyltyrosine (18F-FET) for PET imaging, and 123I-iodomethyltyrosine (
Imaging follow-up and response assessment in clinical trials
Patients should be assessed with the same imaging method throughout a trial, with prespecified imaging parameters. Panel 1 provides a general minimum imaging protocol, which can be applied widely, with supplementary sequences that will be available at specialised centres. At present, follow-up with FLAIR or T2-weighted MRI is the standard of care. These MRI sequences are widely available and can be used routinely in clinical protocols. Routine follow-up should also include T1-weighted images
Extent of resection
The radiological determination of the extent of resection has to be defined in a generally accepted manner. However, whether extent of tumour resection should be assessed by either percentage of tumour resection or by absolute amount of residual tumour, and whether this measurement should be calculated from single dimensional, multidimensional, or linear or true volumetric measures is unclear. Ideally, extent of resection should be calculated by volumetric analysis and subtracting absolute
Cognitive endpoints
In patients with brain tumour, cognitive dysfunction is among the concerns. Objective, validated, and standardised performance-based testing is necessary to assess cognitive function. Patient self-report of their cognitive status is not sufficient as a proxy measure of cognitive function and is often associated with symptoms of depression or fatigue.64 Historically, the MMSE has been used in clinical trials as a measure of cognitive function. This instrument was developed for screening patients
Conclusions: combined approach
Irrespective of whether PFS or OS is taken as the primary endpoint, ancillary measures need to be incorporated into the trial design to capture clinical benefit. For this purpose, measures of cognition, seizure activity, symptom severity and burden, QoL, and neurological deterioration should be considered. Future studies should emphasise the validation and inclusion of these measures in clinical trials. Prospective trials should be used to validate the clinical significance (corresponding to
Search strategy and selection criteria
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