Elsevier

The Lancet Oncology

Volume 12, Issue 6, June 2011, Pages 583-593
The Lancet Oncology

Review
Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas

https://doi.org/10.1016/S1470-2045(11)70057-2Get rights and content

Summary

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

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

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.

References (91)

  • MJ Taphoorn et al.

    An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients

    Eur J Cancer

    (2010)
  • M Klein et al.

    Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low grade gliomas: a comparative study

    Lancet

    (2002)
  • R Mohanraj et al.

    Measuring the efficacy of antiepileptic drugs

    Seizure

    (2003)
  • E Perucca

    Active control trials: endpoints beyond conventional efficacy and tolerability measures

    Epilepsy Res

    (2006)
  • E Shaw et al.

    A prospective randomized trial of low versus high dose radiation in adults with a supratentorial low grade glioma: initial report of a NCCTG-RTOG-ECOG study

    J Clin Oncol

    (2002)
  • F Pignatti et al.

    Prognostic factors for survival in adult patients with cerebral low-grade glioma

    J Clin Oncol

    (2002)
  • EF Chang et al.

    Preoperative prognostic classification system for hemispheric low-grade gliomas in adults

    J Neurosurg

    (2008)
  • RB Jenkins et al.

    A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma

    Cancer Res

    (2006)
  • EG Shaw et al.

    Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial

    J Neurosurg

    (2008)
  • JS Smith et al.

    Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas

    J Clin Oncol

    (2008)
  • SM McBride et al.

    Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

    J Neurooncol

    (2010)
  • HJ Dubbink et al.

    IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide

    Neurology

    (2009)
  • G Kaloshi et al.

    Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome

    Neurology

    (2007)
  • PH Wessels et al.

    Gain of chromosome 7 as detected by in situ hybridization correlates with shorter survival in astrocytoma grade II

    Genes Chromosom Cancer

    (2002)
  • M Weller et al.

    Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker?

    Clin Cancer Res

    (2007)
  • S Everhard et al.

    MGMT methylation: a marker of response to temozolomide in low-grade gliomas

    Ann Neurol

    (2006)
  • MJ van den Bent et al.

    IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

    Clin Cancer Res

    (2010)
  • MJB Taphoorn et al.

    Cognitive functions and quality of life in patients with low-grade gliomas: the impact of radiotherapy

    Ann Neurol

    (1994)
  • JC Reijneveld et al.

    Cognitive status and quality of life in suspected versus proven low-grade gliomas

    Neurology

    (2001)
  • O Surma-aho et al.

    Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients

    Neurology

    (2001)
  • DR Macdonald et al.

    Response criteria for phase II studies of supratentorial malignant glioma

    J Clin Oncol

    (1990)
  • WP Mason et al.

    Low-grade oligodendroglioma responds to chemotherapy

    Neurology

    (1996)
  • J Pallud et al.

    Prognostic significance of imaging contrast enhancement for WHO grade II gliomas

    Neuro Oncol

    (2009)
  • E Mandonnet et al.

    Continuous growth of mean tumor diameter in a subset of grade II gliomas

    Ann Neurol

    (2003)
  • N Danchaivijitr et al.

    Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation?

    Radiology

    (2008)
  • E Biemond-ter Stege et al.

    Treatment of low grade oligodendroglial tumors with PCV chemotherapy

    Cancer

    (2005)
  • K Hoang-Xuan et al.

    Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions

    J Clin Oncol

    (2004)
  • R Soffietti et al.

    Guidelines on management of low-grade gliomas: report of an EFNS-EANO* Task Force

    Eur J Neurol

    (2010)
  • M Bynevelt et al.

    FLAIR imaging in the follow-up of low-grade gliomas: time to dispense with the dual-echo?

    Neuroradiology

    (2001)
  • J Pallud et al.

    Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities

    Neurology

    (2010)
  • J Pallud et al.

    Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas

    Ann Neurol

    (2006)
  • SE Connor et al.

    Magnetic resonance image registration and subtraction in the assessment of minor changes in low grade glioma volume

    Eur Radiol

    (2004)
  • D Ricard et al.

    Dynamic history of low-grade gliomas before and after temozolomide treatment

    Ann Neurol

    (2007)
  • CG Brasil et al.

    Low-grade gliomas: six-month tumor growth predicts patient outcome better than admission tumor volume, relative cerebral blood volume, and apparent diffusion coefficient

    Radiology

    (2009)
  • M Law et al.

    Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade

    AJNR Am J Neuroradiol

    (2004)
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