www.thelancet.com/oncology Vol 12 June 2011 583 Review Lancet Oncol 2011; 12: 583–93 Published Online April 6, 2011 DOI:10.1016/S1470- 2045(11)70057-2 Neuro-Oncology Unit, Daniel den Hoed Cancer Center/ Erasmus University Hospital Rotterdam, Rotterdam, Netherlands (Prof M J van den Bent MD); Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX, USA (J S Wefel PhD, T Armstrong PhD); Neuro-Oncology Center, Departments of Neurology, Neurological Surgery, and Medicine, University of Virginia, Charlottesville, VA, USA (D Schiff MD); Department of Neurology, MC Haaglanden, the Hague, Netherlands (Prof M J B Taphoorn MD); Vrije Universiteit Medical Centre, Amsterdam, Netherlands (Prof M J B Taphoorn); Mayo Clinic Florida, Jacksonville, FL, USA (K Jaeckle MD); University of Michigan Department of Neurology, Ann Arbor, MI, USA (L Junck MD); Department of Integrative Nursing, University of Texas Health Science Center School of Nursing, Houston, TX, USA (T Armstrong); Neuro Oncology Service Intermountain Healthcare, Murray, UT, USA (A Choucair MD); Imperial College, London, UK (A D Waldman PhD); EORTC Headquarters, Brussels, Belgium (T Gorlia MSc); University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (M Chamberlain MD); Department of Radiation- Oncology (MAASTRO), GROW (School for Oncology and Developmental Biology), Maastricht University Medical Centre (MUMC), Maastricht, Netherlands (B G Baumert MD); Brain Tumor and Neuro- Oncology Center, Department of Neurosurgery, Cleveland Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas M J van den Bent, J S Wefel, D Schiff, M J B Taphoorn, K Jaeckle, L Junck, T Armstrong, A Choucair, A D Waldman, T Gorlia, M Chamberlain, B G Baumert, M A Vogelbaum, D R Macdonald, D A Reardon, P Y Wen, S M Chang, A H Jacobs 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. 1–3 The prognosis is related to age, performance status, lesion size, midline involvement, and histology (pure astrocytic vs oligodendroglial elements). 4–6 At present, clinical trials tend to distinguish between clinically defined high-risk and low-risk LGG. 4,5 In one study 4 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. 10–14 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. 17–19 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. 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