Is the volume of low-grade glioma measurable and is it clinically relevant?
Authors: M. C. Chamberlain
Journal: Neuro-Oncology (2014)

Pallud et al in this issue of Neuro-Oncology report a retrospective analysis of untreated adult supratentorial low-grade gliomas (LGG) and their corresponding growth as determined by the velocity of diametric expansion (VDE; authors phraseology), a term describing the change in mean tumor diameter (MTD) as calculated by estimating the volume of tumor over a minimum of two time points.1 As previously posited by the authors, VDE independently predicts for tumor behavior (time to malignant transformation and overall survival) by segregating LGG into 2 categories, slow (best overall survival and lowest malignant transformation rate) and fast VDE (worst outcome, highest malignant transformation rate) tumors defined by tumors with growth   8mm of MTD per year.2–7 New in the current report is the observation that IDH1 mutation (determined by immunohistochemistry or sequencing) in LGG also predicts for longer survival and less frequent malignant transformation. The paper concludes by stating that VDE as well as IDH1 mutational status should be determined in all adult LGG as both represent independent prognostic factors as determined by the study's multivariate analysis.

Critical to these conclusions is the method by which untreated LGG tumor volume is determined. In this regard the method to calculate tumor volume by Pallud has never been validated in an independent study using a different patient data base nor examined in the context of a prospective clinical trial. Tumor volume (V) as previously described in multiple reports by the authors was determined either by manual outline of the MRI defined T2-weighted or FLAIR (fluid attenuated inversion recovery) tumor on digitized images (segmentation method) or by using an ellipsoid approximation of the three largest tumor diameters (volume = D1xD2xD3/2).1–7 In the current study nearly 90% of all tumor volumes were estimated by the ellipsoid approximation. In complex geometric tumors like LGG it is not clear if these 2 methods of volume assessment (segmentation versus ellipsoid approximation) are equivalent as a comparison study has never been performed. Mean tumor diameter (MTD) was calculated by the formula (2 x V)1/3. Glioma growth was then imputed from plotting the MTD over time. As expected in a retrospective analysis, differing MRI scanners were used as were varying sequences (T2W vs. FLAIR vs. both) and MRI parameters (slice and interslice dimensions), technical imaging aspects which likely impact tumor volume calculations. It is unclear if tumor volume calculated by T2 sequences is equivalent to that calculated by FLAIR MRI sequences. Furthermore there was no standardized time between images resulting in highly heterogeneous inter-scan intervals some as short as 6 weeks wherein a change in tumor volume seems highly unlikely in a LGG. The interval between images allowing reproducible tumor volume calculations has never been addressed though the authors recommend a minimum of 3 months between sequential MRIs in previous publications however without supporting data.2–7 The definition of slow versus fast VDE tumors as mentioned was   8mm/year change in MTD whereas the median MTD in the current study (and previous studies by these authors) was 4mm/year. Why 8mm rather than 4mm change in MTD is used as a cut off to describe slow versus fast tumors is not obvious except perhaps to better fit the author's model.

Inherent with respect to the study conclusions were accurate assessment of tumor histology in that the grade of the glioma in large part determines prognosis. This is particularly relevant as a primary study endpoint was overall survival that reflects initial glioma grade. Furthermore the second study endpoint was time to malignant transformation as defined primarily by MRI radiology (appearance of contrast enhancement or change in enhancement pattern, commonly used clinical determinations) without histological confirmation. Under-grading tumor as a LGG may consequently confound the study conclusions. A large majority of patients in the current study underwent biopsy only and therefore a higher grade glioma may not have been appreciated or suspected. This would result in a shortening of both overall survival and time to malignant transformation. Interestingly in the current study this subset of patients i.e. those undergoing biopsy only manifested abbreviated overall survival, fast growth tumors by MTD change and shorter time to malignant transformation. These issues might be resolved by studying a group of patients with near or complete resection in which the diagnosis of LGG is confirmed by central pathology review. Interestingly, several groups have suggested that early resection of LGG appears to decrease the risk of malignant transformation perhaps by resecting transformative malignant tumor clones.8,9

Molecular characterization of gliomas continues to evolve and has an increasingly germane role in the management and prognostication of these tumors.10–13 The authors confirm that the presence of IDH1 mutation confers a survival benefit in LGG, an observation which is concordant with the literature. What is new is that IDH1 mutation appears to delay time to malignant transformation, a novel observation in the current study. Interestingly, IDH1 does not appear to affect the rate of tumor growth whereas 1p19q codeletion confers a slower change in MTD. This appears paradoxical as LGG survival in part is a reflection of tumor volume and attendant consequences on neurological function. The study states IDH1mutation has no impact on spontaneous tumor growth when separated from its frequent co-association with 1p19q codeletion. Why then is there improved survival in this tumor genotype if spontaneous growth is unaffected? Not examined in the current study is the impact of other relevant glioma markers, particularly those that relate to telomere maintenance i.e. ATRX (a-thalassemia, mental retardation X-linked) and TERT (telomerase reverse transcriptase) promoter mutation.10–13 Both markers also confer a survival advantage in LGG. It may be that the context dependent interaction between these markers determines not only overall survival but change in tumor volume as well. This may be an explanation for the paradox seen in the current study wherein IDH1 mutated non-deleted LGG does not appear to have a slower growth rate but yet manifest improved survival and less frequent malignant transformation.

The question as to whether all LGG should be assessed as the authors suggests by tumor volume measurements seems premature. The challenge is to determine whether this MRI parameter (kinetics of tumor volume) adds clinically relevant information, a question not dissimilar to studies segregating LGG based upon perfusion, regional cerebral blood volume and PET imaging, all of which are not considered standard of care but rather remain investigational.14,15