Anaplastic gliomas: an emerging entity

Abstract

WHO grade III tumours or anaplastic gliomas comprise 6−10% of all newly diagnosed primary brain tumours in adults. They are differentiated into three major types: anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA) or anaplastic oligodendroglioma (AO). Although formally and clearly addressed, the diagnosis of both grade and type are areas of subjectivity in diagnostic neuropathology that are not clearly regulated in the current WHO classification. Problems occur in the differentiation between grade II and III astrocytoma, the classification of oligodendroglial tumours with necrosis, and the diagnosis of a mixed glioma, i.e., an oligoastrocytoma. Before the pathological entry criteria are unified tackling imaging questions may seem premature. However, closer correlations between histology and magnetic resonance imaging (MRI) parameters, such as perfusion-weighted imaging or MR spectroscopy or positron emission tomography (PET) may add to the decision on typing and grading in anaplastic tumours. The current standard of care for first-line treatment in anaplastic gliomas is postoperative radioor chemotherapy [1]. The prognostic impact of the surgical resection remains a field of controversy because of the scarcity of prospective clinical data. The best evidence available comes from the 5-aminolevulinic acid (ALA) trial in glioblastoma [2]. This, together with the most recent analysis of surgical data from the Neurooncology Working Group of the German Cancer Society (NOA)-04 trial, makes a strong case for the prognostic value of a gross total resection in anaplastic glioma as well [3]. The NOA trial did not uniformly use postoperative imaging only, but relied in part on the neurosurgical judgment. The next steps have been regarded to define the role and optimal sequencing of combined-modality treatment focussing on radiotherapy and chemotherapy. Traditionally, the standard of care in oligodendroglial tumours has been biased by the conclusions drawn from the landmark work of Gregory Cairncross and David Louis. They introduced procarbazine, lomustine, and vincristine (PCV) chemotherapy and made the observation that patients with oligodendroglioma with 1p/19q co-deletions do better with PCV. Although this was the first prognostic molecular marker in neurooncology, it was discovered only later that improved sensitivity to therapy and not only to PCV is the reason for the relative success in treating these tumours [4]. Consequently, all large trials in the past few years have also focused on PCV. In contrast to glioblastoma [5] and a German trial for glioblastoma [6], it was felt that sequential radioand chemotherapy, but not the immediate combination of both could improve outcome. After completion of three large randomised trials [3,7,8] the standard treatment in 2011 is regarded to be postoperative radioor chemotherapy. The chemotherapy will most likely be temozolomide, as the NOA-04 trial documented a better tolerability compared with PCV [3]. However, conflicting data on the tolerability derive from a UK trial on the recurrent treatment of chemonaive irradiated glioblastoma patients that showed a comparable or even better safety profile of PCV [9]. Similar to the glioblastoma treatment, the ongoing trial initiatives focus on the role of temozolomide in addition to radiotherapy in the newly diagnosed situation. One of the ongoing trials is even aimed at differentiating between the relevance of concomitant versus adjuvant temozolomide in non-co-deleted anaplastic glioma. The answer to this question would probably have an impact beyond the treatment of anaplastic glioma. At recurrence after a radiotherapycontaining primary treatment or radiotherapy alone, temozolomide is considered standard-of-care. The TAVAREC trial of the EORTC (26091) adds the vascular endothelial growth factor inhibitory antibody bevacizumab to temozolomide in the experimental arm of this trial in the first recurrence of lowgrade and anaplastic glioma. Of note, the low-grade tumours must show a contrast-enhancing portion to be considered eligible. These tumours most likely share the same (non-favourable) prognosis with formal anaplastic glioma. The other major development is in the field of molecular markers. Enriching patient populations with comparable prognosis via more objectively defined