Anaplastic Glioma: How to Prognosticate Outcome and Choose a Treatment Strategy

Anaplastic gliomas are classified by the WHO as grade 3 malignant tumors and include the anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma or mixed glioma. These highly aggressive tumors often occur in young adults and typically recur or progress to a grade 4 glioblastoma within several years of diagnosis, despite treatment with surgery, radiotherapy, and chemotherapy. There is some evidence that anaplastic glioma is a molecular precursor to glioblastoma. However, these tumors are uncommon (anaplastic astrocytoma accounts for only 3.2% and anaplastic oligodendroglioma 1.2% of primary brain tumors, compared with the 20.3% incidence of glioblastoma). Furthermore, they are often heterogenous, harboring a more malignant focus not sampled by the neurosurgeon, as these tumors are often diffuse and not amenable to gross total resection. For all these reasons, the anaplastic gliomas were included with glioblastomas in earlier studies examining new therapeutics and their numbers were usually too small to allow for valid subgroup analysis. About 20 years ago, differences in tumor biology suggested that the anaplastic glioma may be sufficiently different from glioblastoma to warrant independent investigation of novel therapies. Two articles in this issue of Journal of Clinical Oncology highlight some of the unique features of anaplastic gliomas and how they may differ from the glioblastoma. Anaplastic oligodendroglioma was the first to be recognized as a discrete subgroup uniquely sensitive to chemotherapy and clearly different from the anaplastic astrocytoma; its chemosensitivity appears linked to loss of heterozygosity for chromosomes 1p and 19q. While the anaplastic oligodendroglioma is distinct from the anaplastic astrocytoma, the anaplastic mixed glioma has been variably reported to have either a prognosis intermediate between the two subtypes or to be more closely linked with one or the other. Codeletion of 1p and 19q may be more predictive of behavior than histology, and two large international randomized trials are about to open based on classification of anaplastic gliomas by their 1p/19q status and not by their pathologic appearance. Given the chemosensitivity of anaplastic oligodendroglioma, it was a surprise when two large randomized control trials comparing radiation therapy (RT) alone to RT plus adjuvant chemotherapy with procarbazine, lomustine, and vincristine (PCV) or neoadjuvant PCV failed to show that chemotherapy improved survival. Chemotherapy did significantly prolong disease-free survival, and most patients randomly assigned to RT alone received chemotherapy at progression, complicating interpretation of the survival data. In this issue of JCO, van den Bent et al have returned to their data from the European Organisation for Research and Treatment of Cancer study and re-analyzed tumor specimens from 152 of the 368 patients enrolled for methylation, and therefore inactivation, of the MGMT promoter, a potential mechanism of chemosensitivity. Unexpectedly, their data show that MGMT promoter methylation is an independent prognostic factor, conferring better outcome even if initial treatment does not include an alkylating agent. However, the authors do not address the observation that patients whose tumors had a methylated promoter and received PCV in addition to RT had the best progression-free survival and overall survival, suggesting that MGMT promoter methylation may be both a prognostic and predictive marker. In addition, those whose tumor had an unmethylated promoter also did better when chemotherapy was incorporated into initial treatment. In contrast, MGMT promoter methylation was not a prognostic factor in their 40 patients whose tumors were re-classified as glioblastoma on central pathologic review. These findings differ from Hegi et al, who described MGMT promoter methylation as a predictor in glioblastoma of response to temozolomide. The results of these studies highlight the uncertainty regarding the optimal treatment of patients with anaplastic oligodendroglioma. Even among experienced neuro-oncologists, there is a wide range of opinion regarding the initial treatment, often, but not always, influenced by 1p/19q status. Now, MGMT status may be a critical molecular characteristic but does not appear to be a predictor of therapeutic response or even a determinant of treatment choice. Treatment of the anaplastic astrocytoma has been less variable. This tumor is more resistant to therapy and patients have a shorter median survival of only 2 to 3 years, compared with 5 years for anaplastic oligodendroglioma. Most physicians in the United States treat patients with maximal safe resection and involved field radiotherapy with concurrent and adjuvant temozolomide, identical to the regimen now considered the standard of care for glioblastoma. However, the potential benefit of adding chemotherapy in these patients has never been established, although temozolomide was initially granted accelerated approval by the US Food and Drug Administration based on its efficacy in patients with recurrent anaplastic astrocytoma. Therefore, better information is essential to improving treatment for these patients. In this issue of JCO, a large German multicenter randomized controlled trial analyzed two different therapeutic approaches to patients with newly diagnosed anaplastic glioma. The investigators employed a highly unusual study design. Patients were JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 35 DECEMBER 1