In addition to RTOG 9813, RTOG 0424, a phase II study of radiation with concurrent and adjuvant TMZ, demonstrated promising results; many practitioners have extrapolated positive results with TMZ in malignant gliomas to the low-grade setting, given the favorable toxicity profile of TMZ

In addition to RTOG 9813, RTOG 0424, a phase II study of radiation with concurrent and adjuvant TMZ, demonstrated promising results; many practitioners have extrapolated positive results with TMZ in malignant gliomas to the low-grade setting, given the favorable toxicity profile of TMZ.31,35 The results of the CODEL study should determine whether TMZ is an appropriate substitute for PCV. While RTOG 9802 clearly established a role for adjuvant chemotherapy in patients with low-grade gliomas, the study did not address the underlying controversy regarding the timing of radiation and chemotherapy. for grade II or III oligodendrogliomas includes both IDH mutation status and combined whole chromosome arm losses of 1p and 19q (1p/19q codeletion). The diagnoses of oligoastrocytoma and anaplastic oligoastrocytoma are now strongly discouraged.9 IDH mutation status and 1p/19q codeletion have prognostic value for gliomas. The Cancer Genome Atlas (TCGA) network performed genome-wide analyses of 293 grades II and III gliomas from adults.11 Three molecular subgroups of WHO grade II and grade III gliomas emerged which correlated with clinical outcomes, recurrence, and survival: (i) IDH-mutant gliomas with 1p/19q codeletion, (ii) IDH-mutant gliomas without 1p/19q codeletion, and (iii) IDH-wildtype gliomas without 1p/19q codeletion. The median survival for patients with mutant IDH plus 1p/19q codeletion, mutant IDH without 1p/19q codeletion, and IDH-wildtype gliomas without 1p/19q codeletion are 8, 6.3, and 1.7 years, respectively.11 Another study looking at 1087 grade IICIV gliomas demonstrated that nearly all tumors could be placed in one of 5 molecular subgroups on the basis of 3 markers: IDH mutation, 1p/19q codeletion, and telomerase reverse transcriptase (mutations (~80%), which are less common in IDH-wildtype GBMs (7%); rather, up to 83% of primary GBMs have frequent promoter mutations.15C17 Patients with IDH-wildtype GBMs have a median OS of 15 months, whereas patients with IDH-mutant GBMs have a median survival of 31 months.18 TMZ, given concurrently with radiation postoperatively and adjuvantly (the Stupp regimen), increases OS in GBMs and is therefore the standard of care. 19 Malignant Transformation of Low-Grade Gliomas As a group, low-grade gliomas are histologically and biologically heterogeneous and are associated with marked diversity in survival times. Although some patients may survive for more than a decade, most tumors recur. At recurrence, a tumor can undergo malignant transformation to a high-grade glioma (grade III or IV), which is associated with worse prognosis.20 On MRI, malignant transformation correlates with the development of focal contrast enhancement, which is often used as a radiographic surrogate of malignant transformation. 21 The interval between initial presentation and malignant transformation is highly variable, with a reported incidence ranging from 17% to 73% and median interval after initial resection ranging from 2.1 to 10.1 years.20 Known risk factors for malignant transformation of an initial low-grade glioma include larger preoperative tumor volume, higher tumor growth rate, and decreased extent of surgical resection.22,23 Genetic alterations associated with malignant transformation in IDH-mutant gliomas include the acquisition of genetic alterations in the retinoblastoma (RB) and Akt?mammalian target of rapamycin (mTOR) pathways, activation of the TRADD MYC DL-O-Phosphoserine and RTK-RAS?phosphatidylinositol-3 kinase (PI3K) pathways, upregulation DL-O-Phosphoserine of the Forkhead box M1 (FOXM1)- and E2F2-mediated cell cycle transitions, and epigenetic silencing of developmental transcription factors.3,24 In a study of 204 patients with grade II gliomas treated prospectively on North Central Cancer Treatment Group clinical trials, malignant transformation occurred in 70% of low-grade astrocytomas compared with 45% in oligodendrogliomas.25 Of note, this study was performed prior to molecular subtyping of gliomas and thus the proportion of malignant transformation in the corresponding molecularly defined groups may differ. The Role of Chemotherapy in the Management of Gliomas The role of TMZ treatment in patients with high-grade gliomas is well established. In general, the treatment paradigm is maximal safe surgical resection followed by adjuvant chemoradiation. The landmark European Organisation for Research and Treatment of DL-O-Phosphoserine CancerCNational Cancer Institute of Canada (EORTC-NCIC) study established that postoperative radiotherapy with concurrent and adjuvant TMZ improved survival in patients with GBM compared with adjuvant radiotherapy alone, and a subsequent study demonstrated improved survival with adjuvant TMZ even for elderly patients receiving adjuvant hypofractionated radiotherapy.26,27 Studies in anaplastic oligodendrogliomas have demonstrated a benefit with the adjuvant procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy regimen.28,29 Recently, it has been shown that adjuvant TMZ.