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Clinical Discussion of the Management of Anaplastic Oligodendroglioma/Oligoastrocytoma

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Clinical Discussion of the Management of Anaplastic Oligodendroglioma/Oligoastrocytoma Original 665 Article Clinical Discussion of the Management of Anaplastic Oligodendroglioma/ Oligoastrocytoma (Both Codeleted and Nondeleted) Mark D. Anderson, MD,a and Mark R. Gilbert, MDb Abstract olecularly driven therapy has become well estab- Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocy- M toma (AOA) are uncommon malignant tumors occurring in adults, lished in the treatment of many subtypes of cancers. but have garnered attention because of a high rate of response to Despite efforts in the past decade to further refine gli- chemotherapy in early studies. However, no clinical trial had dem- oma treatment according to molecular subtypes of ma- onstrated benefit with the addition of chemotherapy to radio- lignancy, no significant progress in the development of therapy alone until the long-term results of RTOG 9402 and EORTC predictive markers has been made. However, molecu- 26951. These studies revealed prolonged survival in patients with anaplastic gliomas harboring the 1p/19q codeletion when treated lar patterns are now emerging that further define these with PCV (procarbazine, lomustine, and vincristine) and radiation tumors and their prognosis, and will potentially alter therapy compared with radiation alone. These studies validated treatment recommendations. Currently, anaplastic oli- the use of 1p/19q codeletion status as a predictive biomarker in godendroglioma (AO) is defined as a malignant tumor these tumors. Additional molecular characterization of these tu- with features of oligodendroglial lineage and histologic mors may provide additional insight into treatment decisions, although these characterizations have yet to be fully elucidated. characteristics, whereas anaplastic oligoastrocytoma Even with the strength of the data advocating the use of combina- (AOA) seem to have a mixture of oligodendroglial tion therapy (PCV and radiotherapy), the incorporation of newer, and astrocytic features; both correspond to WHO grade less-toxic drugs such as temozolomide into many practices in the III.1,2 The reported annual incidence of AO ranges from past decade raises important questions regarding the optimal che- 0.07 to 0.18 per 100,000, and it comprises only 0.5% motherapy regimen. Unfortunately, additional definitive phase III trials will take several years to answer remaining questions. Re- to 1.2% of all primary brain tumors, whereas the ex- 2–4 gardless, it is clear that patients with 1p/19q codeleted AO or AOA act incidence of AOA is not well established. This who can tolerate chemotherapy should not receive radiotherapy is complicated by the discordance even among expert alone. (J Natl Compr Canc Netw 2014;12:665–672) reviewers, because the presence of abnormal astrocytes within an AO can lead to misdiagnosis as an AOA or anaplastic glioblastoma with oligodendroglial features, or an AOA might be misclassified as an AO if the as- trocytic component is thought to be reactive.5 The peak incidence of these tumors is in the fifth decade and both tend to preferentially occur in the frontal lobe, followed by the temporal lobe. From the aDepartment of Neurology, The University of Mississippi Medical Center, Jackson, Mississippi; and bDepartment of Neuro- Because prior results of clinical trials evaluating Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. treatment of AO or AOA with chemotherapy, either Submitted September 2, 2013; accepted for publication alone or in combination with radiotherapy, showed no December 4, 2013. The authors have disclosed that they have no financial interests, survival benefit and produced additional toxicity when arrangements, affiliations, or commercial interests with the compared with radiotherapy alone, standard therapy manufacturers of any products discussed in this article or their competitors. for these anaplastic gliomas was typically radiotherapy Correspondence: Mark R. Gilbert, MD, 1500 Holcombe Boulevard, alone.6–8 However, crossover from patients undergoing Unit 431, Houston, TX 77030. E-mail: [email protected] radiation who receive chemotherapy after progression © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 12 Number 5 | May 2014 666 Original Article Anderson and Gilbert may have affected the ability to discern a survival mutation of either the homolog of Drosophila capicua difference. The growing evidence of the sensitivity (CIC) gene in most cases, and/or the far upstream of oligodendroglioma and oligoastrocytoma to com- binding protein 1 (FUBP1) gene in the remaining bined treatment with procarbazine, lomustine, and 20% of cases with 1p/19q codeletion.23,24 The TP53 vincristine (PCV) led to the consideration of the mutation, which is most commonly observed in astro- early use of chemotherapy for these specific tumors cytic lineage, is rarely described in AO, but is more to delay or augment radiation therapy.9–11 Despite frequently described in AOA, and are inversely re- the absence of strong evidence in a randomized con- lated to the frequency of 1p/19q codeletion in AO trolled study, an increased prevalence of the use of and AOA.25 The 1p/19q codeletion can be tested rou- chemotherapy alone or with radiation has been seen tinely using fluorescent in situ hybridization (FISH) in the past 3 decades.12 analysis, whereas the TP53 mutation can be evalu- Even with therapy, the historical median overall ated with p53 immunohistochemistry (IHC), or with survival for patients with AO has been reported to greater accuracy using mutational analysis. be between 2 and 6 years.6,7,13 In AOA, the average O(6)-Methylguanine-DNA methyltransferase survival has been generally shorter, at around 3 years, (MGMT) promoter methylation and the CpG island although still improved compared with glioblastoma.2 hypermethylation phenotype (CIMP) have also Several studies have established the clinical features been identified in patients with AO and AOA.26 of younger age, higher Karnofsky performance status Both were prognostic markers for survival, but CIMP (KPS), and larger extent of resection as favorable status had a stronger association, suggesting that prognostic features.13–17 Although no environmental MGMT promoter methylation status may be part of factors are known to increase the risk of development a methylation profile.26 The recently described muta- of an oligodendroglial tumor, a single nucleotide tion of the isocitrate dehydrogenase 1 and 2 (IDH1 germline polymorphism on chromosome 8q24.21 has and IDH2) enzymes in glioma cells is also strongly recently been linked with this risk.18,19 associated with a hypermethylated phenotype, lead- ing to some speculation about a mechanistic asso- ciation between IDH mutation and methylation.27 Molecular Characteristics of AO and AOA Patients with IDH mutations also have an improved Inspired by the success of defining molecular subtypes prognosis over those with wild-type IDH, and these of hematologic malignancies and other primary can- mutations may be a substitute for MGMT and CIMP cers, a molecular subtype of oligodendroglial tumors status for evaluating methylation status.28 The muta- that was associated with differences in patient out- tion in the IDH enzymes results in the accumulation come was first described in the 1990s.20 The allelic of 2-hydroxyglutarate (2HG), which is thought to loss of the short arm of chromosome 1 (1p) and the be involved in glioma genesis.29 Notably, most tu- long arm of chromosome 19 (19q) became associated mors with 1p/19q codeletion have either an IDH1 with tumors of oligodendroglial lineage, revealing a or IDH2 mutation.30 Conversely, a separate cohort new diagnostic marker, often termed 1p/19q codele- of tumors do not have the 1p19q codeletion but also tion.20 Additionally, when the 1p/19q codeletion was have an IDH mutation. This latter group has a worse observed, a significant improvement in treatment prognosis than the 1p19q-codeleted subpopulation, response and improved survival were seen, further but an improved prognosis compared with the IDH defining it as a prognostic marker.9 However, in con- wild-type group.25 Additionally, inactivating altera- trast to the positive prognostic implications of the tions in alpha thalassemia/mental retardation syn- typical 1p19q codeletion, patients recognized to drome X-linked (ATRX) have been described in have a relative 1p/19q codeletion because of aneu- association with IDH mutations, and in most cases ploidy may have a significantly worse prognosis and are mutually exclusive to the 1p/19q codeletion, sug- clinical course, and must be differentiated from those gesting they play a role in the development of glioma with a true 1p/19q codeletion.21,22 in patients with the IDH mutation but without the More recently, further analysis revealed that most 1p/19 codeletion31,32 (Table 1). 1p/19q codeletions are produced by a translocation of PI3K mutations, PTEN loss, epidermal growth 1p and 19q. Additionally, there is an accompanying factor receptor (EGFR) amplification, 10q loss, CD- © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 12 Number 5 | May 2014 Original Article 667 Management of Anaplastic Oligodendroglioma/Oligoastrocytoma Table 1 Molecular Subtypes of AO/AOA Survival Molecular Subtypes Composition of Independent of of AO/AOA Subtypes Prevalence in AO Prevalence in AOA Histology I-CF IDH mut and CIC- 77% 23% 8.0 y FUBP1 mut I-A IDH mut and 16% 65% 4.3 y ATRX mut I-X no CIC-FUBP1 or 7% 10% 1.1 y ATRX mut Prevalence in AO and AOA IGS-9 1p19q codel ++, 26% 8.5 y IDH ++,
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