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 astrocytic 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

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, leading to some speculation about a mechanistic association 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-

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 ++, EGFR ~ IGS-17 1p19q codel +, 19% 2.8 y IDH ++, EGFR - IGS-18 1p19q codel –, IGS-18 (19%) 1.2 y IDH ~, EGFR ++ IGS-23 1p19q codel –, IGS-23 (19%) 1.0 y IDH ~, EGFR +

++ present in most samples; + present in some samples; ~ rarely present; – absent in all samples Abbreviations: 1p19q codel, 1p/19q codeletion; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; ATRX, alpha thalassemia/ mental retardation syndrome X-linked; CIC, homolog of Drosophila capicua; EGFR, epidermal growth factor receptor; FUBP1, far upstream binding protein 1; I-A, IDH1/ATRX group; I-CF, IDH1/CIC, FUBP1 group; I-X, neither I-A or I-CF31; IDH, isocitrate dehydrogenase enzyme; IGS, intrinsic glioma subtype34; mut, mutation present.

KN2A loss, or high vascular endothelial growth fac- prospective tissue collection, and were able to amend tor (VEGF) expression are rare molecular features their protocols to retrospectively test tissue samples found in AO and AOA.33 These are generally associ- once those markers were established. For both stud- ated with the IDH wild-type group, but even in rare ies, initial analyses in 2006 showed no significant patients who also have an IDH mutation, they are in- difference in overall survival between the arms that dicators of poor prognosis (Table 1).34 Ki-67 (MIB-1) combined therapies and the arms with radiotherapy index may play a prognostic role in AO, with one alone. However, at the time of publication, the me- study suggesting that values higher than a cutoff of dian survival in the combination arms had not yet approximately 23% portend shorter progression-free been reached in patients with 1p/19q codeletion.6,7 and overall survivals.35 Although a clear improvement in progression-free survival was seen in the patients with 1p/19q codeletion, additional correlative quality-of-life studies Combination Therapy for AO and AOA performed by RTOG 9402 showed no significant RTOG 9402 and EORTC 26951 were complemen- difference in quality-of-life measures for the patients tary phase III clinical trials developed in the mid- with 1p/19q codeletion.6,36,37 1990s based on the early reports of high treatment Additional follow-up data over subsequent years response rates in patients with AO or AOA.6,7,36,38 coupled with extraordinary efforts to complete data RTOG 9402 compared dose-intense PCV therapy regarding 1p/19q codeletion and IDH mutation status followed by radiotherapy and radiotherapy alone, in both studies led to new long-term data.36,38 These whereas EORTC 26951 compared radiotherapy fol- data revealed significant improvements in overall sur- lowed by PCV therapy and radiotherapy alone (Ta- vival among patients with 1p/19q codeletion, with ble 2). Although neither trial was initially designed median overall survivals of 14.7 years and NR (not yet to incorporate 1p/19q codeletion or IDH mutation reached) among those receiving combination therapy status, because neither marker had been described at versus 7.3 years and 9.3 years in those receiving radia- the time, both trials recognized the importance of tion alone in the RTOG and EORTC studies, respec-

Anderson and Gilbert

tively (hazard ratio [HR], 0.47; 95% CI, 0.30–0.72; recently presented.43 Those without the 1p/19q P<.001 and HR, 0.56; 95% CI, 0.31–1.03; P=.0594, codeletion had a median overall survival of 5.8 respectively; Table 2).36,38 As the strongest available years and a median progression-free survival of 1.3 data, the studies indicate radiation alone should no years. Given the small sample sizes, comparisons of longer be considered adequate treatment for patients results from RTOG 0131 and RTOG 9402 are diffi- with 1p19q codeleted AO tumors. However, these cult, although the results look similar (Table 2).43,44 studies were not designed to address the efficacy of To evaluate the use of chemotherapy alone in chemotherapy alone, which has been a widely used anaplastic gliomas (including AOA and AO), the approach by the neurooncology community.39 German Cancer Society Neuro-Oncology Working Additionally, combination therapy was also associ- Group trial NOA-04 randomized patients to either ated with a nonsignificant trend of improved outcome radiation therapy alone or chemotherapy alone. in some of the patients without 1p/19q codeletion in Chemotherapy was either temozolomide or PCV, EORTC 26951 (Table 2). This finding highlights the and crossover between arms was permitted (Table fact that other molecular subtypes defined by markers 2).8 No significant survival differences were found, other than 1p/19q codeletion exist that may benefit even in light of the results from RTOG 9402 and from combination therapy. The previously described EORTC 26951, and definitive conclusions about group with both IDH and ATRX mutations may rep- treatment with chemotherapy alone cannot be resent this additional subtype, because the trend of reached; there were not enough patients with AOA improvement with combination therapy is absent in and AO or reported comparative outcomes strati- the patients with IDH wild-type AO who are without fied by 1p/19q codeletion. However, 1p/19q codele- the 1p/19q codeletion, but this has not yet been vali- tion, MGMT methylation, and the IDH mutation dated in a prospective clinical trial.34,36 were evaluated in these patients and were shown to be prognostic markers. As expected, this trial did confirm that patients receiving temozolomide expe- Temozolomide in Anaplastic Glioma rienced fewer adverse events than those receiving Temozolomide is an oral DNA alkylating agent with PCV.8 Although more adverse events occurred in a much better toxicity profile than either single- the chemotherapy arms than in the radiation-only agent lomustine or the PCV regimen. After the arm, fewer hematologic side effects were reported in initiation of both RTOG 9402 and EORTC 26951, this trial than in RTOG 9402 and EORTC 26951 temozolomide was tested in a series of clinical trials (Table 2). for recurrent glioblastoma and anaplastic glioma, and in 1999 this agent was approved for recurrent nitrosourea (ie, lomustine)–refractory anaplastic Clinical Discussion and Recommendations glioma.40 Small studies demonstrated the activity The NCCN Clinical Practice Guidelines in Oncol- of temozolomide in recurrent AO and AOA.41,42 ogy (NCCN Guidelines) for adult AO and AOA are RTOG 0131 was a clinical trial designed to evalu- currently stratified by 1p/19q codeletion status and ate the role of temozolomide in the treatment of pa- KPS.45 The NCCN Guidelines state that all patients tients with newly diagnosed AO or AOA.43,44 This should undergo maximal resection, with an attempt single-arm phase II trial administered temozolo- at gross total resection, verified by MRI within 72 mide before radiation treatment, similar to RTOG hours of the surgery. Most studies have validated ex- 9402. In this trial, patients with AO were treated tent of surgical resection as a prognostic feature, al- with dose-dense temozolomide followed by radia- though these studies were performed in various types tion therapy with concurrent temozolomide (Table of malignant glioma.13 Additionally, obtaining tissue 2). Results included 2 patients who experienced is important given the implications from molecu- complete responses, and radiotherapy was deferred lar markers. Those with AO or AOA, KPS greater in those patients. Median overall survival has not than or equal to 70, and 1p/19q codeletion are rec- been reached for the patients with 1p/19q codele- ommended to receive either combination radiation tion, but a 6-year overall survival rate of 82% and and chemotherapy or chemotherapy alone (as a 3-year progression-free survival rate of 77% were category 2B option), whereas those without 1p/19q

Management of Anaplastic Oligodendroglioma/Oligoastrocytoma

Table 2 Summary of the RTOG 9402, EORTC 26951, RTOG 0131, and NOA-04 Trials

RTOG 9402 EORTC 26951 RTOG 0131 NOA-04 Chemotherapy Dose-Intense PCV: Standard PCV: Dose-Intense TMZ: PCV: lomustine, 110 regimen lomustine, 130 mg/m2 lomustine, 110 mg/m2 150 mg/m2 po on mg/m2 po on day 1; po on day 1; po on day 1; days 1–7 and 15–21, procarbazine, 60 mg/m2 procarbazine, 60 mg/m2 procarbazine, 60 mg/m2 on a 28-day cycle; po on days 8–21; and po on days 8–21; and po on days 8–21; and then 75 mg/m2 vincristine, 2 mg IV on vincristine, 1.4 mg/m2 IV vincristine, 1.4 mg/m2 IV po on days 1–42 days 8 and 29—on a on days 8 and 29—on a on days 8 and 29—on a during radiation 56-day cycle. TMZ: 42-day cycle 42-day cycle 200 mg/m2 po on days 1–5, on a 28-day cycle Combination RT Standard RT: 33 × 1.8 Gy, for a total dose of 59.4 Gy None

Sequence PCV → RT RT → PCV TMZ → RT CT alone Comparison RT alone RT alone RT alone RT alone arm Significant mOS 4.7 vs 4.6 y mOS 3.5 vs 2.6 y mOS NR mOS 6.9 vs 6.0 y results With 1p/19q mOS 14.7 vs 7.3 y mOS NR vs 9.3 y 6-y OS: 82% Not reported codeletion mPFS 8.4 vs 2.9 y mPFS 13.0 vs 4.2 y 3-y PFS: 77% Not reported Without 1p/19q mOS 2.6 vs 2.7 y mOS 2.1 vs 1.8 y mOS 5.8 y Not reported codeletion mPFS 1.2 vs 1.0 y mPFS 1.2 vs 0.7 y mPFS 1.3 y Not reported Significant Toxicities From Chemotherapy Hematologic 56% 46% 38% PCV 19%, TMZ 4% Toxicity leading 20% 38% 10% PCV 16%, TMZ 6% to abbreviated chemotherapy

Abbreviations: IV, intravenous; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; OS, overall survival; PCV, procarbazine, lomustine, vincristine; PFS, progression-free survival; RT, radiation therapy; TMZ, temozolomide. codeletion are grouped with anaplastic astrocytomas, a more accurate prognosis than histologic morphol- and those with poor performance status (KPS<70) ogy.46 should receive less-aggressive care. Despite the strong evidence for the use of radia- The inclusion of the 1p/19q codeletion status tion and chemotherapy in patients with AO with in the NCCN Guidelines is predicated on the ben- 1p/19q codeletion, important questions remain that efit shown in RTOG 9402 and EORTC 26951 from were not addressed by prior studies. Given the signif- frontline use of radiation therapy and chemotherapy, icant toxicity associated with PCV, many clinicians although RTOG 9402 included patients with a KPS of prefer to use temozolomide, which has an overall 60.36,38 Testing for it in all patients with AOA and AO better toxicity profile. Unfortunately, no prospec- is therefore mandated based on its utility as a predictive studies confirm the therapeutic equivalence of tive marker. The predictive utility of IDH mutations temozolomide. In a retrospective collection includ- is less clear, although it is clearly a prognostic marker. ing 1000 patients with AO, data suggest that PCV However, recent studies suggest alternative molecular may be superior to temozolomide when used without subgroups of AO and AOA, independent from the radiation therapy in patients with the 1p/19q codele- 1p/19q codeletion, that may benefit from combination, though the lack of prospective data precludes tion therapy, associated with mutations in IDH and definitive conclusions.47 The CODEL study was MGMT methylation.26,31,34 A small prospective study originally a randomized phase III study designed to evaluating 107 patients with anaplastic glioma found compare radiation with combined radiation and te- that those with AOA and AO with 1p/19q codeletion mozolomide versus temozolomide alone in patients and/or an IDH mutation had similar outcomes, also with 1p/19q codeletion, but was halted because of suggesting that molecular characteristics will provide the results of RTOG 9402 and EORTC 26951. The

Anderson and Gilbert

revamped protocol will compare radiation with PCV CODEL will provide some preliminary data. Con- and radiation with temozolomide, but will also pro- sequently, any formal recommendations regarding vide some preliminary data regarding the frontline PCV or temozolomide schedule would be speculative use of temozolomide alone, reserving radiation as a and based on personal bias. Although no clear con- salvage regimen. For patients having an anaplastic sensus exists, many physicians prescribe temozolo- glioma without the 1p/19q deletion, the ongoing mide as frontline treatment because of PCV toxicity. CATNON study compares radiation alone; concur- However, the results of RTOG 9402 and EORTC rent radiation and temozolomide; radiation followed 26951 have resulted in a recent increase in the use of by temozolomide; and concurrent radiation and PCV for these patients. This uncertainty underscores temozolomide followed by temozolomide. In light the need for active recruitment and participation in of the experience of the prior clinical trials study- the ongoing CODEL clinical trial. Conversely, the ing patients with AO, these studies will likely take RTOG and EORTC studies provide support for us- years to complete, and several more years for efficacy ing radiation therapy alone for patients without the data to mature. Additionally, final efficacy data may 1p/19q codeletion, although some recent data sug- be difficult to interpret because of challenges from gest that grade III tumors with wild-type IDH may crossover when additional chemotherapy is used at have tumor biology closer to grade IV gliomas, there- progression. by requiring the chemoradiation treatment used for Additionally, the optimal dosing of chemother- glioblastoma.31,34,49 apy and sequence of radiation with chemotherapy Continued molecular studies and the develop- has not been established, because both of the RTOG ment of agents, such as those targeting IDH muta- studies (9402 and 0131) used preradiation dose- tion–related pathways, will likely impact future dis- intense chemotherapy, whereas EORTC 26951 ad- ease classification and lead to more refined treatment ministered radiation followed by standard-dose PCV. recommendations.50 The RTOG 0131 study used a dose-intense temozolomide schedule, but no data comparing standard- dose temozolomide are available, leading to concerns References regarding the optimal schedule for temozolomide 1. 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