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Neuro-Oncology

Oligodendrogliomas: Molecular Biology and Treatment

Neuro-Oncology Unit, Daniel den Hoed Cancer Center/Erasmus University Medical Center, Rotterdam, The Netherlands

Key Words. Oligodendroglioma • Oligoastrocytoma • 1p • 19q • MGMT • Temozolomide

Correspondence: Martin J. van den Bent, M.D., Neuro-Oncology Unit, Daniel den Hoed Cancer Center/Erasmus University Medical Center, PO Box 5201, 3008AE Rotterdam, The Netherlands. Telephone: 31-10-4391415; Fax: 31-10-4391031; e-mail: m.vandenbent{at}erasmusmc.nl

Received November 14, 2008; accepted for publication January 12, 2009; first published online in THE ONCOLOGIST Express on January 31, 2009.

Disclosures

Jacolien E. C. Bromberg: None; Martin J. van den Bent:Consultant/advisory role: Schering Plough; Honoraria: Schering Plough.

Section editors Jean-Yves Delattre and Tracy Batchelor have disclosed no financial relationships relevant to the content of this article.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Target audience: Physicians who wish to advance their current knowledge of clinical cancer medicine in neuro-oncology.

	Learning Objectives

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 

1. Evaluate the current challenges in the histological diagnosis of oligodendroglial tumors and apply best practices to optimize patient outcomes.
   
2. Analyze the molecular alterations in different subsets of tumors with oligodendroglial morphology.
   
3. Formulate treatment options for your patients with newly diagnosed and recurrent oligodendroglial tumors.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Oligodendroglial tumors continue to receive much attention because of their relative sensitivity to chemotherapy. The histological diagnosis of oligodendroglial tumors is subject to considerable interobserver variation. The revised 2007 World Health Organization classification of brain tumors no longer accepts the diagnosis "mixed anaplastic oligoastrocytoma" if necrosis is present; these tumors should be considered glioblastomas (perhaps with oligodendroglial features). The 1p/19q codeletion that is associated with sensitivity to chemotherapy is mediated by an unbalanced translocation of 19p to 1q. Randomized studies have shown that patients with 1p/19q codeleted tumors also have a better outcome with radiotherapy. Histologically more atypical tumors are less likely to have this 1p/19q codeletion; here, other alterations usually associated with astrocytic tumors are often found. Some patients with tumors with classic histological features but no 1p/19q codeletion still have a very favorable prognosis.

Currently, the best approach for newly diagnosed anaplastic oligodendroglial tumors is unclear. Early adjuvant chemotherapy does not provide a better outcome than chemotherapy at the time of progression. The value of combined chemoirradiation with temozolomide has not been proven in these tumors, and could at least theoretically be associated with greater neurotoxicity. Tumors with 1p and 19q loss can also be managed with early chemotherapy, while deferring radiotherapy to the time of further progression. The presently available second-line chemotherapy results are modest, and better salvage treatments are necessary. The molecular explanation for the greater sensitivity of 1p/19q codeleted tumors is still unclear, and this could, in part, be explained by more frequent MGMT promoter gene methylation.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Oligodendroglioma (OD) and mixed oligoastrocytoma (OA) constitute 5%–20% of all glial tumors. They are predominantly tumors of adulthood, with a peak incidence between the fourth and sixth decade of life; low-grade ODs tend to arise in slightly younger patients. Until some 15 years ago, the diagnosis of OD was merely a pathological entity, which changed with the recognition of the marked sensitivity to procarbazine, lomustine, and vincristine (PCV) chemotherapy of these tumors [1, 2]. A second development was the identification of the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) as the typical genetic lesions of OD, occurring in 60%–90% of ODs [3–6]. This was followed by the recognition that these 1p/19q codeleted tumors, in particular, have an excellent response to chemotherapy [4, 7–9]. Patients with ODs with the combined loss of 1p and 19q not only have a better response to chemotherapy, they also have a more indolent clinical course and a longer lasting response to radiotherapy (RT). These observations have led to the current tendency to consider 1p and 19q loss low-grade OD and anaplastic oligodendroglioma (AOD) as a separate biological entity, at least within clinical trials [8, 10]. New data at least question this assumption.

	HISTOLOGY

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
The current World Health Organization (WHO) definition of OD is "a well-differentiated, diffusely infiltrating tumor of adults, typically located in the cerebral hemispheres and composed predominantly of cells morphologically resembling oligodendroglia" [11]. By definition, mixed OA tumors have morphologic characteristics of both astrocytic tumors and pure ODs. Recent European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) trials used the presence of 25% oligodendroglial elements as the arbitrary cutoff point for the diagnosis of a mixed tumor. Since the results of one study that noted that the outcome of patients with mixed anaplastic oligoastrocytoma (AOA) with necrosis was similar to that of glioblastoma patients were available, the recent 2007 WHO classification of brain tumors no longer accepts the diagnosis of mixed OA if necrosis is present [6, 12]. These tumors are now considered amongst the glioblastomas, perhaps with the addition of "with oligodendroglial features." Whether or not there is any clinical significance, however, to identifying such oligodendroglial components in glioblastomas is unclear. Previous studies have shown that these tumors do indeed have a molecular pattern comparable with that of glioblastoma, with epidermal growth factor receptor gene (EGFR) amplification, phosphatase and tensin homologue deleted on chromosome 10 gene (PTEN) mutations, and loss of chromosome 10, but rarely combined 1p and 19q loss [13–15]. Of note, however, another large study did report somewhat better survival in patients with so-called grade 4 OAs (the diagnosis of which required necrosis) than in glioblastoma patients [16]. The median survival time in the AOA grade 4 group was 15.6 months, compared with 10.9 months in the glioblastoma group.

In pure AOD, the impact of necrosis is unclear. Miller et al. [6] did not find any impact of necrosis in pure AOD, nor did a review analysis of the North American prospective randomized study on oligodendroglial tumors [17]. In contrast, a similar European study found that both endothelial proliferation and necrosis were related to survival in AOD patients [18]. These subtle differences may be related to differences in the rather subjective histological criteria. From all studies, it is clear though that the outcome of AOD patients, even with necrosis, remains distinctly better than that of glioblastoma patients, which is not the case for mixed AOAs with necrosis.

	RELIABILITY OF THE HISTOLOGICAL DIAGNOSIS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Several studies have shown that considerable interobserver variation is present in the diagnosis of grade III tumors, including oligodendroglial tumors. In one project, 114 samples from a large prospective European trial were reviewed by nine independent pathologists [19]. The panel reached consensus (six or more of the nine agreeing on the diagnosis) on the diagnosis of AOD in 52% of the tumors that had been diagnosed as AOD by the local pathologists, whereas only 8% of the local diagnoses of AOA were confirmed with consensus. The coefficients of the individual panelists for the 52 cases with a consensus diagnosis of AOD were in the range of 0.46–0.72. A similar study on the North American randomized study investigated the interobserver variation in the diagnosis of "classical for oligodendroglioma" (CFO) (loosely defined as round regular nuclei, monomorphic appearance, perinuclear haloes, etc.) among experienced neuropathologists (Fig. 1) [17]. Tumor specimens from 247 patients were available for this review. Although the authors considered the outcome of the study supportive of an approach to clinical trials on OD, in which patients can only be included after central review, the interobserver agreement was only modest ( = 0.55), and one reviewer did not identify 22% of the CFO cases identified by consensus. In the above-mentioned study on CFO, which used five independent reviewers, a consensus diagnosis (four of five neuropathologists agreeing) was obtained in 83% of cases. In another series, a rather high degree of agreement was reported [20]. Most likely, close interaction among pathologists leads to a better diagnostic agreement, although that holds an element of subjectivity (e.g., within that specific group).

View larger version (176K): [in this window] [in a new window]   Figure 1. Classic oligodendroglial tumor, with fried egg appearance (which actually is an artificial fixation artifact).

	GENETICS: 1P/19Q CODELETION AND TRANSLOCATION

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

	HISTOMORPHOLOGY AND 1P/19Q CODELETION

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
A clear association exists between codeletion of 1p and 19q and a classic histological appearance (perinuclear halo, chicken-wire vascular pattern) [8, 17, 26]. The 1p/19q codeletion is present in 61%–89% of AOD cases, but in only 13%–20% of patients with AOA [6, 27]. Of note, McDonald et al. [27] confirmed the close association between CFO and 1p/19q codeletion, with a higher likelihood of 1p and 19q loss if more pathologists judged the tumor to be CFO. In mixed OAs with predominant oligodendroglial morphology, the percentage of tumors showing 1p and 19q loss drops to 39%, emphasizing that even the presence of minor astrocytic elements significantly reduces the chance of finding 1p and 19q loss [15].

Still, some atypical ODs have 1p/19q codeletions and some typical ODs do not show 1p and 19q loss. However, the outcome of patients with non-1p/19q codeleted tumors but with typical histological appearance was reported to be equally favorable in a large prospective U.S. trial [17]. Another study reported loss of 1p and 19q to be related, in particular, to outcome in patients with tumors with classic histologic features [27].

	OTHER GENETIC ABERRATIONS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Compared with low-grade ODs, AODs usually have additional chromosomal deletions, in particular loss of heterozygosity for 9p and/or deletion of the CDKN2A gene (p16) [15]. These occur in 33%–50% of AODs and are associated with tumor progression. As a rule, other chromosomal abnormalities are found in low-grade and in high-grade ODs with atypical morphological features. These are typically associated with astrocytomas and are usually mutually exclusive with 1p/19q codeletion (e.g., TP53 mutations in low-grade tumors and EGFR amplification, 10q loss, and PTEN mutations in anaplastic tumors) [15, 28–31]. Deletions on chromosome 10 have been reported in 19%–25% of anaplastic oligodendroglial tumors (AOTs) [15, 32]. Amplification of the EGFR gene on chromosome 7p occurs in 20%–30% of AOTs, but reportedly never in those with deletion of 1p and 19q, and correlates with a poor prognosis [14, 15, 33, 34]. Similarly, molecular analysis of the prospective EORTC study on AOTs observed more frequent loss of chromosome 10 and amplification of the EGFR gene in tumors diagnosed as mixed OAs with necrosis [18]. Again, these aberrations were inversely correlated with the 1p/19q codeletion. This suggests that these tumors are derived from different precursor cells. This hypothesis is supported by the marked differences in outcome and prognosis, with a superior outcome in the presence of 1p and 19q loss, and with poor survival in AODs with the loss of 10q and/or the amplification of EGFR [30]. The presence of 10q loss or EGFR amplification in pure AODs is sufficiently rare to suggest an alternate diagnosis (e.g., small cell glioblastoma) [15]. AOAs do not appear to constitute a fixed class of tumors, but rather a morphological continuum between pure ODs and astrocytomas. Only in exceptional cases do mixed tumors show genetically distinct clones of tumor within histologically different areas [35].

In an intriguing study on 70 patients with grade II and III oligodendroglial tumors, a number of prognostically unfavorable genomic alterations were identified, in particular, gain of 7p and 8q and loss of 9p, 10q, and 18q [36]. In the anaplastic tumors, the presence of the 1p/19q codeletion was a favorable prognostic factor, particularly if no other unfavorable genomic aberrations had been identified. Similarly, outcome was equally favorable in patients without 1p/19q codeletion and also without other unfavorable genomic aberrations. However, if 1p and 19q loss was accompanied by unfavorable alterations, the prognosis was poor. Others have reported that the prognostic impact of 1p and 19q loss is mainly present in tumors with classic AOD morphology, but not in oligodendroglial tumors with atypical features or in mixed AOAs [6, 27].

	METHYL GUANINE METHYLTRANSFERASE GENE (MGMT) AND ALKYLTRANSFERASE

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
No clear explanation is yet available for the favorable response to chemotherapy of AOTs as compared with astrocytic tumors. Previous studies suggested that the nuclear enzyme alkyltransferase, also known as methyl guanine methyltransferase (MGMT), which mediates at least part of the cell resistance to alkylating and methylating agents, is less expressed in ODs and perhaps even more so in 1p/19q codeleted tumors [37]. MGMT expression can be silenced by MGMT promoter gene methylation, which was initially reported to occur in 47% of low-grade ODs without a correlation with 1p/19q codeletion [38]. Other studies did, however, find a correlation between 1p/19q codeletion and MGMT promoter methylation, which was observed in up to 80%–90% of 1p/19q codeleted tumors [39–41]. MGMT promoter gene methylation occurs in up to 40%–50% of glioblastomas; it is therefore unlikely that this event alone accounts for the entire difference in sensitivity to chemotherapy between astrocytic tumors and oligodendroglial tumors, or for the greater chemosensitivity in 1p/19q codeleted tumors.

	WHY ARE 1P/19Q CODELETED TUMORS MORE SENSITIVE TO TREATMENT?

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Why 1p/19q codeleted tumors are more sensitive to RT and chemotherapy remains an unanswered question. There are a number of possible explanations: loss of genes that mediate resistance to treatment, the assumption that 1p and 19q loss is an epiphenomenon that identifies a tumor that is more sensitive to treatment (e.g., with less frequent other unfavorable mutations/alterations), or an association between 1p and 19q loss and other genetic events (e.g., MGMT promoter gene methylation). It is clear that ODs with 1p and 19q loss have gene expression profiles that differ from those of other gliomas [42]. The gene expression profile of 1p/19q codeleted ODs partially resembles that of the normal brain (proneural expression pattern) [43].

Several studies have shown that other specific epigenetic aberrations are observed in 1p/19q codeleted tumors. The maternally imprinted DIRAS3 tumor suppressor gene is located on 1p31, the expression of which is significantly decreased because of methylation in ODs with 1p loss [44]. Biallelic DIRAS3 inactivation has been associated with survival. Similarly, the expression of the CITED4 gene on 1p34.2 seems decreased through hypermethylation [45]. Again, CITED4 hypermethylation has been associated with longer survival. EMP3, located at 19q13.3, is another example of a gene that is frequently hypermethylated in OD and astrocytoma, but not in primary glioblastoma [46]. In all these cases, one allele is silenced because of loss and the other through hypermethylation. These findings support a major role for epigenetic phenomena in the pathogenesis of OD.

	IS 1P/19Q CODELETION PREDICTIVE OF OUTCOME TO CHEMOTHERAPY, OR PROGNOSTIC?

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Initial studies observed that response and survival rates were better in patients with OD with combined 1p and 19q loss than in those without 1p and 19q loss. Several studies have found the presence or absence of combined loss of 1p and 19q to be the most important prognostic factor for overall survival in AOTs [5, 47, 48]. The median survival duration was >6–7 years in the presence of the 1p/19q codeletion, and 2–3 years in the absence of the codeletion. For low-grade OD or OA, median survival time were 12–15 years for 1p/19q codeleted patients and 5–8 years for patients without the deletion [15, 21]. In all these studies, patients were treated with either chemotherapy or RT, and the longer progression-free survival time in RT-only treated patients suggests that the 1p/19q codeletion is more a prognostic than a predictive factor [26, 48]. This view was corroborated by studies that suggested that ODs have a more indolent behavior, even prior to the initiation of treatment [8, 10]. Indeed, a study measuring growth speed in low-grade gliomas observed a slower growth rate in 1p/19q codeleted ODs [49]. However, in a recent study of untreated low-grade ODs and AOTs, on multivariate analysis, the presence of 1p and 19q loss was found not to be prognostic for progression-free survival [20]. The overall picture that emerges from this is that 1p/19q codeleted tumors tend to have slower growth rates and to be more responsive to treatment than tumors without this codeletion. In that sense, the 1p/19q codeletion identifies a favorable prognostic subgroup, although it also predicts outcome to treatment. However, it may not really help in deciding on chemotherapy or not, because RT is also likely to give good treatment results.

	TREATMENT OF LOW-GRADE TUMORS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Following the favorable response of AOTs to chemotherapy, chemotherapy as initial treatment, employing either PCV or temozolomide, for patients with progressive low-grade ODs has been investigated in a limited number of retrospective or phase II studies. Radiological response rates, including the category minor response, of 30%–70% have been reported with PCV or with temozolomide, with a median time to progression of 2–3 years [49–52]. Response may be delayed—one series described a median time to maximum response of 12 months—and clinical response (e.g., better seizure control) is frequently more impressive than radiological response. Response rates are higher and time to progression is longer in 1p/19q codeleted tumors. Whether first-line chemotherapy for low-grade OD is superior to RT is unknown; the results of a current EORTC phase III study on this subject are awaited. In the meantime, for patients requiring large RT portals for large tumors, upfront treatment with PCV or temozolomide to avoid or delay the risk for late cognitive defects is a reasonable treatment option.

	TREATMENT OF ANAPLASTIC TUMORS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Newly Diagnosed AOD and AOA: (Neo-)adjuvant Chemotherapy Trials
Two prospective, randomized, controlled trials in AOTs have shown that (neo)adjuvant PCV chemotherapy given in addition to 60 Gy of RT does not result in a longer overall survival time, although it does lead to a longer progression-free survival time. The first of these trials, RTOG 94–02, randomized patients to either four cycles of upfront intensified PCV chemotherapy followed by RT to a dose of 60 Gy or RT only [47]. The second trial (EORTC 26951) randomized patients to 60 Gy of RT followed by six cycles adjuvant PCV or to 60 Gy of RT only [48]. Table 1 summarizes the progression-free survival and overall survival results of these studies. In both trials, the majority of patients randomized to the RT arm received PCV at progression, which most likely explains the longer progression-free survival time without a longer overall survival time. Because of this, these trials in fact investigated early (adjuvant) versus delayed (at the time of progression) PCV chemotherapy. Even in the 1p/19q loss subgroup analysis, no overall survival benefit of early (i.e., adjuvant or neoadjuvant) PCV could be demonstrated (Table 1). The conclusion of both trials is that in AOD, early PCV given sequentially with RT does not provide a superior outcome to initial RT only followed by chemotherapy at the time of recurrence.

Chemoirradiation with Temozolomide?
The current clinical question is whether combined chemoirradiation with temozolomide should also be used for AOTs. The negative outcome of the adjuvant PCV trials is in contrast to the observed survival benefit in glioblastoma patients of combined chemoirradiation with temozolomide, especially in tumors with a methylated MGMT promoter gene [54, 55]. A particular consideration here is that patients with anaplastic tumors with combined 1p and 19q loss have a median survival duration >6–7 years. Hence, the late neurotoxicity of a combined radiochemotherapy approach is potentially an issue. This is clearly less so for tumors without 1p and 19q loss, but here the benefit of the combined regimen is also unproven. Current studies are investigating the role of combined chemoirradiation in AODs, including other grade III tumors, with separate trials for tumors with and without combined 1p and 19q loss.

Upfront Chemotherapy in Newly Diagnosed AOT
The chemosensitivity of OTs has made upfront chemotherapy strategies (with or without subsequent RT) increasingly popular. The major rationale for upfront chemotherapy is the wish to defer RT. A few medium-sized and uncontrolled studies are available, in particular, employing temozolomide. One showed, in a young population (median age, 42 years) with 81% of patients having a Karnofsky Performance Status score of 90/100, a median progression-free survival time of 27 months with a 1-week-on/1-week-off dose-dense temozolomide regimen [56]. A small trial on upfront temozolomide chemotherapy showed a very short time to progression (8 months) in patients without 1p loss, in contrast to all seven patients with 1p loss who were still free from progression at 24 months [57]. In a prospective phase II study carried out by the RTOG, 39 eligible patients were neoadjuvantly treated with 6 months of 1-week-on/1-week-off 150 mg/m² temozolomide, followed by concurrent chemoirradiation with temozolomide [58]. In 32% of patients, an objective response was observed; 10% of patients progressed during neoadjuvant temozolomide. In 28 patients, the 1p/19q status could be assessed; all 17 patients with the 1p/19q codeletion were free from progression at 6 months. No less than 16 of the 20 patients tested had MGMT promoter methylation, all were free from progression at 6 months. Thirteen of the 16 patients with MGMT promoter methylation also had 1p/19q codeletion. The overall survival rate at 30 months was 81%; the 1p/19q codeletion was related to survival. The obvious difficulty in the interpretation of this trial is the short follow-up and absence of control patients, limiting conclusions beyond the well-established superior outcome for patients with 1p/19q codeleted AOTs with upfront temozolomide.

In a phase II trial in 69 patients with newly diagnosed anaplastic or aggressive OD, the intensive PCV regimen was followed by high-dose thiotepa with autologous stem cell rescue, without RT. The median progression-free survival time in the 39 patients who received the autologous stem cell procedure was 78 months, and the median overall survival time had not been reached. Eighteen patients (46%) had relapsed [59]. In view of the patient selection and the absence of a control arm, final conclusions on the meaning of these results are impossible to draw; many patients with AOTs have similar survival times without such intensive treatments. The trial showed, though, that a longer progression-free survival time without initial RT is possible. The German NOA4 trial showed that patients treated with chemotherapy first had a similar survival benefit to patients managed with RT first [53]. That trial, which basically studied sequential treatment (RT first or chemotherapy first), demonstrated that whatever sequence is followed, the results are comparable. The choice for chemotherapy or RT may well come down to deciding between side effects: local side effects of a short series of RT or systemic side effects of (expensive) chemotherapy of 1-year duration.

Second-Line Chemotherapy in Recurrent AOTs
Second-line PCV after failure with temozolomide induced a response in only 17% of patients, but 50% were still free from progression at 6 months and 21% were still free from progression at 12 months [60]. Similarly, 25% of patients had an objective response to temozolomide after PCV and 29% and 11% of patients were free from progression after 6 and 12 months, respectively [61]. Occasionally, patients that do not respond to one regimen are responsive to the other. However, in general, response rates to second-line chemotherapy are modest, even in 1p/19q codeleted tumors (and regardless of the sequence chosen—temozolomide first or PCV first). Still, very few other agents have been systematically evaluated in AOTs. One trial found PCV chemotherapy followed by an autologous bone marrow transplantation after a myeloablative procedure with melphalan to be too toxic, without clearly producing superior results [62]. Response to carboplatin monotherapy was similar to that of temozolomide, with 13% of patients responding and with 35% and 9% 6- and 12-month progression-free survival times, respectively [63]. These results were obtained, however, at the cost of considerable myelotoxicity. In a study of CPT-11 on 22 patients with 1p/19q codeleted AODs, the response rate was 23% and the 6- and 12-month progression-free survival times were 33% and 4.5%, respectively [64]. Despite the upregulation of platelet-derived growth factor (PDGF) signaling pathways in most ODs, the PDGF receptor tyrosine kinase inhibitor imatinib did not show any activity in recurrent OD or AOD/AOA [65]. Clearly, for a further improvement in outcome after failing first-line chemotherapy and RT, other approaches need to be developed.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
The histological diagnosis of OD is still hampered by significant interobserver variation. The clear correlation between classic histology and 1p/19q codeletion has led some to use this codeletion as a marker for OD, and it has even been suggested to build this into the diagnosis. However, it is becoming increasingly questionable whether this nice and simple conclusion is justified. Several studies have now observed that patients with tumors with classic oligodendroglial morphology, even without 1p/19q codeletions, have a better prognosis than those with astrocytic tumors [17, 36, 53]. This argues in favor of the use of more strict morphological criteria for oligodendroglial tumors, although even in the hands of experts up to 20% of CFO cases may not be agreed upon [17]. The recently modified WHO classification considers necrosis to no longer be compatible with the diagnosis of mixed AOA, which should thus be considered glioblastoma (with some oligodendroglial features).

The basic molecular characteristic of 1p/19q codeletion and the explanation for the sensitivity of these tumors to RT and chemotherapy is still unresolved. It is also unclear whether that sensitivity is to be expected in tumors with classic morphology in the absence of the 1p/19q codeletion. Despite the recent data suggesting a favorable subset of these tumors, the initial studies suggested that 1p/19q status was better correlated with response to chemotherapy than with morphology [7, 8].

For today's patients, sequential treatment with RT and chemotherapy, depending on the expected side effects and treatment efficacy, seems to be the optimal approach, with currently no solid data available to help in making the choice between initial RT and initial chemotherapy [53]. The value of concurrent chemoirradiation with temozolomide in these tumors has not been established, nor has it been established whether or not this treatment will induce long-term side effects in patients with an expected long survival time.

	AUTHOR CONTRIBUTIONS

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 
Conception/design: Martin J. van den Bent, Jacolien E.C. Bromberg

Provision of study materials: Martin J. van den Bent, Jacolien E.C. Bromberg

Collection/assembly of data: Martin J. van den Bent, Jacolien E.C. Bromberg

Manuscript writing: Martin J. van den Bent, Jacolien E.C. Bromberg

Final approval of manuscript: Martin J. van den Bent, Jacolien E.C. Bromberg

	REFERENCES

Top Learning Objectives Abstract Introduction Histology Reliability of the Histological... Genetics: 1p/19q Codeletion and... Histomorphology and 1p/19q... Other Genetic Aberrations Methyl Guanine Methyltransferase... Why Are 1p/19q Codeleted... Is 1p/19q Codeletion Predictive... Treatment of Low-Grade Tumors Treatment of Anaplastic Tumors Conclusions Author Contributions References

 

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