From: Subject: Oligodendrogliomas: Molecular Biology and Treatment -- Bromberg and van den Bent 14 (2): 155 -- The Oncologist Date: Mon, 2 Mar 2009 18:39:16 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C99B66.30C8DF50" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C99B66.30C8DF50 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://theoncologist.alphamedpress.org/cgi/content/full/14/2/155 Oligodendrogliomas: Molecular Biology and Treatment = -- Bromberg and van den Bent 14 (2): 155 -- The Oncologist
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First Published Online January = 31,=20 2009
The Oncologist, Vol. 14, No. 2, = 155-163,=20 February 2009; doi:10.1634/theoncologist.2008-0248
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Neuro-Oncology

Oligodendrogliomas: Molecular Biology and=20 Treatment

Jacolien E. C. = Bromberg,=20 Martin J. van den Bent

Neuro-Oncology Unit, Daniel den Hoed Cancer = Center/Erasmus=20 University Medical Center, Rotterdam, The Netherlands

Key Words. Oligodendroglioma =95 Oligoastrocytoma = =95 1p =95 19q =95=20 MGMT =95 Temozolomide

Correspondence: Martin J. van den Bent, M.D., Neuro-Oncology Unit, = Daniel den=20 Hoed Cancer Center/Erasmus University Medical Center, PO Box 5201, = 3008AE=20 Rotterdam, The Netherlands. Telephone: 31-10-4391415; Fax: = 31-10-4391031;=20 e-mail: m.vandenbent{at}erasmusmc.nl

Received November 14, 2008; accepted for publication January 12, = 2009; first=20 published online in THE ONCOLOGIST Express on = January=20 31, 2009.

Disclosures

Jacolien E. C.=20 Bromberg: None; Martin J. van den Bent:Consultant/advisory = role: Schering Plough; Honoraria: Schering Plough.=20

Section editors Jean-Yves Delattre and = Tracy=20 Batchelor have disclosed no financial relationships relevant to the = content=20 of this article.

The content of this = article has=20 been reviewed by independent peer reviewers to ensure that it is = balanced,=20 objective, and free from commercial bias.=20

Target audience: Physicians who wish to = advance=20 their current knowledge of clinical cancer medicine in neuro-oncology.


3D"   =20 Learning Objectives
Top
3D"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=20 patient outcomes.
  2. Analyze the molecular alterations in different subsets = of=20 tumors with oligodendroglial morphology.
  3. Formulate treatment options for your patients with = newly=20 diagnosed and recurrent oligodendroglial = tumors.=20

This article is available for continuing medical education = credit=20 at CME.TheOncologist.com.=20


3D"    ABSTRACT
Top
Learning Objectives
3D"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
 
<= STRONG>Oligodendroglial=20 tumors continue to receive much attention because of their = relative=20 sensitivity to chemotherapy. The histological diagnosis of=20 oligodendroglial tumors is subject to considerable = interobserver=20 variation. The revised 2007 World Health Organization = classification=20 of brain tumors no longer accepts the diagnosis "mixed = anaplastic=20 oligoastrocytoma" if necrosis is present; these tumors should = be=20 considered glioblastomas (perhaps with oligodendroglial = features).=20 The 1p/19q codeletion that is associated with sensitivity to=20 chemotherapy is mediated by an unbalanced translocation of = 19p to 1q.=20 Randomized studies have shown that patients with 1p/19q = codeleted=20 tumors also have a better outcome with radiotherapy. = Histologically=20 more atypical tumors are less likely to have this 1p/19q = codeletion;=20 here, other alterations usually associated with astrocytic = tumors are=20 often found. Some patients with tumors with classic = histological=20 features but no 1p/19q codeletion still have a very favorable = prognosis.

Currently, the best approach for newly diagnosed anaplastic=20 oligodendroglial tumors is unclear. Early adjuvant = chemotherapy=20 does not provide a better outcome than chemotherapy at the = time=20 of progression. The value of combined chemoirradiation with=20 temozolomide has not been proven in these tumors, and could = at=20 least theoretically be associated with greater neurotoxicity. = Tumors=20 with 1p and 19q loss can also be managed with early chemotherapy,=20 while deferring radiotherapy to the time of further = progression.=20 The presently available second-line chemotherapy results are=20 modest, and better salvage treatments are necessary. The = molecular=20 explanation for the greater sensitivity of 1p/19q codeleted=20 tumors is still unclear, and this could, in part, be = explained=20 by more frequent MGMT promoter gene methylation. =


3D"    INTRODUCTION
Top
Learning Objectives
Abstract
3D"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
 
O= ligodendroglioma=20 (OD) and mixed oligoastrocytoma (OA) constitute 5%=9620% of = all glial=20 tumors. They are predominantly tumors of adulthood, with a = peak=20 incidence between the fourth and sixth decade of life; = low-grade ODs=20 tend to arise in slightly younger patients. Until some 15 = years ago,=20 the diagnosis of OD was merely a pathological entity, which = changed=20 with the recognition of the marked sensitivity to = procarbazine,=20 lomustine, and vincristine (PCV) chemotherapy of these tumors = [1,=20 2].=20 A second development was the identification of the combined = loss of=20 the short arm of chromosome 1 (1p) and the long arm of = chromosome 19=20 (19q) as the typical genetic lesions of OD, occurring in = 60%=9690%=20 of ODs [3=966].=20 This was followed by the recognition that these 1p/19q = codeleted=20 tumors, in particular, have an excellent response to = chemotherapy [4,=20 7=969].=20 Patients with ODs with the combined loss of 1p and 19q not = only have=20 a better response to chemotherapy, they also have a more = indolent=20 clinical course and a longer lasting response to radiotherapy = (RT).=20 These observations have led to the current tendency to = consider 1p=20 and 19q loss low-grade OD and anaplastic oligodendroglioma = (AOD) as a=20 separate biological entity, at least within clinical trials = [8,=20 10].=20 New data at least question this assumption.


3D"    HISTOLOGY
Top
Learning Objectives
Abstract
Introduction
3D"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
 
T= he=20 current World Health Organization (WHO) definition of OD is = "a=20 well-differentiated, diffusely infiltrating tumor of adults,=20 typically located in the cerebral hemispheres and composed=20 predominantly of cells morphologically resembling = oligodendroglia"=20 [11].=20 By definition, mixed OA tumors have morphologic = characteristics=20 of both astrocytic tumors and pure ODs. Recent European = Organization=20 for Research and Treatment of Cancer (EORTC) and Radiation = Therapy=20 Oncology Group (RTOG) trials used the presence of 25%=20 oligodendroglial elements as the arbitrary cutoff point for = the=20 diagnosis of a mixed tumor. Since the results of one study = that noted=20 that the outcome of patients with mixed anaplastic=20 oligoastrocytoma (AOA) with necrosis was similar to that of=20 glioblastoma patients were available, the recent 2007 WHO=20 classification of brain tumors no longer accepts the = diagnosis of=20 mixed OA if necrosis is present [6,=20 12].=20 These tumors are now considered amongst the glioblastomas, = perhaps=20 with the addition of "with oligodendroglial features." = Whether or not=20 there is any clinical significance, however, to identifying = such=20 oligodendroglial components in glioblastomas is unclear. = Previous=20 studies have shown that these tumors do indeed have a = molecular=20 pattern comparable with that of glioblastoma, with epidermal = growth=20 factor receptor gene (EGFR) amplification, phosphatase = and=20 tensin homologue deleted on chromosome 10 gene (PTEN)=20 mutations, and loss of chromosome 10, but rarely combined 1p = and 19q=20 loss [13=9615].=20 Of note, however, another large study did report somewhat = better=20 survival in patients with so-called grade 4 OAs (the = diagnosis of=20 which required necrosis) than in glioblastoma patients [16].=20 The median survival time in the AOA grade 4 group was 15.6 = months,=20 compared with 10.9 months in the glioblastoma group. =

In pure AOD, the impact of necrosis is unclear. Miller et al. = [6]=20 did not find any impact of necrosis in pure AOD, nor did a = review=20 analysis of the North American prospective randomized study = on=20 oligodendroglial tumors [17].=20 In contrast, a similar European study found that both = endothelial=20 proliferation and necrosis were related to survival in AOD = patients=20 [18].=20 These subtle differences may be related to differences in the = rather subjective histological criteria. From all studies, it = is=20 clear though that the outcome of AOD patients, even with=20 necrosis, remains distinctly better than that of glioblastoma = patients, which is not the case for mixed AOAs with = necrosis.=20


3D"    RELIABILITY OF THE HISTOLOGICAL DIAGNOSIS=20
Top
Learning Objectives
Abstract
Introduction
Histology
3D"Reliability of the=20 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
 
S= everal=20 studies have shown that considerable interobserver variation = is=20 present in the diagnosis of grade III tumors, including = oligodendroglial=20 tumors. In one project, 114 samples from a large prospective=20 European trial were reviewed by nine independent pathologists = [19].=20 The panel reached consensus (six or more of the nine agreeing = on the=20 diagnosis) on the diagnosis of AOD in 52% of the tumors that = had been=20 diagnosed as AOD by the local pathologists, whereas only 8% = of the=20 local diagnoses of AOA were confirmed with consensus. The = = coefficients of the=20 individual panelists for the 52 cases with a consensus = diagnosis of=20 AOD were in the range of 0.46=960.72. A similar study on the = North=20 American randomized study investigated the interobserver = variation in=20 the diagnosis of "classical for oligodendroglioma" (CFO) = (loosely=20 defined as round regular nuclei, monomorphic appearance, = perinuclear=20 haloes, etc.) among experienced neuropathologists (Fig.=20 1) [17].=20 Tumor specimens from 247 patients were available for this = review.=20 Although the authors considered the outcome of the study = supportive=20 of an approach to clinical trials on OD, in which patients = can only=20 be included after central review, the interobserver agreement = was=20 only modest (3D{kappa}=20 =3D = 0.55),=20 and one reviewer did not identify 22% of the CFO cases = identified=20 by consensus. In the above-mentioned study on CFO, which used = five independent reviewers, a consensus diagnosis (four of = five=20 neuropathologists agreeing) was obtained in 83% of cases. In=20 another series, a rather high degree of agreement was = reported=20 [20].=20 Most likely, close interaction among pathologists leads to a = better=20 diagnostic agreement, although that holds an element of = subjectivity=20 (e.g., within that specific group).



View larger = version=20 (176K):
[in=20 this window]
[in a new window]

  		Figure 1. Classic = oligodendroglial=20 tumor, with fried egg appearance (which actually is an = artificial=20 fixation artifact). =

 = ;

3D"    GENETICS: 1P/19Q=20 CODELETION AND TRANSLOCATION=20
Top
Learning Objectives
Abstract
Introduction
Histology
Reliability of the Histological...
3D"Genetics: 1p/19q = Codeletion=20 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
 
I= t was=20 recently demonstrated that the combined loss of 1p and 19q is = mediated by an unbalanced translocation of 19p to 1q [21,=20 22].=20 Most likely, a centrosomal or pericentrosomal translocation = of=20 chromosomes 1 and 19 results in two derivative chromosomes,=20 der(1,19)(p10;q10) and der(1,19)(q10;p10), after which the = derivative=20 chromosome with the short arm of chromosome 1 and the long = arm=20 of chromosome 19 is lost. A possible explanation for this=20 translocation is the strong homology of the centromeric = regions of=20 chromosomes 1 and 19. For the analysis of 1p loss in OD, it = is=20 important that the loss of the entire short arm of chromosome = 1 is=20 assessed. Partial 1p deletions do occur in glioblastoma, are = not=20 associated with 19q loss, and carry a poor prognostic = significance=20 [23].=20 Because fluorescence in situ hybridization probes used to = assess=20 1p loss are often located on 1p36.6, one needs to be aware = that=20 this will also pick up loss of the tip of 1p. In tumors in = which=20 codeletion of 1p and 19q is present, the codeletion is = generally=20 distributed throughout the tumor, even in areas with more = astrocytic=20 morphology [24].=20 Furthermore, the loss of 1p and 19q is retained at the time = of=20 progression, regardless of morphological changes, suggesting = that=20 1p/19q loss is an early genetic event [15,=20 25].=20


3D"    HISTOMORPHOLOGY AND 1P/19Q CODELETION
Top
Learning Objectives
Abstract
Introduction
Histology
Reliability of the Histological...
Genetics: 1p/19q Codeletion and...
3D"Histomorphology and=20 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=20 association exists between codeletion of 1p and 19q and a = classic=20 histological appearance (perinuclear halo, chicken-wire = vascular=20 pattern) [8,=20 17,=20 26].=20 The 1p/19q codeletion is present in 61%=9689% of AOD cases, = but in only=20 13%=9620% of patients with AOA [6,=20 27].=20 Of note, McDonald et al. [27]=20 confirmed the close association between CFO and 1p/19q = codeletion,=20 with a higher likelihood of 1p and 19q loss if more = pathologists=20 judged the tumor to be CFO. In mixed OAs with predominant=20 oligodendroglial morphology, the percentage of tumors showing = 1p and=20 19q loss drops to 39%, emphasizing that even the presence of = minor=20 astrocytic elements significantly reduces the chance of = finding 1p=20 and 19q loss [15].=20

Still, some atypical ODs have 1p/19q codeletions and some = typical=20 ODs do not show 1p and 19q loss. However, the outcome of = patients=20 with non-1p/19q codeleted tumors but with typical = histological=20 appearance was reported to be equally favorable in a large=20 prospective U.S. trial [17].=20 Another study reported loss of 1p and 19q to be related, in=20 particular, to outcome in patients with tumors with classic=20 histologic features [27].=20


3D"    OTHER GENETIC ABERRATIONS
Top
Learning Objectives
Abstract
Introduction
Histology
Reliability of the Histological...
Genetics: 1p/19q Codeletion and...
Histomorphology and 1p/19q...
3D"Other Genetic=20 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
 
C= ompared=20 with low-grade ODs, AODs usually have additional chromosomal=20 deletions, in particular loss of heterozygosity for 9p and/or = deletion of the CDKN2A gene (p16) [15].=20 These occur in 33%=9650% of AODs and are associated with = tumor=20 progression. As a rule, other chromosomal abnormalities are = found in=20 low-grade and in high-grade ODs with atypical morphological = features.=20 These are typically associated with astrocytomas and are = usually=20 mutually exclusive with 1p/19q codeletion (e.g., TP53=20 mutations in low-grade tumors and EGFR amplification, = 10q=20 loss, and PTEN mutations in anaplastic tumors) [15,=20 28=9631].=20 Deletions on chromosome 10 have been reported in 19%=9625% of = anaplastic oligodendroglial tumors (AOTs) [15,=20 32].=20 Amplification of the EGFR gene on chromosome 7p occurs = in=20 20%=9630% of AOTs, but reportedly never in those with = deletion of 1p=20 and 19q, and correlates with a poor prognosis [14,=20 15,=20 33,=20 34].=20 Similarly, molecular analysis of the prospective EORTC study = on AOTs=20 observed more frequent loss of chromosome 10 and = amplification of the=20 EGFR gene in tumors diagnosed as mixed OAs with = necrosis [18].=20 Again, these aberrations were inversely correlated with the = 1p/19q=20 codeletion. This suggests that these tumors are derived from=20 different precursor cells. This hypothesis is supported by = the marked=20 differences in outcome and prognosis, with a superior outcome = in the=20 presence of 1p and 19q loss, and with poor survival in AODs = with the=20 loss of 10q and/or the amplification of EGFR [30].=20 The presence of 10q loss or EGFR amplification in pure = AODs is=20 sufficiently rare to suggest an alternate diagnosis (e.g., = small cell=20 glioblastoma) [15].=20 AOAs do not appear to constitute a fixed class of tumors, but = rather=20 a morphological continuum between pure ODs and astrocytomas. = Only in=20 exceptional cases do mixed tumors show genetically distinct = clones of=20 tumor within histologically different areas [35].=20

In an intriguing study on 70 patients with grade II and III=20 oligodendroglial tumors, a number of prognostically = unfavorable=20 genomic alterations were identified, in particular, gain of = 7p=20 and 8q and loss of 9p, 10q, and 18q [36].=20 In the anaplastic tumors, the presence of the 1p/19q = codeletion was a=20 favorable prognostic factor, particularly if no other = unfavorable=20 genomic aberrations had been identified. Similarly, outcome = was=20 equally favorable in patients without 1p/19q codeletion and = also=20 without other unfavorable genomic aberrations. However, if 1p = and=20 19q loss was accompanied by unfavorable alterations, the=20 prognosis was poor. Others have reported that the prognostic = impact=20 of 1p and 19q loss is mainly present in tumors with classic = AOD=20 morphology, but not in oligodendroglial tumors with atypical=20 features or in mixed AOAs [6,=20 27].=20


3D"    METHYL GUANINE METHYLTRANSFERASE GENE = (MGMT)=20 AND ALKYLTRANSFERASE =
Top
Learning Objectives
Abstract
Introduction
Histology
Reliability of the Histological...
Genetics: 1p/19q Codeletion and...
Histomorphology and 1p/19q...
Other Genetic Aberrations
3D"Methyl Guanine=20 Methyltransferase...
Why Are 1p/19q Codeleted...
Is 1p/19q Codeletion Predictive...
Treatment of Low-Grade Tumors
Treatment of Anaplastic Tumors
Conclusions
Author Contributions
References
 
N= o clear=20 explanation is yet available for the favorable response to=20 chemotherapy of AOTs as compared with astrocytic tumors. = Previous=20 studies suggested that the nuclear enzyme alkyltransferase, = also=20 known as methyl guanine methyltransferase (MGMT), which = mediates at=20 least part of the cell resistance to alkylating and = methylating=20 agents, is less expressed in ODs and perhaps even more so in = 1p/19q=20 codeleted tumors [37].=20 MGMT expression can be silenced by MGMT promoter gene=20 methylation, which was initially reported to occur in 47% of=20 low-grade ODs without a correlation with 1p/19q codeletion = [38].=20 Other studies did, however, find a correlation between 1p/19q = codeletion and MGMT promoter methylation, which was = observed=20 in up to 80%=9690% of 1p/19q codeleted tumors [39=9641].=20 MGMT promoter gene methylation occurs in up to = 40%=9650% of=20 glioblastomas; it is therefore unlikely that this event alone = accounts for the entire difference in sensitivity to = chemotherapy=20 between astrocytic tumors and oligodendroglial tumors, or for = the=20 greater chemosensitivity in 1p/19q codeleted tumors. =


3D"    WHY ARE 1P/19Q CODELETED TUMORS MORE SENSITIVE TO=20 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...
3D"Why Are 1p/19q=20 Codeleted...
Is 1p/19q Codeletion Predictive...
Treatment of Low-Grade Tumors
Treatment of Anaplastic Tumors
Conclusions
Author Contributions
References
 
W= hy 1p/19q=20 codeleted tumors are more sensitive to RT and chemotherapy = remains an=20 unanswered question. There are a number of possible = explanations:=20 loss of genes that mediate resistance to treatment, the = assumption=20 that 1p and 19q loss is an epiphenomenon that identifies a = tumor that=20 is more sensitive to treatment (e.g., with less frequent = other=20 unfavorable mutations/alterations), or an association between = 1p and=20 19q loss and other genetic events (e.g., MGMT promoter = gene=20 methylation). It is clear that ODs with 1p and 19q loss have = gene=20 expression profiles that differ from those of other gliomas = [42].=20 The gene expression profile of 1p/19q codeleted ODs partially = resembles that of the normal brain (proneural expression = pattern) [43].=20

Several studies have shown that other specific epigenetic = aberrations=20 are observed in 1p/19q codeleted tumors. The maternally = imprinted=20 DIRAS3 tumor suppressor gene is located on 1p31, the=20 expression of which is significantly decreased because of = methylation=20 in ODs with 1p loss [44].=20 Biallelic DIRAS3 inactivation has been associated with = survival. Similarly, the expression of the CITED4 gene = on=20 1p34.2 seems decreased through hypermethylation [45].=20 Again, CITED4 hypermethylation has been associated with = longer=20 survival. EMP3, located at 19q13.3, is another example of = a=20 gene that is frequently hypermethylated in OD and = astrocytoma,=20 but not in primary glioblastoma [46].=20 In all these cases, one allele is silenced because of loss = and the=20 other through hypermethylation. These findings support a = major role=20 for epigenetic phenomena in the pathogenesis of OD. =


3D"    IS 1P/19Q CODELETION PREDICTIVE=20 OF OUTCOME=20 TO CHEMOTHERAPY, OR PROGNOSTIC?=20
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...
3D"Is 1p/19q Codeletion=20 Predictive...
Treatment of Low-Grade Tumors
Treatment of Anaplastic Tumors
Conclusions
Author Contributions
References
 
I= nitial=20 studies observed that response and survival rates were better = in=20 patients with OD with combined 1p and 19q loss than in those = without=20 1p and 19q loss. Several studies have found the presence or = absence=20 of combined loss of 1p and 19q to be the most important = prognostic=20 factor for overall survival in AOTs [5,=20 47,=20 48].=20 The median survival duration was >6=967 years in the = presence of the=20 1p/19q codeletion, and 2=963 years in the absence of the = codeletion.=20 For low-grade OD or OA, median survival time were 12=9615 = years for=20 1p/19q codeleted patients and 5=968 years for patients = without the=20 deletion [15,=20 21].=20 In all these studies, patients were treated with either = chemotherapy=20 or RT, and the longer progression-free survival time in = RT-only=20 treated patients suggests that the 1p/19q codeletion is more = a=20 prognostic than a predictive factor [26,=20 48].=20 This view was corroborated by studies that suggested that ODs = have a more indolent behavior, even prior to the initiation = of=20 treatment [8,=20 10].=20 Indeed, a study measuring growth speed in low-grade gliomas = observed=20 a slower growth rate in 1p/19q codeleted ODs [49].=20 However, in a recent study of untreated low-grade ODs and = AOTs, on=20 multivariate analysis, the presence of 1p and 19q loss was = found not=20 to be prognostic for progression-free survival [20].=20 The overall picture that emerges from this is that 1p/19q = codeleted=20 tumors tend to have slower growth rates and to be more = responsive to=20 treatment than tumors without this codeletion. In that sense, = the=20 1p/19q codeletion identifies a favorable prognostic subgroup, = although it also predicts outcome to treatment. However, it = may not=20 really help in deciding on chemotherapy or not, because RT is = also=20 likely to give good treatment results.


3D"    TREATMENT OF=20 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...
3D"Treatment of Low-Grade = Tumors
Treatment of Anaplastic Tumors
Conclusions
Author Contributions
References
 
F= ollowing=20 the favorable response of AOTs to chemotherapy, chemotherapy = as=20 initial treatment, employing either PCV or temozolomide, for = patients=20 with progressive low-grade ODs has been investigated in a = limited=20 number of retrospective or phase II studies. Radiological = response=20 rates, including the category minor response, of 30%=9670% = have been=20 reported with PCV or with temozolomide, with a median time to = progression of 2=963 years [49=9652].=20 Response may be delayed=97one series described a median time = to=20 maximum response of 12 months=97and clinical response (e.g.,=20 better seizure control) is frequently more impressive than=20 radiological response. Response rates are higher and time to=20 progression is longer in 1p/19q codeleted tumors. Whether = first-line=20 chemotherapy for low-grade OD is superior to RT is unknown; = the=20 results of a current EORTC phase III study on this subject = are=20 awaited. In the meantime, for patients requiring large RT = portals=20 for large tumors, upfront treatment with PCV or temozolomide = to=20 avoid or delay the risk for late cognitive defects is a = reasonable=20 treatment option.


3D"    TREATMENT OF=20 ANAPLASTIC TUMORS=20
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
3D"Treatment of = Anaplastic=20 Tumors
Conclusions
Author Contributions
References
 
<= STRONG>Newly=20 Diagnosed AOD and AOA: (Neo-)adjuvant Chemotherapy = Trials
Two=20 prospective, randomized, controlled trials in AOTs have shown = that=20 (neo)adjuvant PCV chemotherapy given in addition to 60 Gy of = RT does=20 not result in a longer overall survival time, although it = does lead=20 to a longer progression-free survival time. The first of = these=20 trials, RTOG 94=9602, randomized patients to either four = cycles of=20 upfront intensified PCV chemotherapy followed by RT to a dose = of 60=20 Gy or RT only [47].=20 The second trial (EORTC 26951) randomized patients to 60 Gy = of RT=20 followed by six cycles adjuvant PCV or to 60 Gy of RT only = [48].=20 Table=20 1 summarizes the progression-free survival and overall=20 survival results of these studies. In both trials, the = majority of=20 patients randomized to the RT arm received PCV at = progression,=20 which most likely explains the longer progression-free = survival=20 time without a longer overall survival time. Because of this, = these trials in fact investigated early (adjuvant) versus=20 delayed (at the time of progression) PCV chemotherapy. Even = in the=20 1p/19q loss subgroup analysis, no overall survival benefit of = early (i.e., adjuvant or neoadjuvant) PCV could be = demonstrated (Table=20 1). The conclusion of both trials is that in AOD, early = PCV=20 given sequentially with RT does not provide a superior = outcome=20 to initial RT only followed by chemotherapy at the time of=20 recurrence.


View = this=20 table:
[in=20 this window]
[in a new window]

  		Table 1. Median survival = time and=20 5-year overall survival rate according to combined 1p and = 19q loss=20 status in the EORTC 26951 and RTOG 9402 trials on = (neo-)adjuvant PCV=20 chemotherapy in anaplastic oligodendroglial tumors [47,=20 48] =

 = ;
In=20 a rather complex recent German study, patients with grade III = tumors=20 (anaplastic astrocytoma, AOA, AOD) were randomized to either = RT or=20 chemotherapy; within the chemotherapy arm, patients were = further=20 randomized between PCV and temozolomide [53].=20 The trial design included crossover to the other treatment=20 (chemotherapy or RT) at the time of progression. Neither the = initial=20 randomization (RT or chemotherapy) nor the type of = chemotherapy=20 regimen impacted survival. In the first analysis of the = study, MGMT=20 methylation status appeared to be a more important prognostic = factor=20 than 1p/19q status.

Chemoirradiation with Temozolomide?
The current = clinical=20 question is whether combined chemoirradiation with = temozolomide=20 should also be used for AOTs. The negative outcome of the = adjuvant=20 PCV trials is in contrast to the observed survival benefit in = glioblastoma patients of combined chemoirradiation with = temozolomide,=20 especially in tumors with a methylated MGMT promoter = gene [54,=20 55].=20 A particular consideration here is that patients with = anaplastic=20 tumors with combined 1p and 19q loss have a median survival = duration=20 >6=967 years. Hence, the late neurotoxicity of a combined=20 radiochemotherapy approach is potentially an issue. This is = clearly=20 less so for tumors without 1p and 19q loss, but here the = benefit of=20 the combined regimen is also unproven. Current studies are=20 investigating the role of combined chemoirradiation in AODs,=20 including other grade III tumors, with separate trials for = tumors=20 with and without combined 1p and 19q loss.

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

In a phase II trial in 69 patients with newly diagnosed = anaplastic=20 or aggressive OD, the intensive PCV regimen was followed by=20 high-dose thiotepa with autologous stem cell rescue, without=20 RT. The median progression-free survival time in the 39 = patients=20 who received the autologous stem cell procedure was 78 = months,=20 and the median overall survival time had not been reached. = Eighteen=20 patients (46%) had relapsed [59].=20 In view of the patient selection and the absence of a control = arm,=20 final conclusions on the meaning of these results are = impossible to=20 draw; many patients with AOTs have similar survival times = without=20 such intensive treatments. The trial showed, though, that a = longer=20 progression-free survival time without initial RT is = possible. The=20 German NOA4 trial showed that patients treated with = chemotherapy=20 first had a similar survival benefit to patients managed with = RT=20 first [53].=20 That trial, which basically studied sequential treatment (RT=20 first or chemotherapy first), demonstrated that whatever=20 sequence is followed, the results are comparable. The choice = for=20 chemotherapy or RT may well come down to deciding between = side=20 effects: local side effects of a short series of RT or = systemic side=20 effects of (expensive) chemotherapy of 1-year duration. =

Second-Line Chemotherapy in Recurrent = AOTs
Second-line=20 PCV after failure with temozolomide induced a response in = only 17% of=20 patients, but 50% were still free from progression at 6 = months and=20 21% were still free from progression at 12 months [60].=20 Similarly, 25% of patients had an objective response to = temozolomide=20 after PCV and 29% and 11% of patients were free from = progression=20 after 6 and 12 months, respectively [61].=20 Occasionally, patients that do not respond to one regimen are = responsive to the other. However, in general, response rates = to=20 second-line chemotherapy are modest, even in 1p/19q codeleted = tumors=20 (and regardless of the sequence chosen=97temozolomide first = or=20 PCV first). Still, very few other agents have been = systematically=20 evaluated in AOTs. One trial found PCV chemotherapy followed = by=20 an autologous bone marrow transplantation after a myeloablative=20 procedure with melphalan to be too toxic, without clearly = producing=20 superior results [62].=20 Response to carboplatin monotherapy was similar to that of=20 temozolomide, with 13% of patients responding and with 35% = and 9% 6-=20 and 12-month progression-free survival times, respectively = [63].=20 These results were obtained, however, at the cost of = considerable=20 myelotoxicity. In a study of CPT-11 on 22 patients with = 1p/19q=20 codeleted AODs, the response rate was 23% and the 6- and = 12-month=20 progression-free survival times were 33% and 4.5%, = respectively [64].=20 Despite the upregulation of platelet-derived growth factor = (PDGF)=20 signaling pathways in most ODs, the PDGF receptor tyrosine = kinase=20 inhibitor imatinib did not show any activity in recurrent OD = or=20 AOD/AOA [65].=20 Clearly, for a further improvement in outcome after failing=20 first-line chemotherapy and RT, other approaches need to be=20 developed.


3D"    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
3D"Conclusions
Author Contributions
References
 
T= he=20 histological diagnosis of OD is still hampered by significant=20 interobserver variation. The clear correlation between = classic=20 histology and 1p/19q codeletion has led some to use this = codeletion=20 as a marker for OD, and it has even been suggested to build=20 this into the diagnosis. However, it is becoming increasingly = questionable whether this nice and simple conclusion is = justified.=20 Several studies have now observed that patients with tumors=20 with classic oligodendroglial morphology, even without 1p/19q = codeletions, have a better prognosis than those with = astrocytic=20 tumors [17,=20 36,=20 53].=20 This argues in favor of the use of more strict morphological = criteria=20 for oligodendroglial tumors, although even in the hands of = experts up=20 to 20% of CFO cases may not be agreed upon [17].=20 The recently modified WHO classification considers necrosis = to no=20 longer be compatible with the diagnosis of mixed AOA, which = should=20 thus be considered glioblastoma (with some oligodendroglial=20 features).

The basic molecular characteristic of 1p/19q codeletion and = the=20 explanation for the sensitivity of these tumors to RT and=20 chemotherapy is still unresolved. It is also unclear whether=20 that sensitivity is to be expected in tumors with classic = morphology=20 in the absence of the 1p/19q codeletion. Despite the recent=20 data suggesting a favorable subset of these tumors, the = initial=20 studies suggested that 1p/19q status was better correlated = with=20 response to chemotherapy than with morphology [7,=20 8].=20

For today's patients, sequential treatment with RT and = chemotherapy,=20 depending on the expected side effects and treatment = efficacy,=20 seems to be the optimal approach, with currently no solid = data=20 available to help in making the choice between initial RT and = initial chemotherapy [53].=20 The value of concurrent chemoirradiation with temozolomide in = these=20 tumors has not been established, nor has it been established = whether=20 or not this treatment will induce long-term side effects in = patients=20 with an expected long survival time.


3D"    AUTHOR CONTRIBUTIONS=20
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
3D"Author Contributions
References
 
<= B>Conception/design:=20 Martin J. van den Bent, Jacolien E.C. Bromberg

Provision of study materials: Martin J. van den Bent, = Jacolien=20 E.C. Bromberg

Collection/assembly of data: Martin J. van den Bent, = Jacolien=20 E.C. Bromberg

Manuscript writing: Martin J. van den Bent, Jacolien E.C.=20 Bromberg

Final approval of manuscript: Martin J. van den Bent, = Jacolien=20 E.C. Bromberg


3D"    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
3D"References
&nb= sp;

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HOME HELP CONTACT=20 US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF=20 CONTENTS
THE ONCOLOGIST STEM=20 CELLS CME ALPHAMED=20 PRESS JOURNALS

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