Hostname: page-component-5d59c44645-n6p7q Total loading time: 0 Render date: 2024-02-29T12:03:07.425Z Has data issue: false hasContentIssue false

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas

Published online by Cambridge University Press:  09 January 2017

Mairéad G. McNamara*
Affiliation:
Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Institute of Cancer Sciences, Manchester, UK
Haiyan Jiang
Affiliation:
Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada
Mary Jane Lim-Fat
Affiliation:
Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
Solmaz Sahebjam
Affiliation:
Department of Medical Oncology, Moffitt Cancer Centre, Tampa, Florida
Tim-Rasmus Kiehl
Affiliation:
Department of Pathology, University Health Network, Toronto, Canada
Jason Karamchandani
Affiliation:
Department of Pathology, St. Michael’s Hospital, Toronto, Canada
Claire Coire
Affiliation:
Department of Pathology, Trillium Health Centre, Mississauga, Canada
Caroline Chung
Affiliation:
Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Canada Department of Radiation Oncology, MD Anderson Cancer Centre, Houston, Texas
Barbara-Ann Millar
Affiliation:
Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Canada
Normand Laperriere
Affiliation:
Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Canada
Warren P. Mason
Affiliation:
Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
*
Address correspondence to: Mairéad G. McNamara, Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Institute of Cancer Sciences, Manchester M20 4BX, UK Email: Mairead.McNamara@christie.nhs.uk
Rights & Permissions [Opens in a new window]

Abstract

Background: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. Methods: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. Results: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. Conclusions: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

Résumé

Résultats d’un traitement appliqué à des gliomes associés à des codélétions 1p/19q et des délétions partielles.Contexte: À l’instar de la procarbazine, de la lomustine et de la vincristine, les traitements de radiothérapie améliorent le taux de survie général des patients atteints d’oligodendrogliomes/oligoastrocytomes anaplasiques associés à des codélétions 1p/19q. Méthodes: Cette analyse rétrospective s’est penchée sur les résultats d’un traitement offert à des patients atteints d’oligodendrogliomes/oligoastrocytomes et d’oligodendrogliomes/oligoastrocytomes anaplasiques associés à des codélétions/délétions partielles. La survie générale (overall survival) et la survie sans progression (SSP) ont été analysées au moyen de l’estimateur de Kaplan-Meier et de facteurs pronostiques faisant appel au modèle à risques proportionnels de Cox. Résultats: Entre décembre 1997 et décembre 2013, un total de 106 patients ont été inclus dans cette étude. Leur âge médian était de 40 ans (19-66) ; 55% d’entre eux étaient de sexe masculin (n=58). L’échelle de l’Eastern Cooperative Oncology Group était de 0 chez 80 patients (75%). Des codélétions 1p/19q ont été observées chez 66 patients (62%) ; des codélétions incomplètes ont été observées chez 27 d’entre eux (25%) ; enfin, des pertes liées aux chromosomes 1p ou 19q ont été notées chez quatre (4%) et neuf (8%) patients respectivement. On est aussi parvenus à détecter une mutation de l'isocitrate déshydrogénase-1 R132H chez 67 patients sur les 85 qui possédaient assez de matériel génétique. Un traitement initial a été administré à 72 patients (68%), par exemple uniquement de la témozolomide à 52 d’entre eux (49%). Chez 47 patients (44%), la durée médiane de radiothérapie a été de 34,7 mois ; dans le cas de 9 patients atteints d’oligodendrogliomes/oligoastrocytomes anaplasiques associés à des codélétions complètes ou incomplètes à qui l’on n’avait administré qu’un traitement initial à la témozolomide, elle a été de 41,2 mois. Il n’a pas été possible d’obtenir la survie générale moyenne ; toutefois, une survie générale de 5 ans a été de 91% pour tous les groupes (suivi médian : 5,1 ans). Une analyse multivariable de tous les patients a aussi révélé les résultats suivants : administration d’un traitement initial contre aucun traitement (p=0,04) ; échelle de performance 1 contre 0 (p<0,001) ; et codélétion complète/incomplète 1p/19q contre les seules pertes de chromosomes 1p ou 19q (p=0,005). Ces résultats ont été pronostiqués en ce qui regarde la SSP. L’état de l’isocitrate déshydrogénase-1n’a, quant à lui, pas été pronostiqué en ce qui regarde la SSP. Conclusions: Compte tenu des profils de survie similaires en ce qui a trait aux gliomes anaplasiques de bas grade, il se peut que des caractéristiques moléculaires soient plus importantes que le grade histologique. Un suivi à plus long terme ainsi que des études prospectives sont donc nécessaires afin de pouvoir compter sur des orientations définitives concernant le traitement de ces patients.

Type
Original Articles
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2017 

In gliomas, co-deletions of chromosomes 1p and 19q are associated with tumors with “oligodendroglial” morphology. This co-deletion of chromosome regions 1p36/19q13 in oligodendrogliomas was discovered in 1994 and was subsequently found to derive from an unbalanced translocation at (1;19)(q10;p10).Reference Jenkins, Blair and Ballman 1 Combined alterations have been observed in up to 70% of oligodendrogliomas and 50% of mixed oligoastrocytomas.Reference Reifenberger, Reifenberger, Liu, James, Wechsler and Collins 2 , Reference Smith, Alderete and Minn 3 Besides being a relevant diagnostic marker, 1p19q loss has been validated for its prognostic relevance in anaplastic oligodendroglial tumors and mixed oligoastrocytomas. Although 1p19q co-deletion is also present in astrocytomas and mixed oligoastrocytomas,Reference Reifenberger, Reifenberger, Liu, James, Wechsler and Collins 2 , Reference Smith, Alderete and Minn 3 it has been shown to predict increased chemosensitivity in oligodendroglial tumors in particular.Reference Van den Bent, Brandes and Taphoorn 4 , Reference Cairncross, Wang and Shaw 5 The 1p19q co-deletion status is also associated with frontal lobe location and the presence of isocitrate dehydrogenase (IDH) mutations.Reference Alentorn, Sanson and Idbaih 6

Responses to procarbazine, lomustine, and vincristine (PCV) were first reported in small series of patients with recurrent oligodendroglioma and oligoastrocytoma in 1988Reference Cairncross and Mac Donald 7 and 1992,Reference Kim, Hochberg and Thornton 8 respectively. These studies led to randomized phase III trials Radiation Therapy Oncology Group (RTOG) 9402Reference Cairncross, Wang and Shaw 5 and European Organisation for Research and Treatment of Cancer (EORTC) 26951Reference Van den Bent, Brandes and Taphoorn 4 to clarify the role of PCV chemotherapy in anaplastic oligodendroglioma and anaplastic oligoastrocytoma. Long-term results of RTOG 9402 and EORTC 26951 indicated that patients whose tumors harbored a 1p19q co-deletion benefitted from early addition of PCV chemotherapy to radiotherapy; a significant improvement in overall survival (OS) was demonstrated compared with early radiotherapy, even with salvage chemotherapy at tumor relapse.Reference Van den Bent, Brandes and Taphoorn 4 , Reference Cairncross, Wang and Shaw 5

Long-term follow up of RTOG 9802 reported that in patients with high-risk grade II gliomas (with less than gross total tumor resection or who were more than 40 years of age), radiotherapy plus PCV also prolonged both progression-free survival (PFS) and OS, compared with radiotherapy alone.Reference Buckner, Pugh and Shaw 9

However, there are still unanswered questions regarding whether upfront chemotherapy, omitting/deferring radiotherapy, to avoid or delay the late neurocognitive toxicity of radiotherapy should be the initial therapy for anaplastic oligodendrogliomal tumors with co-deleted 1p19q, or whether temozolomide can be substituted for PCV chemotherapy, the former being an oral agent with a superior toxicity profile. Additionally, it is unknown whether excluding radiotherapy from initial management of these tumors impacts unfavorably on survival.

The aim of this study was to review retrospectively outcomes in patients treated at a large academic centre with a diagnosis of 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma and also to examine outcomes in those treated with upfront temozolomide alone.

Materials and Methods

Patient Population

After receiving institutional research ethics board approval, treatment and follow-up data were retrospectively reviewed for patients with a diagnosis of 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma, according to the World Health Organisation (WHO) classification for brain tumors,Reference Kleihues, Burger and Scheithauer 10 - Reference Louis, Ohgaki and Wiestler 12 who underwent treatment at a tertiary cancer institution (Princess Margaret Cancer Centre, Toronto, Canada) in the temozolomide treatment era. Patients without 1p/19q co-deletion/partial deletion were not included in this study.

Treatment

In patients who underwent surgery, partial resection was defined as <90% tumor removal and subtotal resection was defined as <100% but >90% tumor removal. Temozolomide was administered at a dose of 150 to 200 mg/m2 (days 1-5, 28-day cycle). Radiotherapy was planned to a dose of 59.4 Gy in fractions of 1.8 Gy.

Molecular Assessments

Molecular analysis for all tumor specimens was performed in one of three specialist neuropathological centres (Trillium Health Centre, Mississauga; St. Michael’s Hospital, Toronto; and University Health Network, Toronto). Deletion of 1p and 19q were assessed by polymerase chain reaction at the time of tissue diagnosis (Deoxyribonucleic acid was extracted from the tumor tissue and amplified by polymerase chain reaction using primers specific for microsatellite markers located on chromosomes 1p and 19q to assess allelic loss using loss-of-heterozygosity analysis as described elsewhere)Reference Cairncross, Ueki and Zlatescu 13 - Reference Felsberg, Erkwoh and Sabel 15 or by fluorescence in situ hybridization with locus-specific probes for the regions 1p36.6 and 19qReference Van den Bent, Brandes and Taphoorn 4 from 2011 onwards. Incomplete deletion was defined as allelic loss on 1p and 19q, but not at all informative loci.

The presence of the most common IDH-1 mutation (R132H mutation) was assessed by immunohistochemistry as described by Capper et al,Reference Capper, Zentgraf, Balss, Hartmann and von Deimling 16 and 67 samples with available tissue that were not previously reported were analyzed retrospectively. 0(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status was not available for patients because it was not routinely performed during the period studied.

Adverse Events

Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. 17

Statistical Methods

Summary statistics were provided for patient demographics, disease, and treatment factors. The estimates of OS and PFS were calculated using the Kaplan-Meier method. The OS was calculated from the date of tissue diagnosis (before beginning therapy) to the date of death from any cause; living patients were censored on the last follow-up date they were known to be alive. The PFS was calculated for all patients from the date of tissue diagnosis (before beginning therapy) to the date of progression or date of death; patients alive without progression were censored on the date of last follow-up. The survival differences between groups were examined using the log-rank test. Univariable and multivariable analyses were performed using the Cox proportional hazard model. The multivariable model was built using stepwise selection. The selected multivariable model included only variables with p<0.05 on univariable analysis. Variables included in the univariable analysis were age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), extent of surgery, presence of previous low-grade glioma, tumor location (frontal lobe versus other), contrast enhancement, 1p19q status, and IDH1 status. All tests were two-sided with α=0.05. Statistical analyses were performed using the SAS software 9.3 and R, version 3.0.0.

Results

Patients and Treatment

A total of 106 consecutive patients were included who presented to Princess Margaret Cancer Centre, Toronto, from December 1997 to December 2013 for which 1p19q co-deletion status was available. The median follow-up time for all patients was 5.1 years (range, 0.1-16.3). As of December 2013, there were 64 (60%) PFS events and 94 patients (87%) were still alive.

A summary of patient characteristics for all gliomas is detailed in Table 1 (presence of previous low-grade glioma was defined radiologically in 18 patients and histologically in four patients), tumor characteristics and details of surgery in Table 2, and treatment history in Table 3. As expected, upfront treatment was given in the majority of patients with oligoastrocytoma (88%), anaplastic oligodendroglioma (92%), and anaplastic oligoastrocytoma (100%), but only in 31% of patients with oligodendroglioma.

Table 1 Summary of patient characteristics for all gliomas

Table 2 Summary of tumor characteristics and surgery for all gliomas

Table 3 Summary of treatment history for all patients

* Because of rounding, percentages may not equal 100%.

IDH1-R132H immunoreactivity, indicating the presence of a mutation, was reported for 85 (80%) patients with sufficient material available.

The median time to treatment after pathological diagnosis in all patients was 66.5 days. The median time to radiotherapy in all patients to whom it was administered (N=47 [44%]) was 34.7 months (0.5-159.3). Thirty patients (64%) received radiotherapy at a dose of 59.4 Gy in 33 fractions and 17 (36%) received 54 Gy in 30 fractions. The median time to radiotherapy in months (range) for those patients with a diagnosis of oligodendroglioma and oligoastrocytoma who received radiotherapy was 43.2 months (1.0-96.0) and 43.4 months (1.0-86.6), respectively.

The median time to radiotherapy in nine (25%) patients with a diagnosis of anaplastic oligodendroglioma and anaplastic oligoastrocytoma who were 1p19q co-deleted or who had incomplete co-deletion and received temozolomide alone as up-front treatment was 41.2 months (16.3-93.2). In these nine patients, four had radiotherapy at first progression, three at second progression, and two at third progression. The median follow-up time for these 36 patients was 4.1 years (range, 0.4-16.3).

Different treatments were prescribed for patients at progression, and the choice depended on previous treatment received. Options included radiotherapy, surgery, PCV, temozolomide and retreatment with temozolomide if the intervening period was long (>1 year), lomustine, etoposide, and investigational therapies. Of the 64 patients (60%) who had progression in this study, 63 proceeded to treatment at first progression (temozolomide alone, 76%, surgery, 8%, concurrent radiotherapy with temozolomide followed by temozolomide alone, 6%, radiotherapy alone, 5%; other, 5%). Forty-five of 46 patients had treatment at second progression (temozolomide alone, 30%; concurrent radiotherapy with temozolomide followed by temozolomide alone, 20%; surgery, 13%; radiotherapy alone, 11%; lomustine, 11%; other, 15%), 25 of 30 at third progression (temozolomide alone, 29%; surgery, 17%; lomustine, 17%; etoposide, 17%; other, 20%), 17 of 20 at fourth progression, nine of 13 at fifth progression, and four of a possible seven at sixth progression. Those not treated with active treatment at time of progression received best supportive care.

PFS

The Kaplan-Meier plot of PFS in all patients is represented by Figure 1A. Details on median and 2- and 5-year PFS are provided in Table 4 for all groups. There was no significant difference in PFS when stratified by histological group (p=0.6) nor when stratified by 1p19q co-deleted or incomplete 1p19q co-deletion (p=0.59) (thus, 1p19q codeletion/incomplete 1p19q deletion were grouped together for further analysis).

Figure 1 (A) Kaplan-Meier plot of progression-free survival in all patients. (B) Kaplan-Meier plot of overall survival in all patients.

Table 4 Median, 2-year, and 5-year PFS and 5-year OS for all groups

AOA=anaplastic oligoastrocytoma; AOD=anaplastic oligodendroglioma.

* IDH1 status not available for two of the 36 patients.

The median PFS for the IDH1 immunopositive (N=67) and non-IDH1 immunopositive patients (N=18) was 41.4 months (95% confidence interval [CI], 35.4-56.7 months) and 35.8 months (95% CI, 9.4-54.5 months), respectively. The presence of IDH1 immunopositivity (N=67) versus no IDH1 immunopositivity (N=18) was not prognostic for PFS (hazard ratio [HR], 0.71; 95% CI, 0.37-1.34; p=0.28) on univariable analysis.

On univariable analysis for all patients (N=106), only ECOG PS 1 versus 0 (HR, 2.42; 95% CI, 1.39-4.22; p=0.001) and 1p19q status as co-deleted/incomplete deletion versus 1p or 19q loss alone (HR, 0.45; 95% CI, 0.23-0.90; p=0.02) were prognostic for PFS. The presence of previous low-grade glioma was not prognostic for PFS on univariable analysis (HR, 1.38; 95% CI, 0.77-2.47; p=0.28). On multivariable analysis for all patients, receipt of therapy (radiotherapy alone or in combination with temozolomide followed by temozolomide therapy or temozolomide alone) versus none, upfront, resulted in a 45% reduction in risk of progression (HR, 0.55; 95% CI, 0.32-0.97; p=0.04), ECOG PS 1 versus 0 (HR, 2.78; 95% CI, 1.57-4.93; p<0.001) and 1p19q status as co-deleted/incomplete deletion versus 1p or 19q loss alone (HR, 0.36; 95% CI, 0.18-0.74; p=0.005) were prognostic for PFS.

On multivariable analysis for patients with a diagnosis of oligodendroglioma and anaplastic oligodendroglioma alone (N=89), only ECOG PS 1 versus 0 (HR, 2.63; 95% CI, 1.40-4.93; p=0.003) and 1p19q status as co-deleted/incomplete deletion versus 1p or 19q loss alone (HR, 0.43; 95% CI, 0.19-0.99; p=0.047) were prognostic for PFS.

OS

The Kaplan-Meier plot of OS in all patients is represented by Figure 1B. Details on 5-year OS for all groups are provided in Table 4. Median OS was not reached for all groups. The 5-year OS for the oligodendroglioma (90.3% [72.6-96.8]) and anaplastic oligodendroglioma (88.7% [72.2-95.7]) groups were similar, as were the values for the oligoastrocytoma (100% [100]) and anaplastic oligoastrocytoma (100% [100]) groups. Regression-type analysis such as univariable or multivariable analysis on OS was not run because of a low number of events (N=12).

Safety

The most common adverse events reported for patients receiving temozolomide alone as upfront treatment (N=52 [49%]) were thrombocytopenia, fatigue, nausea, and neutropenia, and these were more often grade 1 and 2 events. Two percent of patients had grade 3 thrombocytopenia, fatigue, and neutropenia. There were no reports of grade 3 or 4 cognitive impairment.

Discussion

This study retrospectively reviewed outcomes in patients, treated at a large academic centre, with a diagnosis of 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. For those 36 patients (one death) with a diagnosis of anaplastic oligodendroglioma or anaplastic oligoastrocytoma who had 1p19q co-deleted or incomplete deletion status and who received temozolomide alone as upfront treatment, the median PFS was 46.3 months and the 5-year OS was 96%. Only 25% of these 36 patients received radiotherapy within a median follow-up of 4.1 years; thus, this group may reflect a better prognosis set and indicate selection bias associated with a retrospective study. Although inter-study comparisons cannot be made reliably, the median PFS reported for 43 patients (18 deaths) with 1p19q co-deleted status who received radiotherapy and PCV in the EORTC 26951 studyReference Van den Bent, Brandes and Taphoorn 4 was 156.8 months and the 5-year OS was 76.2%.

Although 5-year OS appears more encouraging in this study, it should be cautioned that there were only 12 deaths at the time of analysis and the median follow-up time for all patients in this study was just over 5 years as compared with more than 11years in EORTC 26951.Reference Van den Bent, Brandes and Taphoorn 4 Thus, mature follow-up of these patients is indicated and thus significant conclusions cannot be drawn. Additionally, an argument can be made that longer PFS and consequent greater time off treatment is more desirable for patients. However, it is important that neurological function and cognition are maintained in a patient group who may live for up to 15 years,Reference Cairncross, Wang and Shaw 5 and in our study there was no grade 3 or 4 cognitive impairment noted in patients treated with temozolomide alone as upfront therapy after a median of just over 5 years of follow-up.

Long-term data from NOA-04Reference Wick, Roth and Wiestler 18 did not support a differential efficacy of primary temozolomide monotherapy or PCV polychemotherapy versus radiotherapy in any of the histological or molecular subgroups of anaplastic glioma, and thus less toxic upfront chemotherapy alone, sparing potential neurological sequelae may be more desirable.

Neurological (cognitive or mood change and peripheral or autonomic neuropathy) adverse effects were among the most frequent severe toxicities after a median of 3 years of follow-up in RTOG 9402,Reference Cairncross, Berkey and Shaw 19 but this may be somewhat attributable to better prospective documentation. It should also be mentioned that radiotherapy technology and application in the present era as opposed to when RTOG 9402,Reference Cairncross, Berkey and Shaw 19 for example, was recruiting patients (1994-2002) will most certainly have improved.

With similar PFS and OS patterns in low-grade and anaplastic gliomas in the current study, molecular characteristics may be more important than histological grade in survival. Indeed, the inclusion of molecular features in a revised WHO classification of brain tumors is under discussion. A recent study has analyzed markers of potential special prognostic interest including alpha thalassemia/mental retardation syndrome x-linked (ATRX), IDH and 1p19q co-deletion in a subset of 100 diffuse gliomas from the NOA-04 trial.Reference Wick, Hartmann and Engel 20 Based on these “integrated” diagnoses, loss of ATRX expression was close to being mutually exclusive with 1p19q co-deletion, and all but four of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations.Reference Reuss, Sahm and Schrimpf 21 These “integrated” diagnoses were reported to have a better association with patient outcome than WHO 2007Reference Reuss, Sahm and Schrimpf 21 and support the combined analysis of grade II and III glioma outcomes as performed in our study. This is also supported by a recent publication from The Cancer Genome Atlas Research Network in which it was reported that prognostically significant subtypes of lower grade glioma were captured more accurately by IDH, 1p19q, and TP53 status than by histological class. 22

Limitations of this study are its retrospective nature with potential for inherent biases in patient treatment decisions in a single institution, nonavailability of some data, the inclusion of patients treated over a 16-year period with the corresponding WHO classification reflecting the era of therapy,Reference Kleihues, Burger and Scheithauer 10 - Reference Louis, Ohgaki and Wiestler 12 nonassessment of MGMT promoter methylation status, and utilization of IDH-1 immunohistochemistry, which identifies only approximately 90% of IDH1 mutations and none of the IDH2 mutations. In the current study, IDH1 positivity was not prognostic for PFS and is possibly attributable to the limited sample size.

However, this study reports on outcomes of a relatively large number of patients with 1p19q co-deleted grade II and III gliomas receiving temozolomide alone in days 1 to 5, more routinely used a 28-day schedule as upfront treatment, extending to a recent era, and is a reflection of how the known chemosensitivity of gliomas is influencing how patients are managed at an academic centre, which is a tertiary referral centre, and how the survival results are favorable despite less than optimal follow-up.

In addition, it has been previously reported that IDH1 mutations and 1p19q co-deletion but not MGMT promoter methylation were independent prognostic factors in EORTC study 26951. In 159 cases in that study available for IDH analysis, only one IDH2 mutation was identified.Reference van den Bent, Dubbink and Marie 23

There are two ongoing randomized trials designed to address the uncertainties in the management of anaplastic oligodendroglioma tumors. In a phase III EORTC/North American intergroup trial (CATNON), patients with non–co-deleted anaplastic gliomas are randomly assigned to one of four treatment arms: radiotherapy, radiotherapy with concurrent temozolomide, radiotherapy followed by temozolomide, and radiotherapy with concurrent and adjuvant temozolomide. 24 In addition, preliminary analysis of the CODEL trial has been presented, 25 , Reference Jaeckle, Vogelbaum and Ballman 26 which is a phase III trial of newly diagnosed anaplastic glioma patients with 1p/19q co-deletions comparing the survival of patients in three different groups: one receiving only radiotherapy (N=12), another receiving radiotherapy and temozolomide (N=12), and a third receiving temozolomide alone (N=12). Patients in the study who received temozolomide only fared worse than the patients in the other two groups, leading an independent medical committee to recommend closing that arm of the study after a median follow-up of 3.4 years. Moving forward, 488 newly diagnosed patients with grade III anaplastic glioma with a 1p/19q co-deletion will be randomized into one arm receiving radiotherapy and the chemotherapy regimen PCV versus another arm of radiotherapy and temozolomide. The adjusted study is expected to be completed by December 2018. Although this trial has faced many obstacles as a consequence of the controversies surrounding the initial management of 1p19q co-deleted tumors, it is hoped that successful completion of this study will furnish definitive guidance on how best to manage these remarkably treatment-sensitive primary brain tumors.

Acknowledgements and Funding

This research was presented in part at the European Society of Medical Oncology conference, Madrid, September 26-30, 2014, and at the Society for Neuro-Oncology conference, Miami, November 13-16, 2014.

Disclosures

The authors do not have anything to disclose.

Statement of Authorship

MGMN undertook conception and design, acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript. HJ undertook statistical analysis and interpretation of data, and drafting, revising and final approval of manuscript. MJL-F undertook acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript. SS undertook conception and design, acquisition of data, interpretation of data, and drafting, revising and final approval of manuscript. T-RK undertook molecular analysis, acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript. JK undertook molecular analysis, acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript. C Coire undertook molecular analysis, acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript. C Chung undertook interpretation of data, and drafting, revising, and final approval of manuscript. B-AM undertook interpretation of data, drafting, revising and final approval of manuscript. NL undertook interpretation of data, and drafting, revising, and final approval of manuscript. WPM undertook conception and design, acquisition of data, interpretation of data, and drafting, revising, and final approval of manuscript.

References

1. Jenkins, RB, Blair, H, Ballman, KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66:9852-9861.CrossRefGoogle Scholar
2. Reifenberger, J, Reifenberger, G, Liu, L, James, CD, Wechsler, W, Collins, VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994;145:1175-1190.Google Scholar
3. Smith, JS, Alderete, B, Minn, Y, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene. 1999;18:4144-4152.Google Scholar
4. Van den Bent, MJ, Brandes, A, Taphoorn, MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344-350.Google Scholar
5. Cairncross, G, Wang, M, Shaw, E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337-343.Google Scholar
6. Alentorn, A, Sanson, M, Idbaih, A. Oligodendrogliomas: new insights from the genetics and perspectives. Curr Opin Oncol. 2012;24:687-693.Google Scholar
7. Cairncross, JG, Mac Donald, DR. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol. 1988;23:360-364.Google Scholar
8. Kim, L, Hochberg, FH, Thornton, AF, et al. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas. J Neurosurg. 1992;85:602-607.Google Scholar
9. Buckner, JC, Pugh, SL, Shaw, EG, et al. Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. J Clin Oncol. 2014;32(Suppl 5s:abstr 2000).Google Scholar
10. Kleihues, P, Burger, PC, Scheithauer, BW. The new WHO classification of brain tumours. Brain Pathol. 1993;3:255-268.Google Scholar
11. Kleihues, P, Louis, DN, Scheithauer, BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002;61:215-225.Google Scholar
12. Louis, DN, Ohgaki, H, Wiestler, OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97-109.Google Scholar
13. Cairncross, JG, Ueki, K, Zlatescu, MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90:1473-1479.Google Scholar
14. Johnson, MD, Vnencak-Jones, CL, Toms, SA, Moots, PM, Weil, R. Allelic losses in oligodendroglial and oligodendroglioma-like neoplasms: analysis using microsatellite repeats and polymerase chain reaction. Arch Pathol Lab Med. 2003;127:1573-1579.Google Scholar
15. Felsberg, J, Erkwoh, A, Sabel, MC, et al. Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival. Brain Pathol. 2004;14:121-130.Google Scholar
16. Capper, D, Zentgraf, H, Balss, J, Hartmann, C, von Deimling, A. (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 2009;118:599-601.Google Scholar
17. Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE). National Cancer Institute Division of Cancer Treatment and Diagnosis. 2010. Available at: http://evs.nci.nih.gov/ftpl/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.Google Scholar
18. Wick, W, Roth, P, Wiestler, B, et al. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol. 2015;33(Suppl abstr 2001).Google Scholar
19. Cairncross, G, Berkey, B, Shaw, E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24:2707-2714.Google Scholar
20. Wick, W, Hartmann, C, Engel, C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874-5880.Google Scholar
21. Reuss, DE, Sahm, F, Schrimpf, D, et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol. 2015;29:133-146.Google Scholar
22. The Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481-2498.Google Scholar
23. van den Bent, MJ, Dubbink, HJ, Marie, Y, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16:1597-1604.Google Scholar
24. Phase III Trial of Anaplastic Glioma Without 1p/19q LOH (CATNON). 2016 Available at: http://clinicaltrials.gov/ct2/show/NCT00626990.Google Scholar
25. Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma. 2016. Available at: http://clinicaltrials.gov/ct2/show/NCT00887146.Google Scholar
26. Jaeckle, K, Vogelbaum, M, Ballman, K, et al. CODEL (Alliance-N0577; EORTC-26081/2208; NRG-1071; NCIC-CEC-2): phase III randomized study of RT vs. RT+TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic glioma. Analysis of patients treated on the original protocol design. Neurology. 2016:(suppl: abstract PL02.005).Google Scholar
Figure 0

Table 1 Summary of patient characteristics for all gliomas

Figure 1

Table 2 Summary of tumor characteristics and surgery for all gliomas

Figure 2

Table 3 Summary of treatment history for all patients

Figure 3

Figure 1 (A) Kaplan-Meier plot of progression-free survival in all patients. (B) Kaplan-Meier plot of overall survival in all patients.

Figure 4

Table 4 Median, 2-year, and 5-year PFS and 5-year OS for all groups