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Pattern of failure in anaplastic glioma patients with an IDH1/2 mutation

Rezidivmuster bei Patienten mit anaplastischem Glioma mit einer IDH1/2-Mutation

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Abstract

Purpose

The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype.

Methods

The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT.

Results

A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6‑year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p < 0.001). There was a component of local relapse in 63%, of marginal relapse in 19% and of distant relapse in 37% of relapses. Isolated local, marginal and distant relapse was evident in 51, 9 and 22%, respectively. A distant relapse pattern was more frequent in IDHmut compared to IDHwt patients (26% vs. 45%, p = 0.005), especially within the first 2 years post-IMRT. In multivariate analysis, distant relapse remained associated with AAmut (p < 0.002) and delayed IMRT until the second relapse (p < 0.001).

Conclusion

Although patients with IDH-mutated AG have improved outcomes, there was a higher proportion of distant relapses occurring during the 2 years after IMRT.

Zusammenfassung

Ziel

Die Studie hat das Ziel, Rezidivmuster (PoF) und deren Bezug zum molekularen Subtyp bei Patienten mit anaplastischem Gliom (AG), welche mit intensitätsmodulierter Strahlentherapie (IMRT) behandelt wurden, auszuwerten.

Methoden

Für Patienten mit AG, die zwischen 2008–2014 behandelt wurden, werteten wir prospektiv erfasste Ergebnisse einschließlich PoF aus. Initial wurde AG gemäß WHO-Klassifikation 2007 definiert. Für diese Studie wurden die Patienten nach WHO 2016 als anaplastisches Oligodendrogliom (AOD), Astrozytom mit Isocitrat-Dehydrogenase-(IDH-)Mutation (AAmut) oder Wildtyp-Astrozytom (AAwt) rekategorisiert. Die Behandlung bestand aus IMRT und Temozolomid (TMZ), wobei seit 2011 für Patienten mit IDH-Mutationen (IDHmut) eine 18F-Fluoroethyltyrosin (FET) und eine 18F-Fluorodeoxyglukose-(FDG-)Positronenemissionstomographie (PET) Teil des Planungsprozesses waren. Die PoF-Analyse unterschied Lokal‑, Marginal- und Fernrezidive basierend auf dem Abstand zum IMRT-Volumen. Die rezidivfreie Überlebensrate (RFS) wurde ab IMRT-Beginn berechnet.

Ergebnisse

Eingeschlossen wurden 156 Patienten mit einer medianen Nachbeobachtungszeit von 5,1 Jahren. Von diesen waren 75% IDHmut, bei 44 % wurde ein Erst- oder späteres Rezidiv behandelt und 73 % erhielten TMZ. Ein Rezidiv mit einer 6‑Jahres-RFS von jeweils 75,0 %, 48,8 % und 2,5 % für AOD, AAmut and AAwt entwickelten 68 % (p < 0,001). Es bestand eine Komponente für ein lokales Rezidiv in 68 %, für ein marginales Rezidiv in 19 % und für ein entferntes Rezidiv in 37 % der Fälle. Isolierte Lokal‑, Marginal- und Fernrezidive lagen jeweils in 51 %, 9 % und 22 % vor. Besonders innerhalb der ersten beiden Jahre seit IMRT war ein entferntes Rezidivmuster häufiger für IDHmut verglichen mit IDHwt (26 % vs. 45 %; p = 0,005). In der multivariaten Analyse blieb die Assoziation zwischen Fernrezidiv und AAmut (p < 0,002) und bis zum zweiten Rezidiv verzögerter IMRT (p < 0,001) bestehen.

Schlussfolgerung

Obwohl Patienten mit IDH-mutiertem AG bessere Ergebnisse erzielen, gab es einen relativ hohen Fernrezidivanteil innerhalb der ersten beiden Jahre seit IMRT.

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Authors and Affiliations

  1. Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards Sydney NSW 2065, Sydney, Australia

    M. Back, D. Jayamanne, D. Brazier, A. Newey, M. Khasraw, M. Kastelan, C. Brown & H. Wheeler

  2. Central Coast Cancer Centre, Gosford Hospital, Gosford, Australia

    M. Back, D. Jayamanne & M. Wong

  3. Genesis Cancer Care, Sydney, Australia

    M. Back

  4. Sydney Medical School, University of Sydney, Sydney, Australia

    M. Back, D. Brazier, A. Newey, M. Khasraw & H. Wheeler

  5. The Brain Cancer Group, Sydney, Australia

    M. Back, G. Schembri, M. Khasraw, M. Kastelan & H. Wheeler

  6. Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia

    D. Bailey & E. Hsiao

  7. Faculty of Health Sciences, University of Sydney, Sydney, Australia

    D. Bailey

  8. NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia

    M. Khasraw & C. Brown

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  1. M. Back
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Corresponding author

Correspondence to M. Back.

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Conflict of interest

M. Back, D. Jayamanne, D. Brazier, A. Newey, D. Bailey, G. Schembri, E. Hsiao, M. Khasraw, M. Wong, M. Kastelan, C. Brown and H. Wheeler declare that they have no competing interests.

Ethical standards

The database for this study was approved by the Institutional Ethics Review Board. Patient data were collected following written informed consent. The research was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Back, M., Jayamanne, D., Brazier, D. et al. Pattern of failure in anaplastic glioma patients with an IDH1/2 mutation. Strahlenther Onkol 196, 31–39 (2020). https://doi.org/10.1007/s00066-019-01467-0

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