Case Presentation: The modern management of oligodendrogliomas James Manfield B.S. University College London

Background Pt 25 y/o male marine CC First seizure HPC Otherwise well. No abnormal findings o/e. No significant PHM, FHM, DH, SH. Underwent biopsy  low-grade oligodendroglioma (1p19q not initially requested) Referred to Dr. Wenke for debulking. Successful stereotactic volumetric resection c. iop CT leaving 1 cm margins.

Pre-op imaging

Oligodendrogliomas Primary glial brain tumors. Grade II and Grade III (anaplastic) Aetiology poorly understood 5-19% of all intracranial tumors; 25% of all gliomas. M:F 2:1. Median age at D years. Most common CC seizure (low grade), focal deficits, ↑ICP or cognitive deficits (high grade).

1p/19q: Why does it matter? 1p/19q co-deletion, mediated by an unbalanced translocation of 19p to 1q. Combined loss present in 60-70% of all ODs (Smith et al. 2000) 1 st CNS neoplasm in which a better genetic signature was correlated with outcome in phase III trials (Cairncross et al. 2006, Van den Bent et al. 2006).

Summary of data Low grade OD/OA median 11.9 years with codeletion vs without [Shaw et. al 2002] 5 years survival 50% higher [Fontaine et al 2008]. Confounding variables. EORTC 26951: AOD 6-7 years c. co-deletion vs without combined loss [Cairncross et al. 2006, van den Bent et al. 2006]. 1p19q found to be most powerful predictor of outcome [Kouwenhoven et al. 2009]. Multiple studies now consistently show longer survival time. Not prognostic but predictive [Weller et al. 2007]

Management: Surgery 3 aims: tissue, mass effect ?better px No RCT data Retrospective study data has limitations 1 uncontrolled study- complete resection in low-grade OD associated with longer disease-free intervals [Berger et al. 1994]. Another study- subtotal resection improves survival [Shaw et al. 1997] In contrast other studies looking at gross total resection have shown no survival benefit [Daumas-Duport 1997 & Kros et al. 1994]. Nevertheless remains the standard of care.

Management: Radiotherapy Low grade One large study on early vs. delayed RT observed an improved progression-free survival after early RT but no increase in overall survival [van den Bent 2005] Anaplastic Mixed results 1p19q status relevant

Management: Chemotherapy PCV original regimen 2/3 of patients with recurrent OD have either a CR or PR to PCV. TtP around months [Sofietti R et al 1998]. AOD [Van den Bent 2008] 2 RCTs: Temozolomide- 2 large phase II trials. Clear alternative. No formal comparison between TMZ and PCV.

Discussion Cochrane Review: 2 RCTs. PCV + RT + surgery vs RT + surg- PCV delays progression, no effect on overall survival. [PCV haematological toxicity]. RCTs confirmed the major predictive role of 1p/19q status. 1p/19q status predicts more indolent behaviour and longer progression free survival after chemo or radiotherapy [Cochrane Review 2008]. Appears to apply to both low grade and high grade tumors, although limited data in low grade ODs [Van den Bendt 2008] Limitations of 1p/19q: With absent co-deletions still 33% show chemo response [Fontaine et al, 2008] Predictive for response to both RT and chemo therefore not appropriate to differentiate.

Optimal management for our patient What to do with a young patient, low grade tumor presenting with seizure. Many treatment modalities available- given length of expected survival must consider late sequalae. Debulking reasonable. Insufficient evidence to justify the risks of aggressive resection. RT- cognitive decline etc. Without good RCT evidence otherwise prudent to observe and delay until progression. Wish to delay RT major rationale for upfront chemotherapy- but no randomized data. Local side effects of 6 weeks RT vs systemic side effects 1 year chemotherapy. Ongoing EORTC trial. 1p19q status may be useful. Potentially renders role of surgery less important. Consider early TMZ delaying RT.

Summary OD tumors remain ultimately fatal Lack of randomized data for optimal management. With longer survival QOL issues and delayed side effects must be considered. 1p19q co-deletion implies better outcome. Predictive, not prognostic. Absence also does not exclude response. A number of questions remain.

References Smith JS, Perry A, Borell TJ, at al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol Feb;18(3): 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 J Clin Oncol 2006 Jun 20;24 (18): van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol Jun 20;24(18): Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol May 1;20(9): Fontaine D, Vandenbos F, Lebrun C, et al. Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice. Rev Neurol (Paris) Jun- Jul;164(6-7): Epub 2008 May 21. Kouwenhoven MC, Gorlia T, Kros JM, et al. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study Neuro Oncol Dec;11(6): Weller M, Berger H, Hartmann C, et al. Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res Dec 1;13(23): Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer Sep 15;74(6): Daumas-Duport C, Tucker ML, Kolles H, et al. Oligodendrogliomas. Part II: A new grading system based on morphological and imaging criteria. J Neurooncol Aug;34(1): Kros JM, Pieterman H, van Eden CG, Avezaat CJ. Oligodendroglioma: the Rotterdam-Dijkzigt experience. Neurosurgery Jun;34(6):959-66; discussion 966. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC randomised trial. Lancet Sep ;366(9490):

References cont. Soffietti R, Rudà R, Bradac GB, Schiffer D. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery Nov;43(5): Van den Bent MJ, Reni M, Gatta G, Vecht C. Oligodendroglioma. Crit Rev Oncol Hematol Jun;66(3): Epub 2008 Feb 12. Quon H, Abdulkarim B. Adjuvant treatment of anaplastic oligodendrogliomas and oligoastrocytomas. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD DOI: / CD

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