Current Treatment of Oligodendrogliomas

NEUROLOGICAL REVIEW Current Treatment of Oligodendrogliomas

James R. Perry, MD; David N. Louis, MD; J. Gregory Cairncross, MD

hat a neurological review is dedicated specifically to the oligodendroglioma is testi- mony to a decade of progress. The unique molecular features and chemosensitivity of the oligodendroglioma were not appreciated 10 years ago; yet today, these features merit such interest to clinicians and pathologists alike that the oligodendroglioma is sepa- Trated from other types of primary brain tumors in both the laboratory and in practice. DIAGNOSIS OF tologically disparate oligodendroglial and OLIGODENDROGLIOMA astrocytic components sharing the same genetic alterations. In practice, the distinction of oligodendroglioma from oligoastro- The diagnosis of oligodendroglioma cur- cytoma is probably not as important as the rently rests on standard light micro- distinction between these 2 oligodendrog- scopic assessment of hematoxylin-eosin– lial lesions and pure astrocytoma, since stained slides. Oligodendroglioma cells many oligoastrocytomas, grade for grade, bear some resemblance to oligodendro- behave clinically and respond to both ra- cytes, suggesting that oligodendroglio- diotherapy and chemotherapy in a fashion mas arise from a cell committed to oligo- very similar to pure oligodendrogliomas.1 dendrocytic differentiation. Nonetheless, Furthermore, high-grade oligodendroglio- there are as yet no immunohistochemical mas with perinecrotic pseudopalisading markers to diagnose oligodendroglial neo- should not be equated with typical glioblas- plasms, and attempts to use various mark- tomas; these necrotic oligodendrogliomas ers of oligodendrocytic differentiation have may also be chemosensitive.2 These diag- not proved reliable in tumor sections. Con- nostic difficulties underscore the need to sequently, the pathologist renders a diag- improve the nosological criteria for oligo- nosis of oligodendroglioma based on the dendroglial neoplasms; molecular analy- subjective light microscopic impression of ses may resolve some of the uncertainties, a moderately cellular tumor with regular, since pure and mixed oligodendrogliomas rounded nuclei, sometimes with peri- havecharacteristicpatternsofchromosomal nuclear halos (“fried-egg appearance”) and loss. For instance, combined chromosome sometimes with branching vasculature and 1p and 19q loss is frequently associated with calcifications. oligodendroglial tumors and may therefore The diagnosis is further complicated constitute important adjuncts for diagno- by the fact that many oligodendrogliomas sis of these lesions.3 contain an astrocytic component, which may be substantial at times; such mixed tu- OLIGODENDROGLIOMAS mors are termed oligoastrocytomas. Oli- ARE ONE OF THE MORE goastrocytomas are not “collision” tumors CHEMOSENSITIVE HUMAN SOLID but rather are clonal neoplasms with the his- CANCERS

Ten years after Cairncross and Macdonald4 From the Department of Medicine (Neurology), Toronto-Sunnybrook Regional Cancer Center, University of Toronto, Toronto, Ontario (Dr Perry); the Department of first reported remarkable examples of Pathology and the Neurosurgical Service, Molecular Neuro-oncology Laboratory, tumor shrinkage after chemotherapy in pa- Massachusetts General Hospital and Harvard Medical School, Boston (Dr Louis); and tients with recurrent anaplastic oligoden- the Department of Medical Oncology, London Regional Cancer Center, London, droglioma, it is clear that oligodendroglio- Ontario (Dr Cairncross). mas are among the most chemosensitive of

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 all human solid malignancies. While procarbazine, lomus- tein) and the presence of a ring-enhancing tumor con- tine (CCNU), and vincristine sulfate, a chemotherapy regi- ferred significantly worse prognosis. men designated PCV, are most often used in practice, oli- These observations demonstrated for the first time godendrogliomas have been shown to be sensitive to a that specific molecular genetic changes may be used as variety of cytotoxic drugs including melphalan, thio- markers of chemosensitivity in malignant gliomas. Also, tepa, temozolamide, paclitaxel (Taxol), and platinum- these molecular features provided important survival in- based regimens.1,5,6 Response, defined by at least a 50% formation above and beyond traditional prognostic fac- reduction in area of enhancing tumor, is seen in about tors such as age and performance status. A patient whose 75% of patients treated with PCV chemotherapy for anaplastic oligodendroglioma has both 1p and 19q loss recurrent anaplastic oligodendroglioma; many of these would be predicted to show a radiographic response to responses are complete. Responses also have been PCV chemotherapy and have a 5-year survival rate of 95%. shown in patients treated upfront with PCV chemo- A patient with a histologically identical tumor, but with therapy before radiotherapy, patients with both pure CDKN2A deletion, would be less likely to respond to che- and mixed oligodendroglial tumors, and patients with motherapy and have an expected survival of 2 years. Lastly, low-grade oligodendroglioma.1,7 a patient with a ring-enhancing anaplastic oligodendro- The basis of this unique chemosensitivity is un- glioma will probably not respond to chemotherapy and clear; presumably, neoplastic cells in the oligodendrog- have a median survival of less than 1 year despite sur- lial lineage are inherently susceptible to the alkylating gery and radiotherapy. effects of cytotoxic chemotherapy. Low levels of the DNA repair protein O6-methylguanine-DNA methyltransfer- TREATMENT OF LOW-GRADE ase have been found in oligodendroglial cells lines, and OLIGODENDROGLIOMAS Silber et al8 recently observed significantly lower O6- methylguanine-DNA methyltransferase activity in hu- Oligodendrogliomas are classified as low grade if they lack man oligodendrogliomas and mixed glioma samples than or have few histological features suggestive of anapla- in astroglial tumors. Glioma O6-methylguanine-DNA sia: namely, high cellularity, nuclear pleomorphism, mi- methyltransferase levels are also inversely correlated with totic figures, endothelial proliferation, and necrosis. The age, which perhaps explains, at least in part, the well- appropriate management of low-grade oligodendroglio- known survival advantage associated with young age (Ͻ45 mas requires individualized consideration, because these years) in patients with malignant glioma. Another in- tumors can be indolently progressive and manifest only triguing hypothesis asserts that, in addition to these as a partial seizure disorder that may often be present for mechanisms, a p53-mediated programmed cell death path- a decade or more; yet, they can also be clinically aggres- way may be activated in oligodendrogliomas after expo- sive and cause a symptomatic, progressively enlarging con- sure to cytotoxic chemotherapy.9 This mechanism may trast-enhancing brain mass. Timing and intensity of post- be similar to observations made in testicular neoplasms; operative therapy is controversial, and it is unclear if oligodendrogliomas rarely harbor p53 gene mutations and patients are best treated at the time of surgical diagnosis frequently display apoptotic tumor cells, yet, like tes- or whether radiotherapy or chemotherapy is best re- ticular cancers, are known to accumulate wild-type p53 served for the time of clinical or radiographic tumor pro- protein. Other authors have suggested that these events gression. At present, nonrandomized retrospective stud- may “prime” the cancer cell to undergo programmed cell ies support maximal feasible surgical resection and death after exposure to chemotherapy.10 Explanations for external-beam radiotherapy when significant residual dis- the chemosensitive nature of oligodendrogliomas await ease is identified on postoperative imaging or when ag- the cloning and characterization of the responsible genes. gressive clinical or pathological features are identified.1 Undoubtedly, radiotherapy is an effective treatment to GENETIC PREDICTORS OF TREATMENT stabilize progressing tumor and to control symptoms such RESPONSE AND SURVIVAL as seizures; however, toxic effects appearing years after cerebral irradiation are a major concern in these pa- Cairncross et al3 recently studied 39 patients with ana- tients because of relatively long survival rates (ie, 80% plastic or aggressive oligodendrogliomas treated with al- at 5 years and 30%-50% at 10 years). It is unclear whether kylating chemotherapy, usually the PCV regimen, who had the tumor-controlling benefits of radiation therapy out- known response and survival outcomes. A variety of clini- weigh its risks in patients with low-grade tumors, al- cal prognostic factors, genetic alterations, and immuno- though it must be stated that radiotherapy is probably histochemical findings were examined in relation to these becoming safer as delivery systems and targeting meth- outcomes. Chromosome 1p loss, found in 70% of cases, ods improve. correlated strikingly with radiological responses to che- There is now a growing body of evidence to sup- motherapy; in fact, 100% of tumors with 1p loss were che- port the notion that low-grade oligodendrogliomas, pure mosensitive. Chromosome 19q loss alone was not asso- or mixed, are chemosensitive. Paleologos et al11 found ciated with response, but the combination of 1p and 19q partial responses in 3 patients and stable responses in 2 loss was tightly associated and predictive of longer recur- patients (out of a total of 5) with low-grade oligoden- rence-free survival. Patients without 1p loss were un- droglioma treated with PCV chemotherapy, and Mason likely to harbor chemosensitive tumors and had a 17-fold et al7 confirmed these results in another study. From these increase in relative risk of death. Other analyses from this studies and additional anecdotal observations, there is study also suggested that deletion of CDKN2A (p16 pro- little doubt that low-grade oligodendrogliomas are sen-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 sitive to chemotherapy; however, the kinetics of radio- gressive, are chemosensitive and that chromosome 1p loss graphic response may be different from what is seen in is an important marker of this phenomenon. As the op- more aggressive or anaplastic tumors. For example, we timal timing and intensity of PCV chemotherapy is clari- and others have noted that nonenhancing low-grade oli- fied for patients with oligodendrogliomas, especially those godendrogliomas typically respond gradually and only with 1p losses, other novel treatment approaches will un- partially when treated with PCV chemotherapy, and some- doubtedly be tested. While other types of gliomas may times only radiographic disease stabilization is achieved.9 or may not be chemosensitive, lessons are yet to be learned These observations have generated interest in the use of from oligodendrogliomas; we strongly support the sepa- lower-dose but longer duration PCV chemotherapy for ration of oligodendrogliomas from other gliomas in the these tumors, and clinical trials to evaluate so-called mini- laboratory and in clinical trials.12 dose PCV chemotherapy are underway. Accepted for publication November 23, 1998. TREATMENT OF ANAPLASTIC Reprints: J. Gregory Cairncross, MD, Department of OLIGODENDROGLIOMAS Medical Oncology, London Regional Cancer Center, 790 Commissioners Rd E, London, Ontario, Canada N6A 4L6. Most patients with anaplastic oligodendrogliomas will respond to PCV chemotherapy; however, as with their less REFERENCES aggressive counterparts, the best timing of such therapy is unclear. Genetic prediction of chemosensitivity using molecular genetic analysis will likely enter into future 1. Perry JR, Cairncross JG. Oligodendrogliomas. In: Vecht Ch J, ed. Handbook of Clinical Neurology. Vol 24. New York, NY: Elsevier Science Inc; 1997:123-136. treatment decisions. For example, a patient with a newly 2. Cairncross JG, MacDonald D, Ludwin S, et al. Chemotherapy for anaplastic oli- diagnosed anaplastic oligodendroglioma harboring a chro- godendroglioma. J Clin Oncol. 1994;12:2013-2021. mosome 1p deletion is so likely to be chemosensitive and 3. Cairncross JG, Ueki K, Zlatescu M, et al. Specific genetic predictors of chemo- have prolonged survival that the best therapy may con- therapeutic and survival in patients with anaplastic oligodendrogliomas. J Natl sist of early postoperative chemotherapy using PCV to- Cancer Inst. 1998;90:1473-1479. 4. Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malig- gether with radiotherapy or using PCV alone until there nant oligodendrogliomas. Ann Neurol. 1988;23:360-364. 3 is evidence of tumor progression. On the other hand, a 5. Chamberlain MC, Kormanik PA. Salvage chemotherapy with paclitaxel for recur- similar patient with unfavorable genetic features might rent oligodendrogliomas. J Clin Oncol. 1997;15:3427-3432. be best treated with current standard care, namely post- 6. Friedman HS, Lovell S, Rasheed K, Friedman AH. Treatment of adults with pro- operative external beam radiotherapy and novel therapy gressive oligodendroglioma with carboplatin (CBDCA): preliminary results. Med Pediatr Oncol. 1998;31:16-18. at the time of tumor recurrence. These dilemmas may be 7. Mason WP, Krol GS, DeAngelis LM. Low-grade oligodendroglioma responds to answered in part by the ongoing randomized inter- chemotherapy. Neurology. 1996;46:203-207. group study of neo-adjuvant PCV chemotherapy vs ra- 8. Silber JR, Bobola MS, Ghatan S, et al. O6-methylguanine-DNA methyltransfer- diotherapy for patients with newly diagnosed anaplastic ase activity in adult gliomas: relation to patient and tumor characteristics. Can- cer Res. 1998;58:1068-1073. oligodendroglioma. 9. Mason W, Louis DN, Cairncross JG. Chemosensitive gliomas in adults: which In the past decade, we have witnessed the emer- ones and why? J Clin Oncol. 1997;15:3423-3426. gence of the oligodendroglioma as a diamond in the rough; 10. Lutzker SG, Levine AJ. A functionally inactive p53 protein in teratocarcinoma cells while treatment advances in glioma therapy have been is activated by either DNA damage or differentiation. Nat Med. 1996;2: modest at best, the unique molecular nature and che- 804-810. 11. Paleologos NA, Vick NA, Kachoris JP. Chemotherapy for low-grade oligoden- mosensitivity of oligodendrogliomas set them apart from drogliomas [abstract]? Ann Neurol. 1994;36:294. other types of glial neoplasms. We know now that oli- 12. Perry JR, DeAngelis LM, Schold SC Jr, et al. Challenges in the design and con- godendrogliomas, pure and mixed, low grade and ag- duct of phase III brain tumor therapy trials. Neurology. 1997;49:912-917.

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