Gliomas classified as grade II by the World Health Organization (WHO) include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. This heterogeneous group of conditions is associated with a more favorable prognosis and longer-term survival than high-grade gliomas (HGGs). Neurosurgical resection and radiation therapy improve survival in symptomatic, progressive, or high-risk grade II gliomas. Until recently, the role of chemotherapy has been less clear. This review draws on insights from the management of HGGs and emerging data on the addition of PCV (procarbazine, lomustine [CCNU], and vincristine) to radiation for these neoplasms. Specifically, this review focuses on the current status of chemotherapeutic management of grade II gliomas, including optimal timing of treatment, and management of 1p19q codeleted and non-codeleted tumors.
Grade II gliomas comprise a heterogeneous group of primary central nervous system (CNS) tumors that vary widely in their histopathology, molecular features, and clinical symptomatology. While diverse, this group of conditions shares a generally indolent course with good prognosis and favorable long-term survival data. The benefits of surgery and radiation therapy (RT) have long been recognized for many types of low-grade lesions in this setting. Emerging data suggest that chemotherapy, although historically reserved primarily for recurrence or progression, may have a substantial impact earlier in the disease course.
In this article, we provide a brief overview of the management of grade II astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas—the three most heavily encountered and studied of the low-grade gliomas (LGGs). For a comprehensive review of other low-grade glial neoplasms, please see recent review articles on this subject.
Classification of Grade II Gliomas: Histologic and Genetic Factors
Grade II gliomas are classified based on the international classification of CNS neoplasms published by the World Health Organization. This classification scheme defines this group based on its histologic features, including hypercellularity, nuclear atypia, pleomorphism, and lack of significant mitotic activity. Lower proliferative indices are common, and necrosis or vascular proliferation, which is diagnostic of high-grade gliomas (HGGs), is not observed. These histopathologic criteria remain the gold standard for diagnosis but are increasingly informed by molecular and immunohistochemical markers.
At present, four genetic markers augment the pathologic evaluation of LGGs and have become increasingly important in understanding and selecting the appropriate treatments for these neoplasms. Combined loss of heterozygosity on the short arm of chromosome 1 and the long arm of chromosome 19 (ie, complete 1p19q codeletion) has become one of the most important markers in the evaluation and management of LGGs. Codeletion of 1p19q reliably differentiates between the more favorable pure oligodendrogliomas and less favorable mixed oligoastrocytomas or astrocytomas. Codeletion is present in at least 75% of all low-grade oligodendrogliomas (LGOs) but only 20% of low-grade astrocytomas (LGAs). Importantly, 1p19q codeletion has been shown repeatedly to have both prognostic and predictive implications. In a recent meta-analysis, codeletion of 1p19q was strongly associated with improved survival in oligodendrogliomas (hazard ratio [HR] = 0.41; 95% confidence interval [CI], 0.30–0.56), in all gliomas (HR = 0.41; 95% CI, 0.34–0.48), and in histologically described astrocytic tumors (HR = 0.52; 95% CI, 0.36–0.75). One large multicenter retrospective study reported an absolute median survival difference of 2.9 years in patients with low-grade gliomas with vs without 1p19q codeletion (P = .0228; see Table). In patients with anaplastic oligodendrogliomas (AOs), the presence of 1p19q codeletion is strongly associated with survival and chemosensitivity to PCV (procarbazine, lomustine [CCNU], and vincristine).[6,7] Thus, this genetic marker has become a key factor in determining the optimal management of oligodendroglial neoplasms and may begin to replace isolated histologic classification.
Other markers have also been shown to support the pathologic evaluation of LGGs but have lesser implications for treatment selection. These include mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) genes. Mutation of IDH1 is common and present in over 85% of LGGs. While this marker portends a more favorable prognosis in general, it does not appear to differentiate between LGG subtypes. There is some suggestion that IDH mutational status may also provide implications for treatment selection and response; prospective data are lacking, however, and further study is ongoing. Mutations of the tumor protein 53 (TP53) gene are more common in astrocytic lesions, having been reported in over 50% of LGAs but only 10% of LGOs. Unlike codeletion of 1p19q, expression of TP53 is not predictive of survival or response to treatment. Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter has become an increasingly important marker in HGGs, in which it appears to be of prognostic importance. Its prevalence in LGGs is higher, and a prospective study of its predictive value in these lesions is lacking.
Overview of the Management of Grade II Gliomas
Medical treatment of grade II gliomas involves a combination of surgery, RT, and chemotherapy and is best conducted by a multidisciplinary team. Surgery is the backbone of management of these neoplasms, providing de facto tissue diagnosis and gross cytoreduction of tumor. The prognostic importance of the extent of surgical resection has been discussed repeatedly in the literature. Because of ethical concerns, no randomized prospective studies have been performed in glioma patients randomized to different extents of resection. Several large retrospective analyses have consistently demonstrated the extent of resection to be independently associated with freedom from seizures and improved survival, with gross total resection (GTR) found to be more favorable than both subtotal resection (STR) and biopsy.[11-15] Without prospective study, however, it is difficult to determine whether this is a result of the surgery itself or whether surgery is a surrogate for differences in underlying tumor biology. Despite advances in intraoperative magnetic resonance imaging (MRI) and other techniques for improving the extent of resection, due to the infiltrative nature of these lesions, residual tumor remains almost universally, and RT and chemotherapy provide important adjuvant treatments.
RT has been shown repeatedly to improve survival in patients with LGG and has long played an important role in their management.[12,17] A number of chemotherapeutics have been investigated in this setting, including dactinomycin, vincristine, carboplatin, etoposide, PCV, temozolomide (TMZ), and combinations of these agents. In general, these have been studied in small phase II, single-arm trials, which have often evaluated radiographic response. The small number of patients studied, favorable long-term survival associated with LGG, heterogeneous populations with a lack of optimal comparators, and reliance on radiographic response in non–contrast-enhancing tumors has limited the ability to arrive at practice-changing conclusions.
1. Forst DA, Nahed BV, Loeffler JS, Batchelor TT. Low-grade gliomas. Oncologist. 2014;19:403-13.
2. 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.
3. Kim YH, Nobusawa S, Mittelbronn M, et al. Molecular classification of low-grade diffuse gliomas. Am J Pathol. 2010;177:2708-14.
4. Zhao J, Ma W, Zhao H. Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis. Neuro Oncol. 2014;16:103-12.
5. Boots-Sprenger SH, Sijben A, Rijnties J, et al. Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution. Mod Pathol. 2013;26:922-9.
6. van den Bent MJ, Brandes AA, 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;31:344-50.
7. 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;31:337-43.
8. Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28:177-83.
9. Everhard S, Kaloshi G, Criniere E, et al. MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol. 2006;60:740-3.
10. Englot DJ, Berger MS, Barbaro NM, Chang EF. Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. J Neurosurg. 2011;115:240-4.
11. McGirt MJ, Chaichana KL, Attenello FJ, et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery. 2008;63:700-7.
12. Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36:549-56.
13. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26:1338-45.
14. Ius T, Isola M, Budai R, et al. Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients: clinical article. J Neurosurg. 2012;117:1039-52.
15. Maichrzak K, Kaspera W, Bobek-Billewicz B, et al. The assessment of prognostic factors in surgical treatment of low-grade gliomas: a prospective study. Clin Neurol Neurosurg. 2012;114:1135-44.
16. Koc K, Anik I, Cabuk B, Cevlan S. Fluorescein sodium-guided surgery in glioblastoma multiforme: a prospective evaluation. Br J Neurosurg. 2008;22:99-103.
17. 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. 2002;20:2267-76.
18. Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012;30:3065-70.
19. 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, SWOG. J Clin Oncol. 2014;32(suppl 5s):abstr 2000.
20. van den Bent MJ, Afra D, de Witte O, et al; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366:985-90.
21. Pignatti F, van den Bent M, Curren D, et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol. 2002;20:2076-84.
22. Daniels TB, Brown PD, Felten SJ, et al. Validation of EORTC prognostic factors for adults with low-grade glioma: a report using Intergroup 86-72-51. Int J Radiat Oncol Biol Phys. 2011;81:218-24.
23. 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. 2006;24:2715-22.
24. Intergroup Radiation Therapy Oncology Group Trial 9402; 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;24:2707-14.
25. Cairncross JG, Wang M, Jenkins RB, et al. Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol. 2014;32:783-90.
26. Boyle FM, Eller SL, Grossman SA. Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro-oncol. 2004;6:300-5.
27. Mikkelsen T, Doyle T, Anderson J, et al. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009;92:57-63.
28. Gan HK, Rosenthal MA, Dowling A, et al. A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors. Neuro Oncol. 2010;12:500-7.
29. Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol. 2004;22:3133-8.
30. Quinn JA, Reardon DA, Friedman AH, et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol. 2003;21:646-51.
31. van den Bent MJ, Taphoorn MJ, Brandes AA, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003;21:2525-8.
32. Pace A, Vidiri A, Galiè E, et al. Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann Oncol. 2003;14:1722-6.
33. Fisher BJ, Lui J, Macdonald DR. A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: preliminary results of RTOG 0424. J Clin Oncol. 2013;31(suppl):abstr 2008.
34. Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990;18:321-4.
35. Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001;19:509-18.
36. Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-96.
37. Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459-66.
38. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003.
39. Shonka NA, Theeler B, Cahill D, et al. Outcomes for patients with anaplastic astrocytoma treated with chemoradiation, radiation therapy alone or radiation therapy followed by chemotherapy: a retrospective review within the era of temozolomide. J Neurooncol. 2013;113:305-11.
40. Scoccianti S, Magrini SM, Ricardi U, et al. Radiotherapy and temozolomide in anaplastic astrocytoma: a retrospective multicenter study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology). Neuro Oncol. 2012;14:798-807.
41. Kizilbash SH, Giannini C, Voss JS, et al. The impact of concurrent temozolomide with adjuvant radiation and IDH mutation status among patients with anaplastic astrocytoma. J Neurooncol. 2014 Jul 4. [Epub ahead of print]
42. Holdhoff M, Grossman SA. Controversies in the adjuvant therapy of high-grade gliomas. Oncologist. 2011;16:351-8.
43. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343:189-93.
44. Baumert BG, Mason WP, Ryan G, et al. Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: a randomized phase III Intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033). J Clin Oncol. 2013;31(suppl):abstr 2007.