DOI: 10.1200/JOP.2016.018622 Journal of Oncology Practice - published online before print December 12, 2016
Treatment Strategies for Low-Grade Glioma in Adults
Diffuse low-grade gliomas include oligodendrogliomas and astrocytomas. The recent 2016 WHO classification has now updated the definition of these tumors to include molecular characterization, including the presence of isocitrate dehydrogenase mutation and 1p/19q codeletion. In this new classification, the histologic subtype of grade II mixed oligoastrocytoma has been eliminated. Treatment recommendations are currently evolving, mainly because of a change in the prognostic factors that are based on molecular and cytogenetic features. Standard of care includes maximal safe surgical resection. Prior randomized clinical trials stratified treatment arms on the basis of extent of resection and age, with patients stratified into low risk (age younger than 40 years and gross total resection) and high risk (age older than 40 years or subtotal resection). Patients who are low risk may undergo routine magnetic resonance imaging surveillance after resection. On the basis of recently published data, it is now recommended that high-risk patients undergo a combination of both radiation and chemotherapy after surgery. These studies, however, do not address the management of patients with low-grade gliomas in the era of genomic medicine. These treatments can also have great impact on quality of life, and therefore treatment recommendations should be done on an individual basis taking into account the current pathology classification, age, extent of resection, quality of life, and patient preference.
Diffuse infiltrating low-grade gliomas are classified as WHO grade 2 tumors and include oligodendrogliomas and astrocytomas.1 They are relatively rare tumors, accounting for only 5% of all primary brain tumors and 15% of all gliomas.2,3 Compared with high-grade gliomas (WHO grade 3 and 4 [glioblastoma]), patients typically present at a younger age, with the peak incidence between ages 35 and 44 years.4 The most typical presentation is seizure, most commonly occurring in patients with oligodendrogliomas.5 Focal neurologic deficits are less common than seen in high-grade gliomas, likely secondary to the slow growth rate and infiltrating nature. In addition, patients are commonly diagnosed incidentally during radiographic evaluations for headache, vertigo, and head trauma. Patients with low-grade gliomas have longer survival than patients with high-grade gliomas, with a median survival of 13 years with aggressive treatments.6 Low-grade gliomas pose unique challenges for clinicians for both treatment decisions of the tumor as well as management of tumor- and treatment-related sequelae. The longevity associated with these tumors lends critical importance to considerations of treatment toxicity of the classic modalities of oncologic treatment, including surgery, radiation, and chemotherapy.
Low-grade glioma represents a spectrum of tumor types with diverse histologic features; however, recently molecular analysis of tumors has become a critical part of tumor classification and prognostication. In 2016, the WHO updated its classification of primary brain tumors to include molecular characterization, now defining tumors both on phenotype and genotype7-20 (Figs 1 and 2). Oligodendrogliomas on traditional hematoxylin and eosin staining have round nuclei and fine delicate branching vessels but are now also defined as having both an isocitrate dehydrogenase (IDH) gene family mutation and combined whole-arm losses of 1p and 19q (1p/19q codeletion).1,14-17 Astrocytomas are characterized by prominent glial fibrillary acidic protein processes, typically also have mutations in IDH, but have intact 1p and 19q chromosomes as well as loss of ATRX.1 Mutations in either IDH1 or IDH2 occur in up to 80% of grade 2 and 3 diffuse gliomas and carry a more favorable prognosis compared with IDH wild-type tumors.17 Several studies have now performed large-scale whole-genome sequencing on low-grade gliomas. The Cancer Genome Atlas Research Network analyzed 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression, and found three prognostically significant subtypes of lower-grade glioma (grade 2 and 3) that were more concordant with molecular signature of IDH, 1p/19q, and TP53 status than with histologic class.19 Patients with lower-grade gliomas with mutations in IDH who had 1p/19q codeletion had the most favorable prognosis and were also associated with mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Patients in the intermediate prognostic class had tumors characterized by IDH mutations without 1p/19q codeletion and were associated with mutations in TP53 (94%) and ATRX inactivation (86%). The patients with the least favorable outcomes consisted of low-grade gliomas without IDH mutations and had mutations in PTEN, EGFR, NF1, TP53, PIK3Ca, PTPN11, and PLCG1 and were molecularly similar to WHO grade 4 glioblastomas. In a separate analysis by Mayo–University of California San Francisco, five molecular subtypes were found based on IDH, 1p/19q codeletion, and TERT promotor mutation status in 1,087 gliomas: triple-positive (mutations in both TERT and IDH plus 1p/19q codeletion), mutations in both TERT and IDH, mutation in IDH only, mutation in none of the three, and mutation in TERT only.18,20,21 With the addition of the molecular characteristics into the classification of low-grade gliomas, there has also been a shift in their definition of malignant transformation.1 When grade 2 oligodendrogliomas transform to higher-grade tumors, they are categorized as grade 3 anaplastic oligodendrogliomas but do not become glioblastomas on the basis of the presence of the 1p/19q codeletion. When grade 2 astrocytomas transform, they can become either grade 3 anaplastic astrocytomas or grade 4 glioblastomas. As more research is performed, likely new biomarkers and combinations thereof will be used for both definition and prognostication of low-grade gliomas.
Surgery remains a mainstay of therapy for low-grade gliomas, but decision making is more complicated than in higher-grade tumors. If a patient is clearly symptomatic from a tumor because of mass effect or uncontrolled seizures, the decision for surgery is straightforward. Many low-grade tumors, however, are discovered incidentally when imaging is done for other reasons, such as trauma, headaches, or vertigo, and are therefore asymptomatic. If the tumor is asymptomatic, or located in eloquent cortex, the decision for surgery can be more complex. It is difficult to obtain controlled data in the setting of long overall survival and several competing priorities, including seizure control and functional preservation, and therefore clear guidelines on the role of surgery have yet to be defined. Several retrospective observational studies have been done evaluating serial imaging observation versus surgical resection in patients with low-grade tumors. One recently published study from Norway analyzed two different centers, one of which favored biopsy and serial observation, the other early surgical resection.22 They found that the center that favored early resection had a significantly longer overall survival, with an estimated 5-year survival of 74% compared with 60% in the center that favored biopsy and observation.22 Data suggest that this is also the case for incidentally discovered low-grade gliomas.23,24 It is clear that there is a significant benefit to a surgical debulking procedure compared with biopsy, because needle biopsies have profound misdiagnosis rates due to the heterogeneous nature of gliomas.25,26 As in the case for high-grade gliomas, the extent of resection also has a significant impact on outcomes of progression-free and overall survival. One recent study prospectively evaluated 28 patients with stratification on the basis of extent of resection: total, subtotal (incomplete when total was the goal), partial (cytoreductive being the goal), and biopsy.27 They found a correlation between extent of resection and both recurrence rate and malignant transformation. A larger study of 216 patients with low-grade gliomas found a 5-year overall survival rate of 97% when the extent of resection was > 90% and a 76% 5-year survival rate if the extent of resection was < 90%.28 A study of 170 patients from Johns Hopkins also found similar results, showing gross total resection was associated with a significantly improved overall survival (P = .017) as well as delay in tumor progression and malignant transformation independent of age, degree of disability, or histologic subtype.29 Therefore, it is recommended that patients with low-grade gliomas undergo the greatest degree of surgical resection that can safely be accomplished.
The precise optimal management of patients with low-grade glioma after surgical resection remains to be determined. The risk-benefit ratio of treatment with radiation and chemotherapy must be weighed for each individual patient. Prior studies stratified patients into high- and low-risk low-grade glioma on the basis of clinical features of age (older or younger than 40 years) and the extent of resection. A large prospective study of observation of patients with low-risk low-grade glioma younger than 40 years who had gross total resections reported 52% of patients had recurrence within 5 years of surgery. On the basis of these data, in patients who are considered low risk, defined as age younger than 40 years with a gross total resection, it is an attractive option to forgo further treatment with radiation and chemotherapy at the time of diagnosis and instead undergo regular magnetic resonance imaging (MRI) surveillance.30 In the era of the new classification of low-grade gliomas, the management of a patient younger than 40 years of age who has had a gross total resection of a grade 2 astrocytoma that is IDH wild type remains unclear. These patients are known to have a poor prognosis, and observation may not be prudent, and, in these cases, immediate radiation with concomitant chemotherapy may be used. It is important that patients undergo long-term close surveillance, because recurrence is nearly universal. In addition, we recommend that patients go no longer than annual MRI scans so they are not lost to follow-up.
If a patient is deemed high risk, defined as older than 40 years or having a subtotal resection, further treatment with radiation and chemotherapy at diagnosis should be considered. Historically, radiation therapy was the mainstay of treatment after surgical resection, with doses of 50 to 54 Gy in 1.8- to 2-Gy fractions over 5 to 6 weeks.8,10 The benefit of early radiation at diagnosis versus at the time of recurrence, however, has been debated. A phase III study randomly assigned patients with low-grade glioma to either postoperative radiation or observation, with radiation permitted at progression. Early radiation prolonged progression-free survival by close to 2 years, but there was no significant difference in overall survival, which was 7.4 years in the radiation group and 7.2 years in the observation group12; quality of life and neurocognition, however, were not assessed. Despite the efficacy of radiation therapy in the treatment of low-grade gliomas, it is not without short- and long-term adverse effects. Radiation is known to have multiple adverse effects, including initial short-term effects of fatigue and long-term effects of cognitive decline and memory deficits as well as vascular damage, endocrine deficits, and secondary malignancies.31
A large phase III trial (RTOG 9802) that was initiated in 1998 randomly assigned patients with high-risk low-grade glioma (patients older than 40 years or with subtotal resection) to radiation alone or radiation plus chemotherapy consisting of procarbazine, the nitrosourea CCNU (lomustine), and vincristine (PCV). The original publication of the study demonstrated an improvement in progression-free survival in patients treated with both radiation and chemotherapy, with no significant improvement in overall survival at 5 years of follow-up.9 Results with longer follow-up, with a median of 11.9 years, now demonstrate a significant benefit in overall survival in patients treated with both radiation and chemotherapy compared with radiation alone. They reported an overall survival of 7.8 years in patients treated with radiation alone, compared with 13.3 years in patients treated with both radiation and chemotherapy.6 Progression-free survival at 10 years was 21% in the patients who received radiation alone, compared with 51% in the patients who received both radiation and chemotherapy. The benefit of radiation and chemotherapy was seen in all histologic subgroups evaluated but did not reach significance in patients with astrocytoma. Further studies are underway investigating the molecular subtypes of tumors that derive the greatest benefit from chemotherapy and radiation at initial diagnosis; however, results thus far suggest responses irrespective of 1p/19q status.6,13,32 The limitation of these retrospective post hoc analyses on the basis of the molecular and cytogenetic analysis is the lack of tissue availability for the majority of the patients who were enrolled in the study. On the basis of the results of this study, we recommend that patients with high-risk low-grade gliomas characterized by older age or subtotal resection strongly consider a combination of radiation and chemotherapy at initial diagnosis. In high-risk patients with a more prognostically favorable oligodendroglioma diagnosis, if there is concern for long-term effects of radiation, one could consider treatment with chemotherapy alone at initial diagnosis (Fig 3).
The choice of chemotherapy is also under active investigation. PCV was originally used in early trials for low-grade glioma on the basis of efficacy in higher-grade tumors.7 It has been largely replaced by temozolomide in later trials because of an improved adverse effect/toxicity profile and the expectation that both alkylating therapies would have similar efficacies, but a direct comparison of the two agents has yet to be completed.11 Although the data have yet to mature, an ongoing large single-arm phase II study (RTOG 0424) investigated radiation therapy with concomitant and adjuvant temozolomide compared with historical controls and has preliminarily shown improved overall survival.33 The ongoing revised randomized phase III trial CODEL (Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma) is comparing nitrosourea versus temozolomide treatment of WHO grade 2 and 3 gliomas with the 1p/19q codeletion. The two treatment arms are radiation followed by PCV and radiation with concurrent and adjuvant temozolomide. The coprimary end points are progression-free survival and neurocognition. It is hoped that the results of this study shed light on this important question.
Because of the potential of short- and long-term adverse effects with radiation, initial use of chemotherapy alone has also been investigated for treatment of high-risk low-grade gliomas. There have been several small phase II trials that suggest that treatment with temozolomide chemotherapy has similar response rates to that of radiation, with tumor stabilization for between 3 and 5 years.34-37 An ongoing large phase III trial (EORTC 22033-26033) is investigating standard radiation therapy compared with 1 year of temozolomide in patients with high-risk low-grade gliomas. High risk in this particular study is defined as patients older than age 40 years, symptomatic, or with tumors growing under observation. Preliminary data from this study after a median follow-up of 45.5 months suggest there is no significant difference in progression-free survival between the two groups (47 months in the radiation therapy arm and 40 months in the temozolomide arm). Progression-free survival, however, is longer in the radiation treatment group compared with treatment with temozolomide for the subgroup of patients with IDH mutations but without codeletion of 1p/19q, consistent with patients with astrocytomas.38,39 It is important to note that radiation therapy alone cannot be considered the current standard-of-care treatment of high-risk low-grade gliomas on the basis of the recent publication of the results of RTOG 9802.
There is no known curative therapy for low-grade gliomas. When low-grade gliomas recur, they may either be the original tumor/grade or they may also undergo malignant transformation into high-grade tumors. Oligodendrogliomas can malignantly transform into anaplastic oligodendrogliomas, and astrocytomas can transform into anaplastic astrocytomas or glioblastomas. Treatment options at the time of recurrence can include further surgery, radiation therapy and/or chemotherapy, or clinical trials. If surgical resection can safely be performed, it is again recommended. If a patient did not receive radiation at initial diagnosis or has had significant time pass before recurrence, radiation therapy may also be an option. Treatment with chemotherapy is also usually a possibility. Choices can include the original chemotherapy, if safe from a toxicity perspective, versus an alternative chemotherapeutic agent. At this time, there are few data to direct treatment decisions at recurrence, but reports do suggest that there may be at least some benefit for treatment with chemotherapy with either temozolomide or PCV.40 Treatments after failure of alkylator-based chemotherapy vary widely, and there is no consensus opinion on the basis of current National Comprehensive Cancer Network and European Association of Neuro-Oncology guidelines.41,42
Because there is no cure for low-grade gliomas, there is active research into the development of novel therapeutics. One focus is the development of effective targeted therapies. Contrary to traditional chemotherapies that are cytotoxic to all rapidly dividing cells, novel targeted therapies are being investigated to target molecules or pathways that are aberrant specifically in the cancer cells. One example is the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway, which regulates cellular proliferation and is frequently activated in low-grade gliomas, making an inhibitor of mammalian target of rapamycin, everolimus, an attractive candidate for treatment of low-grade gliomas.43 Everolimus is currently used in clinical trials for the treatment of high-risk low-grade gliomas, both at initial diagnosis as well as recurrence (NCT00823459, NCT02023905). There is also investigation of targeting angiogenic pathways, such as vascular endothelial growth factor inhibition, using bevacizumab in combination with traditional chemotherapy for recurrent low-grade gliomas (NCT01164189). Another potential strategy under active investigation is targeting the frequently mutated IDH complex on the basis of some promising preclinical data (NCT02073994).44 One downfall of targeted therapies is that inhibition of one specific molecular pathway often can result in compensatory up-regulation of related pathways. Therefore, another area of active investigation includes rational combinations of specific inhibitors or combination therapy with standard treatments.
A hallmark of cancer cells is the avoidance of detection by the immune system. Therefore, immunotherapy is another focus of current research, and there are several different strategies being pursued.45 One of these is vaccine therapy, which is an attractive therapy specifically in low-grade tumors because of their slower growth rate, allowing for multiple immunizations and presumably higher levels of antiglioma immunity. Several vaccine trials are either underway or in development, including those using GBM6-AD-poly-ICLC vaccines and vaccines created from autologous dendritic cells pulsed with autologous tumor lysate (NCT02549833, NCT01635283). In addition, inhibitors of specific immune checkpoints are also being evaluated to harness the body’s own immune system to target cancer cells. However, the majority of the clinical trials with these therapies have been in high-grade tumors. With further research we will have an improved understanding of the molecular characterization of gliomas, and more rational selection of appropriate treatments can be done for patients with specific tumor profiles.
The prognosis of patients with low-grade glioma is affected by multiple variables and can vary greatly, from 2 years to decades. Because of this, quality of life and neurocognition are becoming increasingly important factors in treatment decision making. The ongoing RTOG 0925 trial is currently evaluating neurocognitive function, quality of life, and seizure control in patients with low-risk low-grade gliomas after surgery. There have been several studies demonstrating that there are significantly higher levels of cognitive impairment in patients who receive radiation compared with those who do not undergo this treatment modality.31,46 Therefore, treatment strategies that delay the use of radiation to preserve cognitive function are appealing. As more treatment options for low-grade gliomas become available, quality-of-life measures and outcomes will play key roles in management recommendations.
In conclusion, the standard of care for low-grade gliomas includes maximal safe resection, followed by either MRI surveillance in low-risk patients or chemotherapy and radiation in high-risk patients. The field, however, is evolving in the definition of these tumors, risk stratification, and the treatment recommendations. Future therapies will be focused not only on improving survival but also on quality of life. As improved molecular profiling of these tumors becomes available, more targeted and personalized treatments will be used, and treatment paradigms will likely be shifted.
Conception and design: All authors
Collection and assembly of data: Nancy Ann Oberheim Bush
Data analysis and interpretation: Nancy Ann Oberheim Bush
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.
No relationship to disclose
Consulting or Advisory Role: NeOnc Technologies, Edge Therapeutics, Blaze Bioscience, Agios, Tocagen
Research Funding: Quest Diagnostics (Inst), Roche (Inst), Agios (Inst), Schering-Plough, Novartis
|1.||Louis DN, Perry A, Reifenberger G, et al: The 2016 World Health Organization Classification of tumors of the central nervous system: A summary. Acta Neuropathol 131:803-820, 2016 Crossref, Medline, Google Scholar|
|2.||Tandon A, Schiff D: Therapeutic decision making in patients with newly diagnosed low grade glioma. Curr Treat Options Oncol 15:529-538, 2014 Crossref, Medline, Google Scholar|
|3.||Rees J: Temozolomide in low-grade gliomas: Living longer and better. J Neurol Neurosurg Psychiatry 86:359-360, 2015 Crossref, Medline, Google Scholar|
|4.||Ostrom QT, Gittleman H, Fulop J, et al: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 17:iv1-iv62, 2015 (suppl 4) Crossref, Medline, Google Scholar|
|5.||Schiff D: Low-grade gliomas. Continuum (Minneap Minn) 21:345-354, 2015 Medline, Google Scholar|
|6.||Buckner JC, Shaw EG, Pugh SL, et al: Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344-1355, 2016 Crossref, Medline, Google Scholar|
|7.||Cairncross JG, Macdonald DR: Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23:360-364, 1988 Crossref, Medline, Google Scholar|
|8.||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 36:549-556, 1996 Crossref, Medline, Google Scholar|
|9.||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 30:3065-3070, 2012 Link, Google Scholar|
|10.||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 20:2267-2276, 2002 Link, Google Scholar|
|11.||Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 Crossref, Medline, Google Scholar|
|12.||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 22845 randomised trial. Lancet 366:985-990, 2005 Crossref, Medline, Google Scholar|
|13.||Buckner JC, Gesme D Jr, O’Fallon JR, et al: Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: Efficacy and associations with chromosomal abnormalities. J Clin Oncol 21:251-255, 2003 Link, Google Scholar|
|14.||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 90:1473-1479, 1998 Crossref, Medline, Google Scholar|
|15.||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 66:9852-9861, 2006 Crossref, Medline, Google Scholar|
|16.||Griffin CA, Burger P, Morsberger L, et al: Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 65:988-994, 2006 Crossref, Medline, Google Scholar|
|17.||Houillier C, Wang X, Kaloshi G, et al: IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75:1560-1566, 2010 Crossref, Medline, Google Scholar|
|18.||Killela PJ, Reitman ZJ, Jiao Y, et al: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110:6021-6026, 2013 Crossref, Medline, Google Scholar|
|19.||Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al: Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015 Crossref, Medline, Google Scholar|
|20.||Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499-2508, 2015 Crossref, Medline, Google Scholar|
|21.||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 31:337-343, 2013 Link, Google Scholar|
|22.||Jakola AS, Myrmel KS, Kloster R, et al: Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 308:1881-1888, 2012 Crossref, Medline, Google Scholar|
|23.||Pallud J, Fontaine D, Duffau H, et al: Natural history of incidental World Health Organization grade II gliomas. Ann Neurol 68:727-733, 2010 Crossref, Medline, Google Scholar|
|24.||Potts MB, Smith JS, Molinaro AM, et al: Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg 116:365-372, 2012 Crossref, Medline, Google Scholar|
|25.||Muragaki Y, Chernov M, Maruyama T, et al: Low-grade glioma on stereotactic biopsy: How often is the diagnosis accurate? Minim Invasive Neurosurg 51:275-279, 2008 Crossref, Medline, Google Scholar|
|26.||Jackson RJ, Fuller GN, Abi-Said D, et al: Limitations of stereotactic biopsy in the initial management of gliomas. Neuro-oncol 3:193-200, 2001 Medline, Google Scholar|
|27.||Kiliç T, Ozduman K, Elmaci I, et al: Effect of surgery on tumor progression and malignant degeneration in hemispheric diffuse low-grade astrocytomas. J Clin Neurosci 9:549-552, 2002 Crossref, Medline, Google Scholar|
|28.||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 26:1338-1345, 2008 Link, Google Scholar|
|29.||McGirt MJ, Chaichana KL, Gathinji M, et al: Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 110:156-162, 2009 Crossref, Medline, Google Scholar|
|30.||Shaw EG, Berkey B, Coons SW, et al: Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: Results of a prospective clinical trial. J Neurosurg 109:835-841, 2008 Crossref, Medline, Google Scholar|
|31.||Douw L, Klein M, Fagel SS, et al: Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: Long-term follow-up. Lancet Neurol 8:810-818, 2009 Crossref, Medline, Google Scholar|
|32.||Stege EMB, Kros JM, de Bruin HG, et al: Successful treatment of low-grade oligodendroglial tumors with a chemotherapy regimen of procarbazine, lomustine, and vincristine. Cancer 103:802-809, 2005 Crossref, Medline, Google Scholar|
|33.||Fisher BJ, Hu C, Macdonald DR, et al: Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: Preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys 91:497-504, 2015 Crossref, Medline, Google Scholar|
|34.||Levin N, Lavon I, Zelikovitsh B, et al: Progressive low-grade oligodendrogliomas: Response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression. Cancer 106:1759-1765, 2006 Crossref, Medline, Google Scholar|
|35.||Pouratian N, Gasco J, Sherman JH, et al: Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. J Neurooncol 82:281-288, 2007 Crossref, Medline, Google Scholar|
|36.||Brada M, Viviers L, Abson C, et al: Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol 14:1715-1721, 2003 Crossref, Medline, Google Scholar|
|37.||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 22:3133-3138, 2004 Link, Google Scholar|
|38.||Baumert BG, Hegi ME, Mason WP, et al: Radiotherapy in relation to temozolomide: Subgroup analysis of molecular markers of the randomized phase III study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) in patients with a high risk low-grade glioma. J Clin Oncol 33:(suppl; abstr 2006)2015 Google Scholar|
|39.||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 31:(suppl; abstr 2007)2013 Google Scholar|
|40.||Nahed BV, Redjal N, Brat DJ, et al: Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. J Neurooncol 125:609-630, 2015 Crossref, Medline, Google Scholar|
|41.||Nabors LB, Portnow J, Ammirati M, et al: Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 12:1517-1523, 2014 Crossref, Medline, Google Scholar|
|42.||Soffietti R, Baumert BG, Bello L, et al: Guidelines on management of low-grade gliomas: Report of an EFNS-EANO Task Force. Eur J Neurol 17:1124-1133, 2010 Crossref, Medline, Google Scholar|
|43.||McCubrey JA, Steelman LS, Chappell WH, et al: Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget 3:954-987, 2012 Crossref, Medline, Google Scholar|
|44.||Rohle D, Popovici-Muller J, Palaskas N, et al: An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626-630, 2013 Crossref, Medline, Google Scholar|
|45.||Hanahan D, Weinberg RA: Hallmarks of cancer: The next generation. Cell 144:646-674, 2011 Crossref, Medline, Google Scholar|
|46.||Surma-aho O, Niemelä M, Vilkki J, et al: Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 56:1285-1290, 2001 Crossref, Medline, Google Scholar|