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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/27696; and 4) view/print certificate.
Release date: September 19, 2013; Expiration date: September 19, 2014
Learning Objectives
Upon completion of this activity, participants will be able to:
Evaluate the potential explanations for abbreviated survival in elderly patients diagnosed with glioblastoma
Describe the roles that surgery, radiotherapy, and temozolomide have in the treatment of elderly patients with glioblastoma
Glioblastoma is the most common primary glial brain cancer and despite recent advances remains an incurable disease. The first study in glioblastoma that clearly showed benefit (defined as an improvement in median overall survival [mOS]) from addition of chemotherapy to radiotherapy was the landmark EORTC/National Cancer Institute of Canada (NCIC) trial.1 A total of 573 patients between the ages of 18 and 70 years with glioblastoma and good performance status (ECOG performance status 0-2) were randomized to receive postsurgical radiotherapy or radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. The study showed an improvement in mOS from 12.1 to 14.6 months in the combination versus the radiotherapy monotherapy arm. The 5-year follow-up report showed that in the combination therapy arm, survival was also improved at the 2-, 3-, 4-, and 5-year marks in all subgroups reported.2 This study is currently the only prospective randomized controlled study showing an mOS benefit from the addition of adjuvant chemotherapy in patients with glioblastoma. A significant limitation of this study is that only patients aged 70 years or younger and with good performance status were eligible to participate. However, the median age of patients with newly diagnosed glioblastoma is 60 to 62 years, approximately 45% of patients are older than 65 years (herein defined as elderly patients), and a clear trend toward an increasing incidence of elderly patients with glioblastoma is being seen in developed countries.3 Because patients older than 70 years were not included in this landmark trial, the question of the applicability of this regimen to these patients has remained controversial.
Age has been identified as the most important prognostic factor for survival in glioblastoma. Survival declines after age 50 years, with a further, almost linear decline thereafter.4-6 Population-based studies of patients with newly diagnosed glioblastoma show a mOS of 6 months in elderly patients, which is significantly lower than in younger patients.7-9 Currently, limited prospective data apply to this growing and heterogeneous patient population with respect to treatment (Table 1).
The clinical course of all patients with glioblastoma is commonly associated with progressive decline of neurologic function, including worsening cognitive abilities, loss of motor skills, and decreased ability to perform activities of daily living. In addition, standard treatment for glioblastoma is associated with adverse effects, including postoperative complications (eg, a high rate of thromboembolic events and ischemic injury from surgery, leading to new or amplified neurologic deficits) and side effects from radiotherapy (eg, fatigue, cognitive slowing or impairment, alopecia, lymphopenia), chemotherapy (eg, myelosuppression, immunosuppression, nausea, constipation), and steroid treatment (myopathy, hyperglycemia, weight gain, emotional changes).10 All of these elements of treatment may be of particular concern in elderly patients with glioblastoma, and because performance status and medical fitness in the elderly are largely heterogeneous, treatment options for many elderly patients must be carefully considered.
Possible Reasons for Poor Outcome in Elderly Patients
Possible explanations for the comparatively worse outcome in the large and heterogeneous group of elderly patients with glioblastoma include intrinsic and extrinsic (iatrogenic) factors that lead to the following questions:
Is the biology of glioblastoma different in older versus younger patients?
Do elderly patients receive suboptimal therapy, and are effective treatments withheld?
Do older patients uniformly tolerate less toxicity, and can this contribute to earlier death?
Are the standard therapies of surgery, radiotherapy, and temozolomide-based chemotherapy less effective in older patients?
Biologic and Prognostic Factors of Glioblastoma in Elderly Patients
Two main prognostic biomarkers are known in glioblastoma: methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase 1 (IDH1) mutation status. MGMT promoter methylation has been validated as a major prognostic factor for patients with glioblastoma based on analysis of specimens collected in the landmark EORTC/NCIC trial.11 Approximately 30% to 40% of all newly diagnosed glioblastomas manifest the favorable MGMT promoter methylation. More recent studies showed that MGMT promoter methylation status is not age-dependent, but rather is also a positive prognostic marker for OS in the elderly.12-17 In addition, data from a recently published prospective study in elderly glioblastoma (the German NOA-08 and Nordic trials) showed that MGMT promoter methylation also seems to predict response to temozolomide in elderly patients.18,19
Randomized Controlled Trials Designed for Elderly Patients With Newly Diagnosed Glioblastoma
For several decades it was known that so-called secondary glioblastomas that arise from lower-grade gliomas are associated with improved survival and younger age compared with so-called primary glioblastomas. Several studies document that mutations of IDH1 are associated with and genetically define secondary glioblastoma that is associated with a better OS irrespective of treatment. The incidence of secondary glioblastoma, however, decreases with age and, in contrast to MGMT promoter methylation, IDH1 mutations are age-dependent and only rarely manifest as glioblastoma in elderly patients (<2%).20-22
In addition, other genetic alternations have been shown to possibly have prognostic implications in elderly patients with glioblastoma, including TP53 mutations (worse prognosis) and epidermal growth factor receptor (EGFR) amplification (possible worse prognosis). Similar to MGMT promoter methylation and IDH1 mutations, these markers currently do not influence the choice of treatment or clinical decision-making and, unlike MGMT, have not yet been validated prospectively.23,24
Current Patterns of Care in Treatment of Elderly Patients With Glioblastoma
Several population-based studies report that elderly patients with glioblastoma receive less therapy than younger patients.8,25,26 However, most published data on patterns of care in the elderly with glioblastoma were derived before temozolomide became available and before the EORTC/NCIC study was published.
A SEER database analysis of 4137 patients older than 65 years who were treated between 1994 and 2002 showed that advancing age was associated with decreased use of resection, radiotherapy, and chemotherapy, and with a diminished survival (mOS, 4 months).8 A second SEER database analysis on 2836 patients older than 70 years showed that 86% of patients received some form of treatment, but that only 46% of patients underwent both surgery and radiotherapy.26 In addition, another study reported that the rate of treatment with supportive care only increased with age.9 Reasons posited for diminished care in the elderly were the concern for increased toxicity from treatment with increasing age, patient preference, and perceived therapeutic nihilism on the part of the treating physician.
Limited retrospective data have been published on the rate of treatment-related toxicity in elderly patients with glioblastoma who were treated with surgery followed by temozolomide-based chemoradiation and adjuvant temozolomide (EORTC/NCIC regimen).13,17,27-29 In general, these small retrospective studies suggest increased temozolomide-associated myelotoxicity when compared with a younger cohort of patients with glioblastoma treated in a similar manner.
Extent of Surgery
The survival benefit of surgery in the elderly has never been prospectively determined in a large randomized trial. Consequently, data are based on retrospective studies and a single small prospective study.30-33 A statistically significant difference in survival was observed in several retrospective studies comparing biopsy versus resective surgery in the elderly. A series of 128 patients older than 65 years who underwent either a surgical resection or biopsy showed better survival in those who underwent resection (27 vs 15 weeks).31 A study of patients aged 65 years or older compared 2 cohorts of 40 patients who underwent either surgical resection or biopsy only.32 The median age was 73 years and survival was 5.7 and 4.0 months in the resection and biopsy cohorts, respectively. Another study showed a 60% reduction in the risk of death after a gross total versus partial resection in 394 patients with a median age of 72 years.33
In summary, these data support the use of surgery in selected, healthier elderly patients. These data must be interpreted with caution, because patients who are selected for surgery commonly manifest better performance status, have fewer comorbidities, and likely have surgically accessible disease.
Adjuvant Radiation
The question whether elderly patients with glioblastoma benefit from adjuvant radiotherapy has been determined in a randomized study of 85 patients aged 70 years and older and a Karnofsky performance score of 70 or greater who either received postoperative radiation (50.4 Gy in 28 fractions) or supportive care alone34 (Table 1). The difference in mOS was 6.7 months with radiotherapy versus 3.9 months without. Furthermore, the extent of resection predicted for survival in this study and the effects of resection and radiotherapy seemed to be independent. Importantly, this study showed no significant differences in health-related quality of life. Similarly, a multivariate population-based analysis of 2836 patients older than 70 years from the SEER database showed that OS and cancer-specific survival were significantly improved with radiotherapy.26
Short-course radiation schedules with larger doses of radiotherapy per fraction (so-called hypo-fractionated radiotherapy) have been explored in patients with advanced age and Karnofsky performance score less than 70 (Table 1). Short-course radiotherapy is based on the supposition that 3-weeks of radiotherapy impacts quality of life less than the standard 6-week radiotherapy regimen and is also biologically equivalent. A prospective randomized Canadian study of 100 patients aged 60 or older compared standard radiotherapy (60 Gy in 30 fractions) with the hypofractionated regimen of 40 Gy in 15 fractions.35 mOS was 5.1 months in patients who received standard radiotherapy and 5.6 months in those who received hypofractionated radiotherapy. The authors concluded that hypofractionated radiotherapy is equivalent to standard radiotherapy, and based on this study hypofractionated radiotherapy has been promulgated as a treatment option for patients with advanced age and limited performance status.
Adjuvant Chemoradiation With Temozolomide
Post hoc analysis of the 5-year follow-up data of the EORTC/NCIC study showed a trend toward survival benefit from concurrent and adjuvant temozolomide in all subgroups studied.1,2 This study excluded patients older than 70 years with a compromised performance status. The subgroup analysis of the 170 patients aged 60 to 70 years (87 received radiotherapy alone; 83 received radiotherapy plus temozolomide) showed noticeably improved survival rates in the combination arm at the 2-, 3-, 4-, and 5-year marks. Further subgroup analysis of this trial, however, showed a decreasing relative benefit from the addition of temozolomide to radiation with increasing age, particularly in patients older than 60 years: a hazard ratio of 0.64 in patients aged 61 to 65 years (n=114; P=.096) and 0.87 in those aged 66 to 70 years (n=83; P=.340).36 These conclusions must be interpreted cautiously, because this was a subgroup analysis without prespecified statistics. Further phase III data may become available from the RTOG 0525 study that compared 2 dose schedules of postradiotherapy temozolomide.17 However, how many patients in RTOG 0525 were older than 70 years is unknown, and furthermore the trial did not include a radiotherapy-only comparator arm. A recent retrospective study assessed postsurgery treatment of 105 consecutive patients (only 84 evaluable) aged 65 years or older (median age, 74 years; range, 66-87 years) with newly diagnosed glioblastoma.28 In this study, 41 patients were treated with temozolomide chemoradiation, 23 with radiotherapy only, and 1 with chemotherapy alone, and 19 patients received supportive care only. Improved OS was seen in a univariate analysis, but this was not statistically significant in a multivariate analysis. A retrospective study in patients with glioblastoma aged 65 years or older (median age, 71.9 years) compared 103 patients who received adjuvant chemotherapy with 48 patients who received radiotherapy alone.33 The study showed a 55% decrease in risk of death after adjusting for age, Karnofsky performance status, number of lesions, and extent of surgical resection. A limitation of the study was that most patients were treated before temozolomide became available, and that the criteria for determining treatment allocation were not prespecified. A more recent retrospective analysis showed that in patients with favorable prognosis (single resected tumor and RTOG recursive partitioning analysis, class V), both median and 2-year survival rates were significantly improved with the combination of radiotherapy and temozolomide versus radiotherapy alone in patients aged 60 to 70 years and 71 years and older.29 Several other small retrospective studies in elderly patients with newly diagnosed glioblastoma27,37,38 suggest an added survival benefit from the addition of temozolomide to radiotherapy. The studies were, however, limited by their retrospective nature, size, and selection bias with respect to treatment.
The currently open trial NCIC/EORTC 22061-26062 is randomizing elderly patients with glioblastoma to either hypofractionated radiotherapy (40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide or hypofractionated radiotherapy alone (ClinicalTrials.gov identifier: NCT00482677). The study will provide clarity regarding the role of hypofractionated radiotherapy/temozolomide versus single-modality radiotherapy, but it presupposes no added benefit to the use of 60 Gy radiotherapy in 30 fractions based on the earlier Canadian trial.35
The results of AVAglio and RTOG 0825, 2 studies examining the addition of bevacizumab to radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, were recently presented.39,40 Neither study showed an OS advantage with the addition of bevacizumab, and both concluded that the addition of bevacizumab had no benefit aside from a modest improvement in progression-free survival. These studies and the ANOCEF trial mentioned later indicate that up-front bevacizumab currently has no role in the treatment of newly diagnosed glioblastoma regardless of age or performance status.39-41
Single-Modality Adjuvant Therapy
Two recently published European randomized controlled trials compared single-modality treatments in the up-front treatment of elderly patients with glioblastoma.18,39 This work was partly based on the previous trials that showed increased treatment-related toxicity (discussed earlier), data from the EORTC/NCIC subgroup analysis suggesting limited benefit from combined radiotherapy plus temozolomide in elderly patients, and the universal recognition of shorter mOS in elderly patients with glioblastoma.
The Nordic trial prospectively randomized 342 patients older than 60 years with a good performance status (ECOG 0-2) to 3 different single-modality treatment arms: 1) standard radiation (60 Gy in 30 fractions), 2) hypofractionated radiation (34 Gy in 10 fractions), or 3) single-agent, standard-dose temozolomide (150-200 mg/m2/d for 5 days every 28 days; Table 1).42 The authors concluded that the results were equivalent between the temozolomide and hypofractionated radiotherapy study arms, and that the standard radiotherapy arm was inferior to both. Crossover to alternative therapy (radiotherapy to temozolomide and vice versa) was seen in approximately 35% of all patients. In addition, in a subgroup analysis, patients with MGMT promoter methylation fared better with temozolomide versus hypofractionated radiotherapy, whereas among patients with unmethylated MGMT promoter, hypofractionated radiotherapy was superior to temozolomide.
The German study NOA-08 randomized 373 patients older than 65 years with newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance status of 60 or greater to either radiotherapy alone (60 Gy in 30 fractions) or single-agent temozolomide (dose-dense schedule; Table 1).18 The authors concluded that temozolomide was noninferior to radiotherapy alone in this patient group. As in the Nordic trial, this study showed the equivalence (noninferiority) of single-modality treatment with either radiotherapy or temozolomide. Furthermore, the study confirmed the role of MGMT promoter methylation in elderly patients with glioblastoma as a predictive tool in clinical decision-making, wherein elderly patients with methylated tumors had superior OS when treated with temozolomide.
Two studies by the French ANOCEF study group in elderly patients with newly diagnosed glioblastoma (meeting the criteria of age ≥70 years, biopsy only, and Karnofsky performance status <70) compared temozolomide only versus best supportive care and, recently, temozolomide plus bevacizumab.41 These studies concluded that temozolomide only was superior to best supportive care and that the addition of bevacizumab to temozolomide added no benefit to temozolomide only. The authors conclude that temozolomide only is a practical treatment choice in elderly patients with glioblastoma.
Opinion Statements/Conclusions
Matthias Holdhoff
Currently available data on the treatment of elderly patients with glioblastoma are limited because of the lack of a prospective randomized trial comparing standard combination therapy as defined by the landmark EORTC/NCIC trial1 with single-modality treatment (radiotherapy or temozolomide). Overall, evidence suggests a benefit from resection followed by adjuvant radiotherapy or temozolomide in elderly patients. Retrospective data and subgroup analysis of the EORTC/NCIC data also suggest an added benefit from adjuvant chemoradiation with temozolomide. Until further prospective randomized data become available, it appears reasonable to offer elderly patients with glioblastoma standard therapy with radiotherapy and concomitant and adjuvant temozolomide (EORTC/NCIC regimen) if they are believed to be clinically fit to tolerate combination therapy. Age alone is not a sufficient criterion on which to base therapy selection for any individual patient with glioblastoma. In addition, conventional performance status assessment (Karnofsky performance status or ECOG) does not reliably apply to all patients with brain cancers, because the score can be influenced by focal neurologic deficits caused by tumor location, which may not reflect whether a patient would tolerate a certain therapy. Clinical judgment is still required to carefully determine each individual patient’s clinical fitness. MGMT promoter methylation status is a prospectively validated prognostic and predictive marker in elderly patients with glioblastoma; it may be a useful adjunct in clinical decision-making in elderly patients who are frail, and serve as a tie-breaker in patients for whom the risk versus benefit from addition of temozolomide is uncertain.
Suggested nonprotocol approach in the treatment of elderly patients with newly diagnosed glioblastoma.
Abbreviations: MGMT, methylguanine methyltransferase; RT, radiotherapy; TMZ, temozolomide; TMZ5/23, temozolomide given at 150-200 mg/m9/d on days 1-5 on an every-28-day cycle.
aFactors to consider include age, performance status, organ function, comorbidities, and patient preference.
bNot evidence-based.
cEvidence-based.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 9; 10.6004/jnccn.2013.0134
Marc Chamberlain
A practical issue is whether an unspecified end point that is tumor response based on MGMT methylation status, as determined in the NOA-08 and Nordic trials of elderly patients with glioblastoma, changes clinical practice or even clinical trial design. This is particularly relevant because the EORTC/NCIC is conducting another randomized trial in elderly patients with glioblastoma comparing hypofractionated radiotherapy (40 Gy in 15 fractions) with or without standard-dose temozolomide. If radiotherapy alone is inferior therapy in elderly patients with methylated MGMT tumors, the question of whether this treatment might then compromise survival is difficult to answer, because the response based on MGMT methylation was never powered sufficiently to determine the answer unequivocally. Nonetheless, compelling evidence seems to show that temozolomide adds benefit only to the MGMT methylated cohort of elderly patients with newly diagnosed glioblastoma, suggesting that treatment practice should change to include MGMT methylation determination when considering either hypofractionated radiotherapy or temozolomide alone for elderly patients with glioblastoma outside of a clinical trial. In elderly patients with unmethylated MGMT, both the Nordic and German NOA-08 trials would recommend hypofractionated radiotherapy without temozolomide as the preferred treatment. The ANOCEF trials conclude that temozolomide alone is an appropriate therapy in elderly patients who underwent biopsy only, have impaired performance, and with newly diagnosed glioblastoma. Currently, no prospective evidence shows that the EORTC/NCIC treatment regimen improves survival in elderly patients with glioblastoma, notwithstanding continued controversy as to generalizability of this trial to elderly and performance-impaired patients with newly diagnosed glioblastoma. The algorithm in Figure 1 reflects the ongoing debate regarding how best to treat elderly patients with glioblastoma. Determining a standard of care for elderly patients with newly diagnosed glioblastoma would constitute a significant achievement, and based on the ANOCEF, NOA-08, and Nordic trials, that realization seems to be closer.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network
Ms. Green has disclosed that she has no relevant financial relationships.
CE AUTHORS
Deborah J. Moonan, RN, BSN, Manager, CE Supporter Outreach
Ms. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations
Ms. Gregory has disclosed that she has no relevant financial relationships.
References
- 1.↑
Stupp R, Mason WP, van den Bent MJ et al.. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996.
- 2.↑
Stupp R, Hegi ME, Mason WP et al.. 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;10:459–466.
- 3.↑
Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 2012;14(Suppl 5):v1–49.
- 4.↑
Curran WJ Jr, Scott CB, Horton J et al.. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704–710.
- 5.
Wrensch M, Minn Y, Chew T et al.. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 2002;4:278–299.
- 6.↑
Ohgaki H, Dessen P, Jourde B et al.. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64:6892–6899.
- 7.↑
Paszat L, Laperriere N, Groome P et al.. A population-based study of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2001;51:100–107.
- 8.↑
Iwamoto FM, Reiner AS, Panageas KS et al.. Patterns of care in elderly glioblastoma patients. Ann Neurol 2008;64:628–634.
- 9.↑
Kita D, Ciernik IF, Vaccarella S et al.. Age as a predictive factor in glioblastomas: population-based study. Neuroepidemiology 2009;33:17–22.
- 10.↑
Wen PY, Schiff D, Kesari S et al.. Medical management of patients with brain tumors. J Neurooncol 2006;80:313–332.
- 11.↑
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.
- 12.↑
Piccirilli M, Bistazzoni S, Gagliardi FM et al.. Treatment of glioblastoma multiforme in elderly patients. Clinicotherapeutic remarks in 22 patients older than 80 years. Tumori 2006;92:98–103.
- 13.↑
Sijben AE, McIntyre JB, Roldan GB et al.. Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme. J Neurooncol 2008;89:97–103.
- 14.
Gerstner ER, Yip S, Wang DL et al.. MGMT methylation is a prognostic biomarker in elderly patients with newly diagnosed glioblastoma. Neurology 2009;73:1509–1510.
- 15.
Brandes AA, Franceschi E, Tosoni A et al.. Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 2009;115:3512–3518.
- 16.
Minniti G, Salvati M, Arcella A et al.. Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol 2011;102:311–316.
- 17.↑
Gilbert MR, Wang M, Aldape KD et al.. RTOG 0525: a randomized phase III trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM) [abstract]. J Clin Oncol 2011;29(Suppl):Abstract 2006.
- 18.↑
Wick W, Platten M, Meisner C et al.. temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012;13:707–715.
- 19.↑
Reifenberger G, Hentschel B, Felsberg J et al.. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer 2012;131:1342–1350.
- 20.↑
Parsons DW, Jones S, Zhang X et al.. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807–1812.
- 21.
Yan H, Parsons DW, Jin G et al.. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765–773.
- 22.↑
Hartmann C, Hentschel B, Wick W et al.. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 2010;120:707–718.
- 23.↑
Batchelor TT, Betensky RA, Esposito JM et al.. Age-dependent prognostic effects of genetic alterations in glioblastoma. Clin Cancer Res 2004;10:228–233.
- 24.↑
Holdhoff M, Ye X, Blakeley JO et al.. Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas. J Neurooncol 2012;110:279–285.
- 25.↑
Barnholtz-Sloan JS, Williams VL, Maldonado JL et al.. Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma. J Neurosurg 2008;108:642–648.
- 26.↑
Scott J, Tsai YY, Chinnaiyan P, Yu HH. Effectiveness of radiotherapy for elderly patients with glioblastoma. Int J Radiat Oncol Biol Phys 2011;81:206–210.
- 27.↑
Minniti G, De Sanctis V, Muni R et al.. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 2008;88:97–103.
- 28.↑
Tanaka S, Meyer FB, Buckner JC et al.. Presentation, management, and outcome of newly diagnosed glioblastoma in elderly patients. J Neurosurg 2013;118:786–798.
- 29.↑
Barker CA, Chang M, Chou JF et al.. Radiotherapy and concomitant temozolomide may improve survival of elderly patients with glioblastoma. J Neurooncol 2012;109:391–397.
- 30.↑
Vuorinen V, Hinkka S, Farkkila M, Jaaskelainen J. Debulking or biopsy of malignant glioma in elderly people—a randomised study. Acta Neurochir (Wien) 2003;145:5–10.
- 31.↑
Kelly PJ, Hunt C. The limited value of cytoreductive surgery in elderly patients with malignant gliomas. Neurosurgery 1994;34:62–66; discussion 66-67.
- 32.↑
Chaichana KL, Garzon-Muvdi T, Parker S et al.. Supratentorial glioblastoma multiforme: the role of surgical resection versus biopsy among older patients. Ann Surg Oncol 2011;18:239–245.
- 33.↑
Iwamoto FM, Cooper AR, Reiner AS et al.. Glioblastoma in the elderly: the Memorial Sloan-Kettering Cancer Center experience (1997-2007). Cancer 2009;115:3758–3766.
- 34.↑
Keime-Guibert F, Chinot O, Taillandier L et al.. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356:1527–1535.
- 35.↑
Roa W, Brasher PM, Bauman G et al.. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004;22:1583–1588.
- 36.↑
Laperriere N, Weller M, Stupp R et al.. Optimal management of elderly patients with glioblastoma. Cancer Treat Rev 2013;39:350–357.
- 37.↑
Combs SE, Wagner J, Bischof M et al.. Radiochemotherapy in patients with primary glioblastoma comparing two temozolomide dose regimens. Int J Radiat Oncol Biol Phys 2008;71:999–1005.
- 38.↑
Fiorica F, Berretta M, Colosimo C et al.. Glioblastoma in elderly patients: safety and efficacy of adjuvant radiotherapy with concomitant temozolomide. Arch Gerontol Geriatr 2010;51:31–35.
- 39.↑
Chinot O, Wick W, Mason W et al.. Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: mature progression-free survival and preliminary overall survival results in AVAglio [abstract]. Neuro Oncol 2012;14(Suppl 6):Abstract OT-03.
- 40.↑
Gilbert MR, Dignam J, Won M et al.. RTOG 0825: phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM) [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 1.
- 41.↑
Reyes-Botero G, Honnorat J, Chinot OL et al.. Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 2020.
- 42.↑
Malmstrom A, Gronberg BH, Marosi C et al.. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916–926.
