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Figure 1.
Treatment Patterns by Year of Diagnosis for Patients at Least 65 Years Old in the National Cancer Database
Treatment Patterns by Year of Diagnosis for Patients at Least 65 Years Old in the National Cancer Database

CT indicates chemotherapy, and RT, radiation therapy. Corresponding percentages for treatment groups by year are displayed in eTable 1 in the Supplement.

Figure 2.
Overall Survival (OS) by Treatment Group
Overall Survival (OS) by Treatment Group

CT indicates chemotherapy, and RT, radiation therapy.

Figure 3.
Overall Survival (OS) by Treatment Group Stratified by Age
Overall Survival (OS) by Treatment Group Stratified by Age

CT indicates chemotherapy, and RT, radiation therapy.

Table 1.  
Patient Characteristics
Patient Characteristics
Table 2.  
Overall Survival Analysesa
Overall Survival Analysesa
1.
Keime-Guibert  F, Chinot  O, Taillandier  L,  et al; Association of French-Speaking Neuro-Oncologists.  Radiotherapy for glioblastoma in the elderly.  N Engl J Med. 2007;356(15):1527-1535.PubMedGoogle ScholarCrossref
2.
Malmström  A, Grønberg  BH, Marosi  C,  et al; Nordic Clinical Brain Tumour Study Group (NCBTSG).  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(9):916-926.PubMedGoogle ScholarCrossref
3.
Wick  W, Platten  M, Meisner  C,  et al; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society.  Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial.  Lancet Oncol. 2012;13(7):707-715.PubMedGoogle ScholarCrossref
4.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in oncology: central nervous system cancers. http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed November 13, 2015.
5.
Stupp  R, Brada  M, van den Bent  MJ, Tonn  JC, Pentheroudakis  G; ESMO Guidelines Working Group.  High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.  Ann Oncol. 2014;25(suppl 3):iii93-iii101.PubMedGoogle ScholarCrossref
6.
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(10):987-996.PubMedGoogle ScholarCrossref
7.
Bilimoria  KY, Stewart  AK, Winchester  DP, Ko  CY.  The National Cancer Data Base: a powerful initiative to improve cancer care in the United States.  Ann Surg Oncol. 2008;15(3):683-690.PubMedGoogle ScholarCrossref
8.
Scoccianti  S, Magrini  SM, Ricardi  U,  et al.  Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (italian Association of Radiation Oncology).  Neurosurgery. 2010;67(2):446-458.PubMedGoogle ScholarCrossref
9.
Yabroff  KR, Harlan  L, Zeruto  C, Abrams  J, Mann  B.  Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006.  Neuro Oncol. 2012;14(3):351-359.PubMedGoogle ScholarCrossref
10.
Kleinbaum  DG, Klein  M.  Evaluating the Proportional Hazards Assumption: Survival Analysis. New York, NY: Springer; 2012.
11.
Bland  JM, Altman  DG.  Multiple significance tests: the Bonferroni method.  BMJ. 1995;310(6973):170.PubMedGoogle ScholarCrossref
12.
Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161.PubMedGoogle ScholarCrossref
13.
Cochran  WG, Rubin  DB.  Controlling bias in observational studies: a review.  Sankhyā: Indian J Statist, Ser A.1973:417-446.Google Scholar
14.
Zarnett  OJ, Sahgal  A, Gosio  J,  et al.  Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis.  JAMA Neurol. 2015;72(5):589-596.PubMedGoogle ScholarCrossref
15.
Kristiansen  K, Hagen  S, Kollevold  T,  et al.  Combined modality therapy of operated astrocytomas grade III and IV. confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group.  Cancer. 1981;47(4):649-652.PubMedGoogle ScholarCrossref
16.
Walker  MD, Alexander  E  Jr, Hunt  WE,  et al.  Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial.  J Neurosurg. 1978;49(3):333-343.PubMedGoogle ScholarCrossref
17.
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(5):459-466.PubMedGoogle ScholarCrossref
18.
Sahebjam  S, McNamara  M, Mason  WP.  Management of glioblastoma in the elderly.  Clin Adv Hematol Oncol. 2012;10(6):379-386.PubMedGoogle Scholar
19.
Putz  F, Knippen  S, Lahmer  G, Fietkau  R, Semrau  S.  A model to predict the feasibility of concurrent chemoradiotherapy with temozolomide in glioblastoma multiforme patients over age 65 [published online May 20, 2015].  Am J Clin Oncol. doi:10.1097/COC.0000000000000198.PubMedGoogle Scholar
20.
Lawrence  YR, Li  XA, el Naqa  I,  et al.  Radiation dose-volume effects in the brain.  Int J Radiat Oncol Biol Phys. 2010;76(3)(suppl):S20-S27.PubMedGoogle ScholarCrossref
21.
Thon  N, Kreth  S, Kreth  F-W.  Personalized treatment strategies in glioblastoma: MGMT promoter methylation status.  Onco Targets Ther. 2013;6:1363-1372.PubMedGoogle ScholarCrossref
22.
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(9):1583-1588.PubMedGoogle ScholarCrossref
23.
Roa  W, Kepka  L, Kumar  N,  et al.  International Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme.  J Clin Oncol. 2015;33(35):4145-4150.PubMedGoogle ScholarCrossref
24.
Brem  SS, Bierman  PJ, Brem  H,  et al; National Comprehensive Cancer Network.  Central nervous system cancers.  J Natl Compr Canc Netw. 2011;9(4):352-400.PubMedGoogle Scholar
25.
Gállego Pérez-Larraya  J, Ducray  F, Chinot  O,  et al.  Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial.  J Clin Oncol. 2011;29(22):3050-3055.PubMedGoogle ScholarCrossref
26.
Reifenberger  G, Hentschel  B, Felsberg  J,  et al; German Glioma Network.  Predictive impact of MGMT promoter methylation in glioblastoma of the elderly.  Int J Cancer. 2012;131(6):1342-1350.PubMedGoogle ScholarCrossref
27.
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. 2015;17(suppl 4):iv1-iv62.PubMedGoogle ScholarCrossref
28.
Hegi  ME, Diserens  AC, Gorlia  T,  et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma.  N Engl J Med. 2005;352(10):997-1003.PubMedGoogle ScholarCrossref
29.
Scott  CB, Scarantino  C, Urtasun  R,  et al.  Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06.  Int J Radiat Oncol Biol Phys. 1998;40(1):51-55.PubMedGoogle ScholarCrossref
30.
Arvold  ND, Tanguturi  SK, Aizer  AA,  et al.  Hypofractionated versus standard radiation therapy with or without temozolomide for older glioblastoma patients.  Int J Radiat Oncol Biol Phys. 2015;92(2):384-389.PubMedGoogle ScholarCrossref
31.
Minniti  G, Lanzetta  G, Scaringi  C,  et al.  Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma.  Int J Radiat Oncol Biol Phys. 2012;83(1):93-99.PubMedGoogle ScholarCrossref
32.
Tsang  DS, Khan  L, Perry  JR,  et al.  Survival outcomes in elderly patients with glioblastoma.  Clin Oncol (R Coll Radiol). 2015;27(3):176-183.PubMedGoogle ScholarCrossref
33.
Lacroix  M, Abi-Said  D, Fourney  DR,  et al.  A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival.  J Neurosurg. 2001;95(2):190-198.PubMedGoogle ScholarCrossref
Original Investigation
July 2016

Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide EraA National Cancer Database Analysis

Author Affiliations
  • 1Department of Radiation Oncology, University of Colorado School of Medicine, Aurora
  • 2Department of Radiation Oncology, University of Illinois at Chicago School of Medicine, Chicago
  • 3Department of Radiation and Cellular Oncology, University of Chicago School of Medicine, Chicago, Illinois
  • 4Department of Radiation Oncology, University of Texas Southwestern, Dallas
  • 5Division of Neuro-Oncology, Department of Neurology, University of Colorado School of Medicine, Aurora
  • 6Department of Neurosurgery, University of Colorado School of Medicine, Aurora
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Neurol. 2016;73(7):821-828. doi:10.1001/jamaneurol.2016.0839
Abstract

Importance  The optimal management for elderly patients with glioblastoma (GBM) is controversial. Following maximal safe resection or biopsy, accepted treatment paradigms for elderly patients with GBM include combined-modality therapy (CMT) with both radiotherapy (RT) and chemotherapy (CT), RT alone, and CT alone.

Objective  To evaluate the overall survival (OS) outcomes associated with RT, CT, and CMT for elderly patients with GBM in the modern temozolomide era.

Design, Setting, and Participants  In this retrospective cohort study of a prospectively maintained, multi-institutional national cancer registry, the National Cancer Database was queried for elderly patients (≥65 years) with newly diagnosed GBM from January 1, 2005, through December 31, 2011, with complete data sets for RT, CT, tumor resection, Charlson-Deyo comorbidity scores, age, sex, and year of diagnosis. Data analysis was performed from October 2015 through December 2015.

Interventions  Combined-modality therapy, RT, CT.

Main Outcomes and Measures  Survival by treatment cohort was estimated using the Kaplan-Meier method and analyzed using the log rank test, univariate and multivariate Cox models, and propensity score–matched analyses.

Results  A total of 16 717 patients (median [range] age, 73 [65-≥90 y]; 8870 [53%] male) were identified. The median OS by treatment was 9.0 (95% CI, 8.8-9.3) months with CMT (8435 patients), 4.7 (95% CI, 4.5-5.0) months with RT alone (1693 patients), 4.3 (95% CI, 4.0-4.7) months with CT alone (1018 patients), and 2.8 (95% CI, 2.8-2.9) months with no therapy (5571 patients) (P < .001). On multivariate analysis, CMT was superior to both CT alone (hazard ratio, 1.50 [95% CI, 1.40-1.60]; P < .001) and RT alone (hazard ratio, 1.47 [95% CI, 1.39-1.55]; P < .001), whereas no differences were observed between CT alone vs RT alone (P = .60). Propensity score–matched analyses redemonstrated improved OS with CMT over CT alone (P = .002) and RT alone (P < .001); no differences were observed between CT alone vs RT alone (P = .44). On subgroup analyses, a consistent OS advantage was observed with CMT over both CT alone and RT alone across each age stratification (65-69, 70-74, 75-79, and ≥80 years) and among patients treated with or without tumor resection (all P < .001).

Conclusions and Relevance  In this analysis of multimodality therapy for elderly patients with GBM, OS was superior with CMT compared with CT alone and RT alone. Survival was similar between CT alone and RT alone, and both CT alone and RT alone were superior to no therapy. This analysis supports the use of CMT for suitable elderly candidates.

Introduction

For elderly patients (≥65 years) with newly diagnosed glioblastoma (GBM), the optimal integration of radiotherapy (RT) and chemotherapy (CT) represents an ongoing controversy in the field of neuro-oncology. Although level I evidence exists to support an overall survival (OS) advantage of RT over best supportive care (BSC),1 2 randomized trials evaluating elderly populations have demonstrated no advantage of RT alone over CT alone with temozolomide, and subgroup analyses from each of these trials suggest that CT may be the more important single-modality therapy for patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter-methylated tumors.2,3 Nevertheless, elderly patients who present with a favorable performance status are often suitable candidates for combined-modality therapy (CMT) with both RT and CT, which is offered as the standard of care for younger patients.4-6

At present, no randomized data are available for elderly patients with GBM to clarify the effect on OS of CMT vs RT alone or CT alone. In this analysis, using data from the National Cancer Database (NCDB) we evaluated associated OS outcomes for CMT, RT, and CT for elderly patients with GBM in the modern temozolomide era.

Box Section Ref ID

Key Points

  • Question What are the associated survival outcomes for elderly patients (≥65 years) with glioblastoma treated with radiotherapy (RT), chemotherapy (CT), and combined-modality therapy with RT and CT?

  • Findings In this cohort study of more than 16 000 patients, combined-modality therapy was associated with significantly better median survival than RT alone or CT alone, with benefits that remained significant on multivariate analyses, propensity score matching, and in all age and tumor resection subgroups.

  • Meaning This analysis supports the use of combined-modality therapy for elderly patients with newly diagnosed glioblastoma, similar to strategies used in younger patients.

Methods

The NCDB is a hospital-based cancer registry that collects data from American College of Surgeons–Commission on Cancer accredited facilities. The database is sponsored by the American College of Surgeons and the American Cancer Society and includes approximately 70% of all malignant cancers diagnosed in the United States.7 Patient demographic characteristics, comorbidities, tumor characteristics, and overall survival (OS) are recorded, as well as therapies delivered during the first course of treatment and prior to any documented disease progression including surgery, RT, and CT. This analysis was performed with the approval of the University of Colorado School of Medicine institutional review board.

The NCDB was queried for patients 65 years of age or older3 with newly diagnosed GBM, with complete data sets for RT, CT, surgery, Charlson-Deyo comorbidity score, age, sex, and year of diagnosis. Molecular data including MGMT status were not available for analysis. The search was confined to the years 2005 or later in an effort to limit analyses to the temozolomide era for GBM management. The landmark EORTC-NCIC trial, published in 2005, demonstrated improved OS with the addition of temozolomide to RT and established temozolomide as the standard CT agent for adult GBM.6 It is important to note, however, that data regarding specific CT agents administered are not available in the NCDB. Patterns of care analyses suggest that temozolomide-based regimens may have been administered in approximately 97% of patients receiving systemic CT for GBM even during the early years of this study interval.8,9 Cases in which death occurred within 1 month of diagnosis were omitted from analysis. Therapeutic RT was defined as 10 to 35 fractions (Fx) to coincide with the minimum Fx number to show equivalence to the standard regimen of 60 Gy delivered over 30 Fx in a randomized trial specific to elderly patients.2 Radiotherapy to 9 Fx or less was considered palliative and was not used to define treatment cohort status. For analysis, patients were divided into treatment cohorts including CMT with both RT and CT, CT alone, RT alone, and no therapy.

Survival was estimated using the Kaplan-Meier method. Univariate comparisons were performed using the log rank test and unadjusted Cox proportional hazards models. Multivariate comparisons were made using Cox models adjusted for variables selected a priori including comorbidity score, age, sex, race, year of diagnosis, and tumor resection. The proportional hazards assumption was assessed for covariates in all final models and returned no significant results.10(pp161-200) Median follow-up was calculated using the reverse Kaplan-Meier method.

To further account for confounding variables, propensity score–matched analyses were performed to compare the survival outcomes among the 3 treatment cohorts (CMT vs CT alone, CMT vs RT alone, and CT alone vs RT alone). Significance levels for pairwise propensity score–matched comparisons were corrected using the Bonferroni method to reduce the likelihood of a type I error.11 One-to-one matching without replacement was completed using the nearest-neighbor match on the logit of the propensity score for treatment approach (derived from age, sex, race, year, comorbidity, and tumor resection status). The caliper width was 0.05 × the standard deviation of the logit of the propensity score,12 which is estimated to eliminate more than 99% of the bias due to confounding variables.13

Results

Our search returned 16 717 patients at least 65 years old with newly diagnosed GBM from 2005 to 2011. The median (range) age was 73 (65-≥90) years, and 8870 (53%) were male. A total of 8435 (50%) patients received CMT, 1693 (10%) received RT alone, 1018 (6%) received CT alone, and 5571 (33%) received no therapy. Treatment patterns over time are displayed in Figure 1 (corresponding percentages are displayed in eTable 1 in the Supplement). The median and mode number of RT Fx was 30 (range, 10-35 Fx). Patient characteristics are displayed in Table 1. Increases in CMT administration were observed in the setting of tumor resections, younger age, male sex, white race, lower comorbidity scores, and during the latter years of the study interval.

At last follow-up, 15 677 patients (94%) were deceased. The median (range) follow-up was 49.5 (1-105) months. Kaplan-Meier OS estimates are displayed in Figure 2. The median OS estimates were 9.0 (95% CI, 8.8-9.3) months for patients receiving CMT, 4.7 (95% CI, 4.5-5.0) months with RT alone, 4.3 (95% CI, 4.0-4.7) months with CT alone, and 2.8 (95% CI, 2.8-2.9) months with no therapy (P < .001). On univariate survival analysis, when compared with CMT, the hazard of mortality was increased for patients treated with RT alone (HR, 1.73 [95% CI, 1.64-1.82]; P < .001), CT alone (HR, 1.56 [95% CI, 1.46-1.67]; P < .001), and no therapy (HR, 2.59 [95% CI, 2.50-2.68]; P < .001).

On multivariate survival analyses adjusted for tumor resection, comorbidity scores, age, sex, race, and year, CMT remained superior to RT alone (HR, 1.47 [95% CI, 1.39-1.55]; P < .001), CT alone (HR, 1.50 [95% CI, 1.40-1.60]; P < .001), and no therapy (HR, 2.15 [95% CI, 2.07-2.23]; P < .001) (Table 2). No significant differences were observed between CT alone and RT alone (RT alone HR, 0.98 [95% CI, 0.90-1.06]; P = .60). In the same model, when compared with no therapy, a reduction in the hazard of mortality was observed with CT alone (HR, 0.70 [95% CI, 0.65-0.75]; P < .001), RT alone (HR, 0.68 [95% CI, 0.65-0.72]; P < .001), and CMT (HR, 0.47 [95% CI, 0.45-0.48]; P < .001) (eTable 2 in the Supplement).

Propensity score–matched analyses with one-to-one matching were performed to compare the survival outcomes within the 3 treatment cohorts. Patient characteristics were well balanced overall with the exception of small differences in race (eTables 3-5 in the Supplement). The corrected α value for significance was set at P = .017. On comparison of 1017 CT alone with 1017 matched CMT patients, the hazard of mortality remained increased for patients treated with CT alone (HR, 1.15 [95% CI, 1.05-1.26]; P = .002) vs those treated with CMT. Similarly, on comparison of 1643 RT alone with 1643 matched CMT patients, the hazard of mortality remained increased for patients treated with RT alone (HR, 1.21 [95% CI, 1.12-1.29]; P < .001) vs those treated with CMT. On comparison of 977 CT alone with 977 matched RT alone patients, no differences in OS were observed (RT alone HR, 0.97 [95% CI, 0.88-1.06]; P = .44).

Subgroup analyses evaluating the effect of treatment were performed for stratifications by age (65-69, 70-74, 75-79, and ≥80 years) and tumor resection (eTable 6 in the Supplement). When stratified by age, the magnitude of the observed OS advantage with CMT over single-modality therapy remained consistent across all age subgroups (HRs with RT alone or CT alone, range 1.44-1.73, all P < .001). Kaplan-Meier OS estimates by treatment for each age subgroup are displayed in Figure 3. When stratified by tumor resection, the observed OS advantage with CMT over single-modality therapy was also consistent for patients treated with and without tumor resection (HRs with RT alone or CT alone, range 1.46-1.59, all P < .001). No significant differences were observed between CT alone and RT alone within any age or tumor resection subgroup.

Discussion

The optimal management for elderly patients with newly diagnosed GBM represents an ongoing controversy in the field of neuro-oncology.14 Although the survival advantages of RT15,16 and later temozolomide CT6,17 have been established by randomized trials reported over the past 4 decades, the benefit of CMT over single-modality therapy remains unclear in aging populations. Early studies from the 1970s and 1980s demonstrated a consistent survival advantage with RT among trial-eligible patients,15,16 establishing adjuvant RT as the standard of care for nonelderly patients who presented with a favorable performance status. In 2005, the landmark EORTC-NCIC trial6 demonstrated improved OS with temozolomide CT in addition to RT and established CMT as the new standard of care for nonelderly patients; although, individuals older than 70 years were notably excluded from this trial. In 2007, a French cooperative (ANOCEF) randomized trial limited to patients 70 years or older demonstrated an unequivocal OS advantage with RT over BSC, providing the first level I evidence for RT specific to elderly patients.1 Subsequently, 2 randomized trials comparing single-modality strategies for patients older than 65 years demonstrated no significant OS advantage of RT alone over CT alone with temozolomide,2,3 introducing new controversies to the management paradigms for this population. At present, no randomized data are available to clarify the effect on OS of CMT over single-modality strategies with either RT alone or CT alone among elderly patients who are candidates for multimodality therapy.

In this analysis, we report the outcomes for more than 16 000 patients in the United States 65 years or older with newly diagnosed GBM who were treated with varying combinations of RT, CT, and surgery in the modern temozolomide era. In this population, a consistent OS advantage was observed for patients treated with CMT over single-modality therapy with RT alone or CT alone. The benefits of CMT remained significant in multivariate models and propensity score–matched analyses controlling for important clinical variables notably including age, comorbidity scores, and tumor resection. Subgroup analyses demonstrated a consistent OS benefit with CMT over single-modality therapy across sequential age stratifications (65-69, 70-74, 75-79, and ≥80 years) and tumor resection subgroups. Conversely, no significant differences in OS were observed in multivariate, propensity score–matched analyses, or subgroup analyses between the single-modality treatment strategies involving RT alone vs CT alone.

To our knowledge, this analysis represents the largest report of multimodality therapy outcomes specific to elderly patients with GBM in the temozolomide era. To guide the management of this population, which has historically been underrepresented in randomized trials,18 the National Comprehensive Cancer Network stratifies contemporary recommendations on the basis of performance status.4 Recommended therapies for patients with a favorable Karnofsky performance status (KPS, ≥60) include CMT (ie, RT and temozolomide), RT alone, and temozolomide alone, whereas patients with an unfavorable performance status (KPS, <60) are recommended to receive single-modality therapy with RT alone, temozolomide alone, or BSC. Similar recommendations are also reported in European Society for Medical Oncology guidelines.5 Acceptance in the neuro-oncology community of single-modality adjuvant strategies for elderly patients with GBM generally arises from the challenges that older patients may have in completing aggressive multimodality therapies,14,19 concerns for increased RT-related central nervous system effects in older patients,20 and the reports of randomized trials showing no OS advantage of RT alone over temozolomide alone.2,3

In the NOA-08 trial, 373 patients older than 65 years were randomized to dose-dense temozolomide alone vs standard RT alone (60 Gy/30 Fx) and demonstrated no significant differences in survival.3 Similarly, the Nordic trial randomized 342 patients 60 years or older (later amended to ≥65 years) to standard dose temozolomide alone, hypofractionated RT alone (34 Gy/10 Fx), or standard fractionation RT alone (60 Gy/30 Fx), and demonstrated a prolongation in median OS with either temozolomide alone or hypofractionated RT alone over standard fractionation RT.2 Subgroup analyses based on MGMT status from each of these trials suggest that, among patients who are candidates for only 1 modality of therapy, temozolomide may be the more important intervention for MGMT promoter-methylated tumors (approximately 35%-45% of patients) whereas RT may be more important for tumors that are nonmethylated (approximately 55%-65% of patients).21 However, neither study can inform the selection of elderly patients who would benefit most from the combination of both temozolomide and RT, and oncologists are left with the challenge of reconciling these results with level I evidence supporting CMT in younger patients.6,17

In light of the aforementioned controversies, the most important findings of the present analysis are related to the significant OS advantage observed with CMT over single-modality approaches and the consistent OS benefits observed on subgroup analyses across sequential age stratifications (65-69, 70-74, 75-79, and ≥80 years). A number of smaller retrospective institutional series, prospective observational cohorts, and population-based analyses have reported similar advantages with CMT over single-modality therapy with RT alone or CT alone (eTable 7 in the Supplement). The NCIC-EORTC phase 3 trial (NCT00482677), which has now completed accrual, will compare the outcomes for patients at least 65 years of age treated with RT+temozolomide vs RT alone in a randomized setting. However, because all patients in the NCIC-EORTC trial received RT, this study will not be able to address the benefit of adding RT to CT vs CT alone, which was associated with a substantial survival advantage in the present analysis. While the results of prospective trials are awaited, this large analysis of a prospectively maintained national tumor registry offers meaningful support to CMT for elderly patients who are suitable candidates and wish to pursue multimodality therapy.

Comparisons of single-modality treatment strategies with RT alone vs CT alone demonstrated no significant differences in OS in this analysis. These observations appear generally consistent with the aforementioned randomized NOA-08 trial.3 The 3-arm Nordic trial provided more nuanced results, with the observation of improved OS with temozolomide alone over standard fractionation RT but similar OS between temozolomide alone and hypofractionated RT. Moreover, the Nordic trial also reported improved OS for patients older than 70 years treated with hypofractionated RT over standard fractionation RT2 and separate randomized trials have demonstrated equivalence of hypofractionated RT with longer RT schedules,22,23 supporting the role of hypofractionated RT in the elderly GBM population. However, similar comparisons of RT schedules were considered inappropriate for this registry analysis because national guideline recommendations contemporary to the study interval still reserved hypofractionated RT for patients with poor prognosis and limited KPS.24 This analysis also demonstrated superior outcomes with single-modality strategies of both CT alone and RT alone over no therapy. These outcomes are largely consistent with the randomized ANOCEF trial of RT vs BSC1 and data supporting temozolomide over BSC from phase 2 and retrospective analyses.25,26 To our knowledge, this NCDB data set is the largest reported analysis to support an OS advantage of CT alone over BSC in the temozolomide era.

This analysis has several limitations. Although the demographic characteristics of patients in this analysis are similar to those of contemporary trials and population-based data,2,3,27 it is important to acknowledge that no centralized pathologic review could be performed. The status of MGMT promoter methylation, which represents a favorable prognostic factor for survival and a predictive factor for CT response,2,3,28 was unavailable and potential imbalances favoring CT delivery among patients with MGMT promoter-methylated tumors could have artificially improved the survival outcomes associated with CT administration. Thus, it is possible that analyses adjusted for MGMT status might have suggested smaller survival differences in comparisons involving the addition of CT (ie, CMT vs RT alone and CT alone vs no therapy) and potentially superior outcomes for RT alone over CT alone, rather than equivalence. The validated prognostic factor of patient performance status was also unavailable.29 Although comorbidity scores and factors such as age, sex, race, and surgical status can provide some surrogates for patient performance and health care access, these factors cannot directly account for disparities in health and performance status. The range of unmeasured performance statuses in this analysis may have also contributed to the inferior OS outcomes observed by treatment strategy when compared with data from clinical trials and series from high-volume centers.2,3,30-32 No data were available for analysis regarding treatment-related toxic effects, cognitive performance, or quality of life. Furthermore, there is no information on the use of salvage therapies for recurrent disease. Chemotherapy data were limited to CT administered during the temozolomide era without data regarding specific agents or treatment schedules. Available surgical coding was limited to tumor resection vs biopsy only, without prognostic information regarding the extent of tumor resection.33 Disparities were also observed among baseline characteristics across treatment groups. Efforts to account for these disparities and the critical limitation of patient selection included the use of multivariate models, propensity score–matched analyses with well-balanced patient characteristics, and subgroup analyses evaluating the impact of therapy stratified by age and tumor resection status.

Conclusions

In this analysis, we report the survival outcomes associated with different treatment strategies in a large cohort of elderly patients with newly diagnosed GBM treated in the temozolomide era. When controlling for critical variables including age, comorbidity scores, and tumor resection, CMT was associated with a consistent OS advantage over single-modality therapy with either CT alone or RT alone. The benefits of CMT remained significant in propensity score–matched analyses and across sequential age stratifications (65-69, 70-74, 75-79, and ≥80 years). Analyses of single-modality treatment strategies demonstrated comparable survival with CT alone and RT alone, and both were superior to no therapy. Overall, this analysis supports the use of CMT for suitable elderly patient candidates.

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Article Information

Accepted for Publication: March 1, 2016.

Corresponding Author: Chad G. Rusthoven, MD, Department of Radiation Oncology, University of Colorado School of Medicine, 1665 N Aurora Ct, Ste 1032, Mail Stop F706, Aurora, CO 80045 (chad.rusthoven@ucdenver.edu).

Published Online: May 23, 2016. doi:10.1001/jamaneurol.2016.0839.

Author Contributions: Dr Rusthoven had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rusthoven, Koshy, Amini, Kavanagh.

Acquisition, analysis, or interpretation of data: Rusthoven, Koshy, Sher, Ney, Gaspar, Jones, Karam, Ormond, Youssef, Kavanagh.

Drafting of the manuscript: Rusthoven, Koshy, Ney, Youssef.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Rusthoven, Koshy, Sher, Jones, Karam.

Administrative, technical, or material support: Rusthoven, Ormond.

Study supervision: Rusthoven, Youssef, Kavanagh.

Conflict of Interest Disclosures: None reported.

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