By Rajiv S. Magge, MD

Assistant Professor of Neurology, Weill Cornell Brain Tumor Center

Dr. Magge reports no financial relationships relevant to this field of study.

SYNOPSIS: In a retrospective cohort study of elderly patients with glioblastoma, overall survival was superior with combined-modality therapy (radiation and chemotherapy) compared with chemotherapy alone or radiation alone.

SOURCE: Rusthoven CG, Koshy M, Sher DJ, et al. Combined-modality therapy with radiation and chemotherapy for elderly patients with glioblastoma in the temozolomide era: A National Cancer Database analysis. JAMA Neurol 2016; May 23. doi: 10.1001/jamaneurol.2016.0839. [Epub ahead of print].

More than half of patients with glioblastoma (GBM) are at least 65 years of age at presentation. Unfortunately, these elderly patients tend to have a poorer prognosis, potentially related to poor performance status, medical comorbidities, increased vulnerability to drug side effects, polypharmacy, and less aggressive goals of care. The landmark EORTC-NCIC trial established the standard-of-care treatment for GBM, consisting of concurrent radiation and temozolomide chemotherapy followed by adjuvant chemotherapy.1 However, individuals older than 70 years of age were excluded from that trial. Since that time, there has been extensive controversy regarding the optimal management of elderly GBM patients. It is not clear whether this population should receive radiation therapy (RT), chemotherapy (CT), or combined-modality therapy (CMT, both radiation and chemotherapy).

In a retrospective cohort study, Rusthoven et al queried the National Cancer Database (NCB) for elderly patients ( 65 years old) with newly diagnosed GBM between 2005 and 2011, collecting complete data sets that included any RT, CT, tumor resection, Charlson-Deyo comorbidity scores, age, sex, and year of diagnosis. Survival of the treatment cohorts (RT alone, CT alone, or CMT) was estimated using the Kaplan-Meier method and further analyzed using the log rank test, univariate and multivariate Cox models, and propensity score-matched analyses.

The group identified 16,717 patients at least 65 years of age with newly diagnosed GBM in the NCB. The median age was 73 years and 8,870 (53%) were male. At presentation, 5,337 (32%) underwent biopsy only to establish diagnosis while 11,380 (68%) had some type of tumor resection. In terms of treatment, 8,435 (50%) patients received CMT (i.e., both RT and CT), 1,693 (10%) received RT alone, 1,018 (6%) received CT alone, and 5,571 (33%) received no therapy (best supportive care). CMT administration was observed more frequently in the setting of tumor resection, younger age, male sex, white race, lower comorbidity scores, and during the later years of the study.

The median overall survival (OS) by treatment cohort was 9.0 (95% confidence interval [CI], 8.8-9.3) months with 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 < 0.001). CMT remained superior to all the other groups on multivariate survival analyses, which adjusted for tumor resection, comorbidity scores, age, sex, race, and year of diagnosis. No significant difference in survival was observed between CT alone and RT alone, which were both superior to no therapy. The survival advantage for CMT over single-modality therapy was consistent within subgroup analyses, which stratified patients by age and tumor resection.

COMMENTARY

This large retrospective cohort study of patients queried from the NCB demonstrated improved overall survival with combined radiation therapy and chemotherapy for GBM in patients at least 65 years of age. Unfortunately, even with these data, the exact standard of care for older patients is still controversial. As acknowledged by the authors, a significant limitation of the study was the lack of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status of the tumors within the database. MGMT is a DNA repair enzyme that repairs DNA alkylation, which may make cancers less susceptible to DNA-alkylating agents such as temozolomide. Several studies have shown that patients with tumors that are MGMT hypermethylated (i.e., less functioning MGMT enzyme) have significantly improved survival with the addition of chemotherapy. As the status of MGMT methylation is unclear, it could be responsible for the different survival outcomes across the cohorts. Another important limitation of the study is the absence of data regarding performance status, which can carry heavy weight regarding prognosis and treatment efficacy.

On presentation, maximal safe resection with preservation of neurologic function (instead of biopsy) is generally preferred, but this, of course, depends on tumor location/size, goals of care, and other medical comorbidities. After surgery, the combination of both radiation therapy and chemotherapy can carry significant toxicity, but is probably indicated in patients with suitable performance status and good overall health. Shorter courses of hypofractionated radiation therapy have been shown to be better tolerated than standard regimens in older GBM patients with similar survival. Further, radiation alone may be an effective alternative in patients with unmethylated MGMT tumors, poor functional status, or significant medical problems. Conversely, emerging data support the use of temozolomide monotherapy in frail elderly patients with MGMT-methylated tumors.

The optimal treatment of GBM in older patients continues to be clarified. The field eagerly awaits new data, including the results of the EORTC-NCIC Phase III trial, which will compare the outcomes of elderly patients treated with RT and temozolomide chemotherapy vs. RT alone in a randomized fashion.

REFERENCE

  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.