Management of Glioblastoma Multiforme in Elderly Patients: A Review of the Literature

doi:10.1016/j.wneu.2017.04.153

World Neurosurgery

Volume 105, September 2017, Pages 53-62

https://doi.org/10.1016/j.wneu.2017.04.153 Get rights and content

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, occurs most commonly in individuals older than 65 years of age, and is universally fatal. Increasing age compounds the poor prognosis of GBM, as elderly patients have markedly worse outcomes than younger patients. However, many of the studies previously investigating optimal treatment regimens exclude patients older than the age of 65 years and thus may not represent the best approaches to ensuring prolonged survival with preserved quality of life. This review aims to highlight the current literature on surgical and medical management, including our own experience, for GBM in the elderly patients, and to provide rational treatment approaches for a vulnerable, often-overlooked, patient population.

Introduction

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and occurs most commonly in individuals older than 65 years of age.¹ This aggressive, quickly fatal disease has a median survival of approximately 14 months, but only after maximal therapy of resection, chemotherapy (ChT), and radiotherapy (RT).² The universally poor prognosis of GBM is compounded with increasing age, as elderly patients have markedly worse outcomes than younger patients, with median survival ranging between 4 and 9 months.3, 4, 5, 6, 7 The standard of care for GBM includes maximal safe resection with adjuvant RT and concomitant temozolomide (TMZ).⁸ However, the clinical trials that guided these treatment recommendations specifically excluded elderly patients, and thus their efficacy in the elderly may not be applicable.⁹ Furthermore, elderly patients are more likely to be treated conservatively due to fear of treatment toxicity, increased complication rates, and inability to tolerate extensive procedures.4, 5, 6, 7, 10, 11

Although age is a confounder of mortality in patients with GBM, there may be other factors contributing to poor outcomes. The “baby boomer” generation continues to grow in number, and thus it is important to identify therapeutic approaches to improve survival in this often-forgotten patient population. This review aims to highlight the current literature on surgical and medical management of GBM in elderly patients, including our own experience, and to provide rational treatment approaches for frequently debated situations.

Section snippets

Extent of Resection in Elderly Patients with GBM

Several studies, including randomized clinical trials, have demonstrated the survival benefit of maximum safe resection as first-line treatment of GBM.12, 13, 14, 15, 16, 17, 18, 19 Although there is some debate between the optimal percent of tumor bulk removed and postoperative residual tumor volume, there is no debate that greater extent of resection is associated with improved survival in patients of all ages, including elderly patients. Oszvald et al.¹¹ performed a subset analysis of 146

RT or TMZ for GBM in Elderly Patients

In the International Atomic Energy Agency Randomized Phase III study, Roa et al.²³ investigated whether a short 1-week RT regimen could be a treatment option for elderly or frail patients with newly diagnosed GBM.²⁴ Frail patients were defined as ≥50 years old with a KPS of 50%–70%; elderly and frail patients were defined as ≥65 years old with a KPS of 50%–70%; and elderly patients were defined as ≥65 years old with a KPS of 80%–100%.²³ A total of 98 patients were included in this study and

RT with Concomitant TMZ for Elderly Patients with GBM

Adjuvant RT and concomitant TMZ is the standard of care for patients with GBM after histologic assessment of neurosurgical resection or biopsy specimen and, with the recent updates of the WHO guidelines, the mutational status of isocitrate dehydrogenase (IDH).²⁸ However, elderly patients often are not provided standard of care, given their increased risk of treatment toxicity, high complication rate, and overall vulnerability, including greater probability of comorbid conditions. This leads to

Recurrent GBM in Elderly Patients

Although many avenues for treatment of primary GBM in the elderly have been explored, studies investigating treatment of recurrent GBMs in this population are scarce. Generally, in these patients, best supportive care usually is pursued, given the poor prognosis and the risk of compromised quality of life. Socha et al.³⁹ studied data from the International Atomic Energy Agency trial²³ and identified 84 elderly and/or frail patients who had recurrence of their primary disease. A total of 41 of

Molecular Considerations in GBM

The World Health Organization's 2016 classification of central nervous system tumors introduces a paradigm shift in glioma classification and relies on molecular markers to diagnose and define subtypes of glioma, including GBM.28, 43 With this new classification system, GBMs can be either IDH-mutant or IDH-wild type, with the former having a less-aggressive although still uniformly fatal clinical course. However, this does not bring any changes to the practice of treating elderly patients with

Conclusions

Currently, there is no established standard of care for elderly patients with GBM; however, significant data show there are treatment options available that not only improve OS, but also do not necessarily compromise quality of life. It has been demonstrated in several studies that when possible, the neurosurgeon should aim for GTR of tumor in elderly patients, regardless of age; if GTR is not possible, STR results in improved OS compared with those patients who undergo operative biopsy alone

References (51)

A.M. Stark et al.
Glioblastoma multiforme—report of 267 cases treated at a single institution
Surg Neurol
(2005)
M. Hoffermann et al.
Treatment results and outcome in elderly patients with glioblastoma multiforme–a retrospective single institution analysis
Clin Neurol Neurosurg
(2015)
H. Baker
Radiotherapy in the elderly and frail with glioblastoma
Lancet Oncol
(2015)
A. Malmström 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)
W. Taal et al.
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
Lancet Oncol
(2014)
S.E. Combs et al.
Postoperative Treatment of Primary Glioblastoma Multiforme With Radiation and Concomitant Temozolomide in Elderly Patients
Int J Radiat Oncol Biol Phys
(2008)
M. Wrensch et al.
Epidemiology of primary brain tumors: current concepts and review of the literature
Neuro Oncol
(2002)
C. Adamson et al.
Glioblastoma multiforme: a review of where we have been and where we are going
Expert Opin Investig Drugs
(2009)
K.L. Chaichana et al.
Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival
J Neurosurg
(2011)
F.M. Iwamoto et al.
Patterns of care in elderly glioblastoma patients
Ann Neurol
(2008)

F.M. Iwamoto et al.

Glioblastoma in the elderly

Cancer

(2009)

S. Tanaka et al.

Presentation, management, and outcome of newly diagnosed glioblastoma in elderly patients

J Neurosurg

(2013)

J.G. Scott et al.

Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases

Neuro Oncol

(2011)

R. Babu et al.

Glioblastoma in the elderly: the effect of aggressive and modern therapies on survival

J Neurosurg

(2016)

R. Stupp et al.

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med

(2005)

J.S. Barnholtz-Sloan et al.

Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma

J Neurosurg

(2008)

Á. Oszvald et al.

Glioblastoma therapy in the elderly and the importance of the extent of resection regardless of age

J Neurosurg

(2012)

D. Kuhnt et al.

Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance

Neuro Oncol

(2011)

M. Lacroix et al.

A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival

J Neurosurg

(2001)

K.R. Lamborn

Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis

Neuro Oncol

(2004)

D. Orringer et al.

Extent of resection in patients with glioblastoma: limiting factors, perception of resectability, and effect on survival

J Neurosurg

(2012)

N. Sanai et al.

Glioma extent of resection and its impact on patient outcome

Neurosurgery

(2008)

N. Sanai et al.

An extent of resection threshold for newly diagnosed glioblastomas

J Neurosurg

(2011)

W. Stummer et al.

Extent of resection and survival in glioblastoma multiforme

Neurosurgery

(2008)

K.G. Abdullah et al.

Factors associated with increased survival after surgical resection of glioblastoma in octogenarians

PloS One

(2015)

Cited by (14)

First validation of the G-8 geriatric screening tool in older patients with glioblastoma
2019, Journal of Geriatric Oncology
Citation Excerpt :
The definition of “older patients” remains problematic, because it varied among studies validating the G8 scale, and among different studies in general (with the cut-off ranging from 65 to 70 years) [14]. Sixty-five years was used as the threshold in one previous review, taking into account the epidemiology of cancer [23]. Since the publication of the 2005 International Society of Geriatric Oncology guidelines (SIOG) [6], various screening tools have been devised, among which only five were developed specifically for older cancer populations.
Management of glioblastoma, with a very poor prognosis, remains a challenge in older patients because of coexisting comorbidities and the increased risk of toxic treatment effects. The use of screening tools to identify vulnerable patients is essential. This study was performed to establish whether the G8 scale can be used for screening older patients with glioblastoma.
We retrospectively reviewed the files of patients assessed by the G8 scale and diagnosed with glioblastoma at a single center from January 2010 to July 2017. Patients aged 65 years or older were classified into three groups (more efficiently than two groups) according to their G8 score to identify those with a poor prognosis: high score group, G8 score 14.5–17; intermediate score group, G8 score 10.5–14; and low score group, G8 score < 10.5.
Of 89 patients, 19% were classified into the high score group, 43% into the intermediate score group, and 38% into the low score group. Median overall survival was four months in the low score group, 15 months in the intermediate score group, and 42 months in the high score group (p < .0001). On multivariate analysis, G8 score was a significant independent predictor of overall survival (hazard ratio: 55.46; 99.5% confidence interval: 13.42–229.13; p < .0001).
Here, we highlighted the possibility of using the G8 score, with possibly three cut-offs, in the management of older patients with glioblastoma and determined the prognostic role of this quick and easy screening tool.
Glioblastoma Survival Outcomes at a Tertiary Hospital in Appalachia: Factors Impacting the Survival of Patients Following Implementation of the Stupp Protocol
2018, World Neurosurgery
Citation Excerpt :
The low overall median survival of our patient population may be explained by the fact that most of the patients were >60 years old at the time of diagnosis (Table 1). Our finding of low median and 1-year survival in the elderly group corroborates other studies, which also found a low median survival of 4–6 months in this population, sometimes even with standard treatment.17,18 In such cases, attention shifts toward maintaining a good quality of life.
Glioblastoma is a fatal brain cancer with low median and yearly survival rates. Standard of care for treating glioblastoma is gross total resection (GTR) coupled with the Stupp protocol, but various factors influence the interventions undertaken and survival achieved. As health disparities exist in rural areas, survival in these areas needs to be assessed to understand which factors detract from the successes of these standard medical interventions.
We retrospectively determined impact of age at diagnosis, number of lesions, the molecular marker O⁶-methylguanine methyltransferase (MGMT), extent of surgery, and completion of the Stupp protocol on survival in patients treated at West Virginia University Hospitals. We also compared our findings with a pre–Stupp protocol study done in West Virginia in 1996.
Age <60 years at diagnosis, having the MGMT gene methylated, having a unifocal tumor, receiving GTR, adhering to the Stupp protocol, and undergoing a treatment course of GTR followed by the Stupp protocol significantly increased survival. Comparison with the 1996 study showed that although overall median survival has not increased, all interventions involving GTR have resulted in a significantly higher survival.
We can serve our patient population by offering GTR to all adult patients with glioblastoma when no contraindications exist and ensuring that patients follow the Stupp protocol. After discharge, the Stupp protocol may not be followed or completed for a variety of reasons. In the future, we aim to assess these reasons and analyze other significant interventional and socioeconomic factors that influence survival.
Reactive oxygen species in plasma medical science (PAM and cancer therapy)
2018, Plasma Medical Science
Glioblastoma: Biology, diagnosis, and treatment
2018, Encyclopedia of Cancer
Glioblastoma accounts for the majority of malignant primary brain tumors and is an aggressive cancer with high morbidity and mortality. Despite surgical resection, radiation and chemotherapy, survival can still be as little as 15 months. This article aims to provide a concise summary of this cancer, discussing its history, epidemiology, etiology and classification, its clinical presentation and diagnosis, and current treatment modalities as well as their rationale. There continue to be significant advances that hold great promise for treatments for this tumor, and we discuss several key developments that are on the horizon.
Brain metastases in the elderly – Impact of residual tumor volume on overall survival
2023, Frontiers in Oncology
Palliative care of older glioblastoma patients in neurosurgery
2022, Journal of Neuro-Oncology

View all citing articles on Scopus

: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

View full text

Literature ReviewManagement of Glioblastoma Multiforme in Elderly Patients: A Review of the Literature

Introduction

Section snippets

Extent of Resection in Elderly Patients with GBM

RT or TMZ for GBM in Elderly Patients

RT with Concomitant TMZ for Elderly Patients with GBM

Recurrent GBM in Elderly Patients

Molecular Considerations in GBM

Conclusions

Surg Neurol

Clin Neurol Neurosurg

Lancet Oncol

Lancet Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Epidemiology of primary brain tumors: current concepts and review of the literature

Neuro Oncol

Glioblastoma multiforme: a review of where we have been and where we are going

Expert Opin Investig Drugs

Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival

J Neurosurg

Patterns of care in elderly glioblastoma patients

Ann Neurol

Glioblastoma in the elderly

Cancer

Presentation, management, and outcome of newly diagnosed glioblastoma in elderly patients

J Neurosurg

Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases

Neuro Oncol

Glioblastoma in the elderly: the effect of aggressive and modern therapies on survival

J Neurosurg

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med

Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma

J Neurosurg

Glioblastoma therapy in the elderly and the importance of the extent of resection regardless of age

J Neurosurg

Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance

Neuro Oncol

A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival

J Neurosurg

Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis

Neuro Oncol

Extent of resection in patients with glioblastoma: limiting factors, perception of resectability, and effect on survival

J Neurosurg

Glioma extent of resection and its impact on patient outcome

Neurosurgery

An extent of resection threshold for newly diagnosed glioblastomas

J Neurosurg

Extent of resection and survival in glioblastoma multiforme

Neurosurgery

Factors associated with increased survival after surgical resection of glioblastoma in octogenarians

PloS One

Literature Review
Management of Glioblastoma Multiforme in Elderly Patients: A Review of the Literature