Glioblastoma in the elderly: Current and future trends

doi:10.1016/j.critrevonc.2006.06.014

Critical Reviews in Oncology/Hematology

Volume 60, Issue 3, December 2006, Pages 256-266

https://doi.org/10.1016/j.critrevonc.2006.06.014 Get rights and content

Abstract

Data from a prospective trial large enough to provide a reliable analysis of outcome and prognostic factors in elderly patients with glioblastoma (GBM) are not yet available in the literature. Extensive tumor removal appears to offer patients the best possible chance of a speedy neurological recovery. Adequate radiotherapy (RT) should always be given to elderly patients if they have undergone gross total debulking and have maintained a good performance status. It is, however important to bear in mind that the risk of long-term cognitive impairment may be higher in patients on high-dose RT and that a short course of accelerated RT can achieve the same survival. Rather than being ruled out on principle, chemotherapy should be considered on the basis of an accurate assessment of the factors that might compromise the individual patient's tolerance to drugs administered. Temozolomide appears to be the best available chemotherapy in this population of patients.

Section snippets

Epidemiology

The importance of cancer treatment in elderly patients has recently come to the fore due to the progressive increase in life expectancy in the western world. The annual age-standardized mortality from brain tumors has almost doubled for men, being 15.7/100,000 between 1978 and 1985 and 28.4/100,000 between 1986 and 1992 [1]. The study of cancer in elderly patients calls for a definition of the population under study. The age at which patients are considered ‘elderly’ varies in the literature.

Prognostic factors

Advanced age is the most relevant prognostic factor for patients with GBM [4], [10], although the reasons for its biologically aggressive behavior in the elderly are still unknown. Commonly applied prognostic factors, such as performance status and neurological status, assessed in recursive partitioning analysis (RPA) [10], should always be considered in elderly GBM patients. In a systematic analysis of 14 histological variables (such as necrosis, vascular proliferation and calcification) in

Treatment

Most studies report an average survival of 4–8 months in elderly patients with GBM [22], [23]. The significantly diminished survival, compounded by a poor functional status in many cases, thus throws doubt upon any decision to undertake “aggressive therapy” (e.g. surgical resection, radiotherapy and chemotherapy) in this subgroup of patients with a confirmed diagnosis of GBM. Advocates of “aggressive therapy” using one or more of the post-biopsy treatment modalities argue that an older patient

Supportive care

Any decision to administer the best possible supportive care may be fraught with difficulties. Corticosteroids are the mainstay in treatment of brain edema and intracranial hypertension. However, as elderly patients often have diabetes, chronic gastritis, osteoporosis, hyperlipemia and cataract, dexamethasone should be administered cautiously in this patient category. In these patients, anti-epileptic drugs (AED) may markedly affect vigilance and lead to insomnia, thus severely compromising

Surgery

Thanks to the recent, significant progress made in neurosurgery, elderly patients can be selected to undergo biopsy or resection: CT and MRI allow a more accurate preoperative diagnosis of brain lesions. Until recently, however, these techniques were not optimally utilized for elderly patients with brain lesions [25] and most studies in the literature also predated the development of image-guided surgical resection techniques that allow for safer resection of brain tumors. With the availability

Radiotherapy

Radiation therapy has a survival advantage over supportive care; it can also improve and control existing compromised symptoms in elderly GBM patients, as observed by Bauman et al. [33], Meckling et al. [31] and Thomas et al. [34], in cohorts of more than a hundred patients [31], [33], [34], [35]. These authors found an improvement in symptoms ranging from 18 to 38%, a disease stabilization of up to 78%, only a small percentage of patients having clinical deterioration. The study conducted by

Chemotherapy

The administration of chemotherapy in elderly patients is a widely debated issue. The pharmacokinetics of the drugs to be used should always be borne in mind when administering chemotherapy to elderly patients and some general considerations should also be made [49]. Patients in this age group often have a decrease in gastrointestinal motility, splanchnic blood flow and secretion of digestive enzymes, together with mucosal atrophy and the reduced absorption of oral chemotherapy such as

Conclusions

Due to the lack of randomized trials, in clinical practice elderly patients are often managed according to the treating physician's anecdotal experiences or intuitive assumptions drawn from literature on glioma in adults rather than on appropriate sound scientific data from “geriatric” neurooncological trials. A multidimensional geriatric evaluation of the aged individual with cancer should help oncologists to predict tolerability to radio- and chemotherapeutic treatments, prompt them to tailor

Reviewers

Prof. Dr. Rolf-Dieter Kortmann, Department of Radiooncology, University of Leipzig, Stephanstr. 9, DE-04103 Leipzig, Germany.

Dr. Roger Stupp, Multidisciplinary Oncology Center, University of Lausanne Hospitals, 46, rue du Bugnon, CH-1011 Lausanne, Switzerland.

Prof. Pierre-Yves Dietrich, Division of Oncology, Laboratory of Tumor Immunology, University Hospital of Geneva, 24, Rue Micheli-du-Crest, CH-1211 Geneva 4, Switzerland.

References (73)

A.N. Wymenga et al.
Treatment of cancer in old age, shortcomings and challenges
Neth J Med
(2001)
C.B. Scott 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)
A.L. Quan et al.
Epidermal growth factor receptor amplification does not have prognostic significance in patients with glioblastoma multiforme
Int J Radiat Oncol Biol Phys
(2005)
D.S. Mohan et al.
Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution
Int J Radiat Oncol Biol Phys
(1998)
J.J. Grau et al.
Radiotherapy of the brain in elderly patients
Pro Eur J Cancer
(2000)
E.L. Chang et al.
Hypofractionated radiotherapy for elderly or younger low-performance status glioblastoma patients: outcome and prognostic factors
Int J Radiat Oncol Biol Phys
(2003)
G.S. Bauman et al.
A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme
Int J Radiat Oncol Biol Phys
(1994)
R. Thomas et al.
Hypofractionated radiotherapy as palliative treatment in poor prognosis patients with high grade glioma
Radiother Oncol
(1994)
C.A. Marijnen et al.
Radiotherapy is effective in patients with glioblastoma multiforme with a limited prognosis and in patients above 70 years of age: a retrospective single institution analysis
Radiother Oncol
(2005)
A.A. Brandes et al.
Radiotherapy of the brain in elderly patients
Contra Eur J Cancer
(2000)

J.R. Simpson et al.

Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials

Int J Radiat Oncol Biol Phys

(1993)

A.A. Brandes et al.

The treatment of elderly patients with high-grade gliomas

Semin Oncol

(2003)

G.J. Yuen

Altered pharmacokinetics in the elderly

Clin Geriatr Med

(1990)

S.D. Baker et al.

Pharmacology of cancer chemotherapy in the older person

Clin Geriatr Med

(1997)

C.A. Baraldi-Junkins et al.

Hematopoiesis and cytokines. Relevance to cancer and aging

Hematol Oncol Clin North Am

(2000)

M.L. Rosenblum et al.

Age-related chemosensitivity of stem cells from human malignant brain tumours

Lancet

(1982)

A.A. Brandes

State-of-the-art treatment of high-grade brain tumors

Semin Oncol

(2003)

K.J. Murray et al.

Quality-adjusted survival analysis of malignant glioma. Patients treated with twice-daily radiation (RT) and carmustine: a report of Radiation Therapy Oncology Group (RTOG) 83-02

Int J Radiat Oncol Biol Phys

(1995)

S. Villa et al.

Efficacy of radiotherapy for malignant gliomas in elderly patients

Int J Radiat Oncol Biol Phys

(1998)

A. Fleury et al.

Descriptive epidemiology of cerebral gliomas in France

Cancer

(1997)

R. Yancik

Cancer burden in the aged: an epidemiologic and demographic overview

Cancer

(1997)

W.J. Curran et al.

Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials

J Natl Cancer Inst

(1993)

A. Brandes et al.

Treatment of high-grade gliomas in the elderly

Oncology

(1998)

N.H. Greig et al.

Increasing annual incidence of primary malignant brain tumors in the elderly

J Natl Cancer Inst

(1990)

P.J. Jukich et al.

Trends in incidence of primary brain tumors in the United States, 1985–1994

Neurooncology

(2001)

J.E. Riggs

Rising primary malignant brain tumor mortality in the elderly. A manifestation of differential survival

Arch Neurol

(1995)

P. Kleihues et al.

World Health Organization (WHO) pathology and genetics of tumours of the nervous system

(2000)

P.C. Burger et al.

Patient age, histologic features, and length of survival in patients with glioblastoma multiforme

Cancer

(1987)

A. Korshunov et al.

The prognostic relevance of molecular alterations in glioblastomas for patients age <50 years

Cancer

(2005)

S. Kunwar et al.

Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival

Cancer Res

(2001)

T.T. Batchelor et al.

Age-dependent prognostic effects of genetic alterations in glioblastoma

Clin Cancer Res

(2004)

M.L. Simmons et al.

Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients

Cancer Res

(2001)

J.S. Smith et al.

PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme

J Natl Cancer Inst

(2001)

B.K. Kleinschmidt-DeMasters et al.

Glioblastomas in the older old

Arch Pathol Lab Med

(2005)

P.E. McKeever et al.

Proliferation index is related to patient age in glioblastoma

Neurology

(2001)

M. Preusser et al.

No prognostic impact of survivin expression in glioblastoma

Acta Neuropathol (Berl)

(2005)

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Citation Excerpt :
Older patients with a presentation consistent with GBM often undergo needle biopsy followed by consideration of adjuvant treatment [23,24]. Aggressive surgery is not typically offered in light of their previously reported poor survival rates with median survival being typically around 4 months as compared to 14 months for the general population [9,25–28]. The medical co-morbidities in this age group also make long surgical times less tolerable.
Elderly Glioblastoma multiforme (GBM) patients have a worse prognosis and receive variable treatments. MGMT gene promoter methylation is linked with improved survival in GBM. We examined treatments administered and survival including in relation to MGMT methylation status in elderly GBM patients.
Patients ≥65 years with diagnosed GBM between 1/01/2007 and 30/04/2009 and undergoing either a biopsy, subtotal (STR) or gross total resection (GTR) were included. The collected information included MGMT status [methylated (ME) vs. unmethylated (UN)] and survival data. p < 0.05 was considered significant.
59 patients were identified with median age at diagnosis being 72.68 years (65.72–85.04). Treatment included surgery (25 GTR, 8 STR, 26 biopsy), chemoradiation (22) and radiotherapy alone (20). Overall median overall survival (MOS) was 219 days. MOS with chemoradiation was 316 days vs. 143 days without it (p = 0.011). 47 patients had definite MGMT status (28 ME, 19 UN). In ME patients, 9/28 received temozolamide compared to 10/19 in UN category. Temozolamide administration in patients with definite MGMT status was based on WHO performance status (p = 0.007). MOS in UN group was 308 days vs. 167 days in ME group (p = 0.068). In a multivariate Cox model including use of temozolamide, WHO score and methylation status, only temozolamide use was significantly associated with a reduced risk for death (HR 0.443, 95% CI 0.200–0.982, p = 0.045).
In this small cohort of patients, chemoradiation in suitable elderly GBM patients seemed to afford a survival benefit. MGMT methylation was not associated with an improved survival with temozolamide being the only factor leading to a better survival. Temozolamide use should be considered irrespective of MGMT status in this population with future large prospective studies needed to elucidate this further.
Performance status during and after radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma multiforme
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Citation Excerpt :
Approximately 22% of all patients with GBM are 70 years of age or older.1,2 The median survival time in patients over the age of 70 is approximately 4 months with best supportive care.3 However, there is no consensus on the treatment of elderly patients with newly diagnosed GBM.
For elderly patients with glioblastoma multiforme (GBM), radiotherapy plus concomitant and adjuvant temozolomide has resulted in longer survival. We investigated patient performance status, treatment-related toxicity and overall survival (OS) following treatment. Twenty patients aged 70 years or older with a newly diagnosed GBM were treated with radiotherapy (60 Gy in 16 patients and 40 Gy in four patients) plus concomitant and adjuvant temozolomide. We assessed age, the extent of tumor removal, and initial performance status as possible prognostic factors for OS and good performance status following treatment. The median OS was 11.8 months (95% confidence interval [CI], 8.7–14.8). The median time for patients to reach an Eastern Cooperative Oncology Group (ECOG) performance status grade 2 was 3.0 months (95% CI, 2.4–3.5), and the time to ECOG performance status grade 3 was 5.8 months (95% CI, 1.6–9.9). World Health Organization grade III or grade IV toxicity was observed in four patients (20%), leucopenia and thrombocytopenia was noted in two patients, and major infection occurred in two patients. Univariate analysis showed a significantly longer OS (p = 0.003) and a longer time with good performance status for gross total removal (GTR) (p = 0.003). An initial good performance status was related to a good performance status during and after treatment (p = 0.003). Based on multivariate analysis, GTR was significantly associated with a longer OS (hazard ratio [HR] = 0.236; 95% CI, 0.060–0.922, p = 0.038) and a good performance status (HR = 0.124; 95% CI, 0.022–0.693, p = 0.017). During and after treatment, elderly patients with GBM frequently exhibited an early deterioration of performance status. Therefore, in light of a rapidly fatal illness, elderly patients should be treated to preserve and respect their quality of life.
Pneumocystis jirovecii pneumonia prophylaxis during temozolomide treatment for high-grade gliomas
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Bearing in mind that older and frail patients have a higher risk for contracting infections during chemotherapy, PcP prophylaxis can be considered for this specific patient group [104,105]. However, PcP prophylaxis during treatment of elderly glioblastoma patients was not addressed in two major reviews, probably as one-third to one-half of glioblastoma patients over 65 years do not receive standard chemoradiation [106,107]. Therefore, we suggest the following prophylaxis categories for patients treated with chemoradiation or during dose-dense temozolomide treatment in 21 of 28-day-regimen:
Intracranial Tumors
2010, Brocklehurst's Textbook of Geriatric Medicine and Gerontology
Is geriatric assessment adapted to radiotherapy?
2008, Cancer/Radiotherapie
Le cancer du sujet âgé représente un problème important de santé publique qui va s’accroître encore dans les années à venir en raison de l’amélioration de l’espérance de vie et du vieillissement de la population. Le pronostic de ces cancers est plus péjoratif que chez les sujets jeunes, du fait d’un diagnostic souvent tardif, de fréquentes comorbidités et d’une prise en charge souvent considérée comme suboptimale. Les traitements de référence en cancérologie ont été essentiellement validés pour les adultes jeunes ou des populations âgées sélectionnées, les données expérimentales collectées sur les plus vulnérables restant très rares. L’avènement de l’oncogériatrie depuis une quinzaine d’année a permis d’envisager deux aspects fondamentaux, que sont l’évaluation gériatrique, de la plus simplifiée à la plus approfondie, et le développement d’essais thérapeutiques spécifiques des populations âgées. Par ailleurs, une politique institutionnelle forte a permis la promotion, sur le territoire national, d’expériences régionales sous la forme d’unités pilotes de coordination en oncogériatrie (UPCOG). La question de l’intérêt d’une évaluation gériatrique en radiothérapie est liée principalement aux difficultés de tolérance et d’observance de ce traitement, mais aussi à son efficacité et nous en évoquons les principales indications curatives, adjuvantes métastatiques ainsi que les voies de recherche en cours.
Cancer in the elderly represents a major public health topic and its importance will increase in the future because of increased life expectancy and ageing. Cancer prognosis is worse due to late diagnosis, frequent comorbidities and treatment often considered as suboptimal. Reference treatments were primarily validated for younger or selected elderly patients and experimental data collected on most vulnerable are rare. Oncogeriatrics development for 15 years made it possible to consider two fundamental aspects, which are the geriatric evaluation, from the most simple to the complete one, and the development of specific trials. In addition, a strong institutional policy allowed promotion, on the French national territory, of regional experiments thanks to Pilot Units of Oncogeriatrics Coordination (UPCOG). The question of the interest of a geriatric evaluation in radiotherapy is related mainly to the difficulties of tolerance and observance of this treatment, but also with its effectiveness and this review explores the main curative, adjuvant and palliative indications as well as research perspectives.
Radiotherapy of adult glial tumors: New developments and perspectives
2008, Revue Neurologique
Les gliomes de l’adulte (OMS grades II, III et IV) représentent un ensemble complexe et hétérogène de tumeurs cérébrales primitives. Leur pronostic dépend de multiples facteurs (âge, autonomie, histologie, biologie et thérapeutiques). La radiothérapie tient une place importante dans leur traitement, après la chirurgie. Sa place s’évalue dans un rapport efficacité/tolérance : survies globale et sans récidive, effets secondaires, complications et séquelles. Les techniques d’imagerie et les logiciels de fusion d’images TDM–IRM, TDM–TEP, permettent une évaluation plus précise des volumes à traiter et des tissus sains avoisinants (organes à risque [OAR]). L’objectif est de délivrer une dose homogène dans le volume cible et de réduire au maximum les doses dans les OAR. L’informatique dédiée permet d’optimiser les protocoles grâce à la simulation virtuelle et à la dosimétrie en trois dimensions. Les rayonnements utilisés sont le plus souvent des photons X délivrés en conditions stéréotaxiques ou conformationnelles non coplanaires. Les doses proposées sont de 50,4 à 60 Gy selon le grade (1,8–2 Gy par fraction). Les médianes de survie (MS) sont très différentes selon le grade de malignité. Cependant, une approche globale de ces tumeurs est erronée car il s’agit de populations hétérogènes de par leurs différents facteurs pronostiques. S’ajoutent des facteurs biologiques et génétiques : inactivation d’une enzyme de réparation de l’ADN, la MGMT pour les glioblastomes (GBM) ; délétion 1p 19q pour les gliomes de grade II et III (plus fréquemment présente dans les tumeurs oligodendrogliales). Un agent alkylant, le témozolomide (TMZ), intervient plus souvent dans la prise en charge de ces patients. La stratégie optimale n’est pas établie et ne se conçoit que dans le cadre d’essais thérapeutiques. L’amélioration du contrôle tumoral nécessite la recherche et l’étude d’autres techniques et d’agents moléculaires. En fin de compte, quelle est la place de la radiothérapie en 2008, quelles sont les techniques, comment les optimiser ? Notre objectif est de faire le point sur nos connaissances actuelles et sur les perspectives de la radiothérapie des gliomes de grade II à IV de l’adulte.
Adult gliomas (WHO grade II, III and IV) are heterogeneous primitive brain tumors. The prognosis of these tumors depends on multiple factors such as age at diagnosis, Karnofsky score, histopathology, biology and treatments. Radiotherapy (RT) plays an important role in the treatment strategy, after surgery. RT has been evaluated in terms of survival, median time to progression and toxicity. Techniques of RT have improved, during the last two decades: neuro-imaging (CT-scan, MRI and PET) and dedicated computers for dosimetry make it possible to deliver an homogeneous dose in the target volume while sparing normal tissues. Photons X are usually delivered with stereotactic or conformational noncoplanar techniques. Total doses delivered range from 50.4 to 60 Gy (1.8–2 Gy/fraction). Median survivals are different with regard to the tumor grade. However, genetic and biological factors also are important prognostic factors such as inactivation of the MGMT gene for glioblastomas and loss of heterozygosity (LOH) 1p/19q, usually associated with pure oligodendroglioma. During the 1990s, temozolomide (TMZ) was specifically developed as a chemotherapy agent against primary brain tumors. The current TMZ/RT regimen in newly diagnosed GBM has been proposed as a standard treatment. The optimal treatment strategy is not known. New clinical trials are needed to assess new techniques of RT; a further improvement in medical treatment requires novel agents.

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Alba A. Brandes holds the present position as Chairman of Medical Oncology Department, Bellaria-Maggiore Hospital, AUSL Città di Bologna Italy. From 1987 to 1989 she was a staff member in the Medical Oncology Department, Venice Hospital; from 1989 to 2005 in the Medical Oncology Department, Padova University Hospital, Italy and from 2003 to 2006 Head of Neurooncology Unit and associate professor of Medical Oncology at School of Oncology, University of Padova from 1989 to 1999. She holds the national position as President of the Italian Cooperative Group of Neuroncology (GICNO). Her research interests are in clinical studies of brain, sarcoma, breast, lung and ovary cancers. Publications include author or co-author of more than 100 peer-reviewed articles (on tumors of the brain, breast, lung and ovary) in addition to over 200 abstracts and book chapters.

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Glioblastoma in the elderly: Current and future trends

Abstract

Section snippets

Epidemiology

Prognostic factors

Treatment

Supportive care

Surgery

Radiotherapy

Chemotherapy

Conclusions

Reviewers

Neth J Med

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Pro Eur J Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Contra Eur J Cancer

Int J Radiat Oncol Biol Phys

Semin Oncol

Clin Geriatr Med

Clin Geriatr Med

Hematol Oncol Clin North Am

Lancet

Semin Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Descriptive epidemiology of cerebral gliomas in France

Cancer

Cancer burden in the aged: an epidemiologic and demographic overview

Cancer

Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials

J Natl Cancer Inst

Treatment of high-grade gliomas in the elderly

Oncology

Increasing annual incidence of primary malignant brain tumors in the elderly

J Natl Cancer Inst

Trends in incidence of primary brain tumors in the United States, 1985–1994

Neurooncology

Rising primary malignant brain tumor mortality in the elderly. A manifestation of differential survival

Arch Neurol

World Health Organization (WHO) pathology and genetics of tumours of the nervous system

Patient age, histologic features, and length of survival in patients with glioblastoma multiforme

Cancer

The prognostic relevance of molecular alterations in glioblastomas for patients age <50 years

Cancer

Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival

Cancer Res

Age-dependent prognostic effects of genetic alterations in glioblastoma

Clin Cancer Res

Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients

Cancer Res

PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme

J Natl Cancer Inst

Glioblastomas in the older old

Arch Pathol Lab Med

Proliferation index is related to patient age in glioblastoma

Neurology

No prognostic impact of survivin expression in glioblastoma

Acta Neuropathol (Berl)