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. 2008 Fall;12(4):45–48. doi: 10.7812/tpp/08-027

Prognostic Factors for Long-Term Survival after Glioblastoma

Mohammad Sami Walid a
PMCID: PMC3037140  PMID: 21339920

Abstract

Long-term survivors of glioblastoma (GB) are rare. Several variables besides tumor size and location determine a patient's survival chances: age at diagnosis, where younger patients often receive more aggressive treatment that is multimodal; functional status, which has a significant negative correlation with age; and histologic and genetic markers.

Introduction

Of the estimated 17,000 primary brain tumors diagnosed in the US each year, approximately 60% are gliomas.1,2 Glioblastoma (GB), or grade IV astrocytoma, is the most aggressive of primary tumors of the brain for which no cure is available.1,3 Management remains palliative and includes surgery, radiotherapy, and chemotherapy. With optimal treatment, patients with GBs have a median survival of less than one year.1 About 2% of patients survive three years.4 Previously reported long-term survivors (LTSs) of GB may have been patients who actually harbored other low-grade gliomas.5 The overall prognosis for GB has changed little since the 1980s, despite major improvements in neuroimaging, neurosurgery, radiotherapy, and chemotherapy techniques.

Methods

LTSs are defined as those who survive longer than two years.1 Despite extensive clinical trials, prediction of clinical outcome for individual patients has remained an elusive goal. In search of factors or predictors of long-term survival, we queried the literature using PubMed and Google and the keywords glioblastoma prognostic factor long survival, and then reviewed the articles, comparing their results for common findings.

Results

We found that patient survival depends on the following clinical and biologic parameters: tumor size and location, treatment, age at presentation, Karnofsky performance score (KPS) at presentation, histologic findings, and molecular genetic factors.

Tumor Size and Location

GB is a highly infiltrating tumor and most of the time cannot be resected completely; hence, surgery often consists of incomplete debulking. The feasibility and extent of surgical resection depends on tumor size and eloquence of the brain areas (location). Supratentorial and cerebellar tumors are more amenable to surgical treatment and thus carry better prospects than tumors in the brainstem or diencephalon. Stereotactic biopsy, followed by radiotherapy, may be a more appropriate treatment for these patients.6 Case management with best supportive care for patients with unresectable, primary, biopsy-proven GB results in a median survival time of three months.6,7

Treatment

Clinical evidence suggests that an aggressive and multimodal treatment results in longer survival.8–14 Total or subtotal resection, combined with radiotherapy and chemotherapy, is the mainstay of treatment. New therapies that are still under investigation have shown some promising results. For example, in a 2007 report of a study by Dehdashti et al, brachytherapy was used as a boost to radiotherapy: three patients lived 11, 16, and 18 years, respectively, in the basic group, but unfortunately, statistics did not reveal any significant association with brachytherapy.15 In another example, temozolomide has recently proved to significantly prolong survival when used as an adjuvant chemotherapy to radiotherapy.16 Regarding intra-arterial chemotherapy, a survival benefit in comparison with intravenous administration was not established.17

Age at Presentation

Nearly all studies showed a significant negative relationship between advancing age and duration of postoperative survival.8–18 In a 2005 report of a study by Korshunov et al,18 the percentage of patients younger than age 40 years who survived more than five years was 34%, compared with 6% for patients age 40 years old and older. The researchers suggested age 40 years as the most appropriate cutoff for dividing patients with GB into groups according to prognosis.

Karnofsky Performance Score at Presentation

Many studies' findings show that higher KPS at presentation correlates with improved outcome.4,15,19–21 This is most probably linked to the factor of younger age at diagnosis.

Tumor size and location, treatment, age at presentation, and KPS at presentation allow stratification of patients into risk groups. Using recursive partitioning analysis, Lamborn et al22 identified four risk groups. The two lower-risk groups included patients younger than age 40 years, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with a KPS >70, subtotal or total resection, and between ages 40 and 65 years. The highest-risk group included all patients older than age 65 years and patients between ages 40 and 65 years with either KPS <80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients older than age 65 years, for patients older than age 40 years with KPS <80, and for those treated with brachytherapy.

… aggressive and multimodal treatment results in longer survival.8–14

Histologic Findings

The higher the grade of tumor, the more malignant the tumor is and the worse the prognosis is. Tumors are graded mainly on the basis of their proliferation index, which is an important prognostic factor in GB. The Ki-67 protein is expressed in all phases of the cell cycle except G0 and serves as a good marker for proliferation. Studies that have evaluated proliferation index by Ki-67 immunohistochemistry in GB have shown a significant correlation between high proliferation rates and shorter disease-free and overall survival.5,12,13

The cytologic and histologic composition of glioblastoma has an impact on survival. Microcystic change, the presence of cells with obvious astrocytic differentiation (fibrillary astrocytes), and the subjective impression that areas of better differentiation are present has been associated with a better outcome.23 Another histologic factor, calcification, was in one study associated with a better prognosis.24 A significant relationship also exists between the presence of necrosis and poor outcome.23 Korshunov et al25 found that some histologic and genetic markers that were significant for outcome appeared to be closely related to biology of single cytologic subsets (see “Molecular Genetic Factors”), so they divided GB into three cytologic subsets: small-cell GB (SGB), pleomorphic-cell GB (PGB), and gemistocytic GB (GGB).

Molecular Genetic Factors

Cytogenetic and molecular genetic studies of GB have shown that the most frequent alterations encountered in these tumors are loss of heterozygosity on chromosome arm 10q (60%–90%), mutations in p53 (25%–40%), PTEN mutations (30%), overexpression of MDM2 (10%–15%), and epidermal growth factor receptor (EGFR) gene amplification.1 More p53 expression was reported in LTSs (>3 years) and overexpression of MDM2 in short-term survivors (<3 years).26 Korshunov et al25 found that the number of p53-positive tumors prevailed among the PGB, whereas the number of tumors with EGFR and MDM2 positivity was significantly greater in SGB. GGB contained the significantly lowest mean proliferating cell nuclear antigen (PCNA) labeling index (LI), greater number of p21ras-positive cases, and higher mean apoptotic index (AI). Thus, there is a relationship between histologic and genetic markers. Survival time in patients with SGB, EGFR, and MDM2 positivity and PCNA LI >40% was found to be significantly shorter, whereas presence of p21ras and AI >0.5% were associated with prolonged survival. In another study, Korshunov et al18 found that being younger than age 40 years is strongly associated with a favorable prognosis. EGFR amplification, loss of 9p21, and gain of chromosome 9 had prognostic significance for all patients, whereas gain of chromosome 7 and loss of 10q23/PTEN showed clinical importance only for patients age 40 years and older. Krex et al19 studied 55 patients with GB who lived more than three years. They found significantly more frequent O6-methylguanine–DNA methyltransferase (MGMT) hypermethylation in LTSs.19 Interestingly, the protein product of MGMT gene, 06 alkylguanine–DNA alkyltransferase, was shown to be involved in tumor resistance to alkylating agents. Silencing of the MGMT gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.27–30 Clinical trials for malignant gliomas now often include determination of MGMT expression status.

Recently, Marko et al31 identified a set of 1478 genes with significant differential expression (p < 0.01) between long-term and short-term survivors and, with additional mathematic filtering, isolated a 43-gene “fingerprint” that distinguished survival phenotypes. Gene ontology analysis of the fingerprint demonstrated pathophysiologic functions for the gene products that are consistent with current models of tumor biology, suggesting that differential expression of these genes may contribute etiologically to the observed differences in survival.

Conclusion

GBS are highly malignant tumors that are difficult (but not impossible) to eradicate and that carry a dismal prognosis. LTSs are rare. Several factors besides tumor size and location determine patient's survival chances after diagnosis of GB. Age and functional status are two important prognostic aspects that seem to be correlated. Proliferation index and genetic markers have also been related to age.32,33 Moreover, younger patients often receive aggressive and multimodal treatment. Thus, age at diagnosis plays a pivotal role in the prognosis for GB patients (Figure 1).

Figure 1.

Figure 1

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Interaction of prognostic factors for patients with glioblastoma.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

graphic file with name i1552-5775-12-4-45-f1001.jpg

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Acknowledgments

Katharine O'Moore-Klopf of KOK Edit provided editorial assistance.

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