Introduction
Diffuse gliomas are the most common primary central nervous system tumors, accounting for about 30% of all brain tumors in Japan [
1]. Median age at glioblastoma (WHO grade IV) diagnosis is 63.0 years and higher than median age at diagnosis of lower-grade gliomas [
1]. Recently, the number and percentage of elderly people are rising in Japan, and hence diffuse gliomas in the elderly are becoming more common [
1,
2]. As this demographic tends to fare worse than non-elderly population, there are major concerns regarding prediction of clinical behavior and treatment outcomes.
In clinical practice, physicians are usually apprehensive in offering aggressive treatments to elderly patients because of concerns relating to treatment tolerance due to advanced age, co-morbidities or underlying propensity for complications [
3,
4]. Although treatment-associated toxicity in the elderly appears to be higher and optimal treatment for elderly patients remains controversial, treatment tolerance seems to be dependent on individual predisposition as well as comorbid conditions [
5‐
8]. Clinical consequences are often complicated by additional considerations common to elderly populations.
Adult diffuse gliomas have highly variable clinical behavior, response to therapy, and outcomes [
9,
10]. Recently, mutations in
IDH, TP53, TERT promoter and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been highlighted as clinically relevant prognostic markers of diffuse gliomas [
9‐
13]. Some of these molecular parameters are required for integrative diagnosis for 2016 CNS WHO Classification [
14]. Some molecular markers have also been reported as being predictive of the potential benefit from specific therapeutic intervention. Particularly in elderly patients,
MGMT promoter methylation status is reportedly to be important information for deciding adjuvant treatment regimen [
8,
15‐
17]. The prevalence and impact of previously established biomarkers are considered as a main area of investigation for diffuse gliomas in the elderly.
This study aims to demonstrate the current state of clinical practice for elderly patients with diffuse gliomas and molecular analyses of diffuse gliomas in the elderly. In the multi-institutional retrospective cohort study of 140 elderly cases treated at 13 hospitals in Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network), we elucidate both clinical and pathological features of elderly glioma cases, as well as treatment outcomes and prognostic factors of glioblastoma (GB) patients in a real-world setting.
Discussion
In this study, we retrospectively analyzed 140 elderly patients with diffuse gliomas treated at 13 hospitals in the Kansai Network. The cohort had several clinical and molecular characteristics: age ≥ 80 years (26.4%), lower-grade glioma (18.6%), preoperative KPS scores below 70 (51.4%), resection (34.3%), adjuvant RT + TMZ (68.6%), MGMT promoter methylation (48.6%), IDH1/2 mutation (7.7%) and TERT promoter mutation (60.9%). Higher age (≥ 80 years) and TERT promoter mutated were associated with poor prognosis. Resection and adjuvant RT + TMZ were identified as independent good prognostic factors.
Large cohort studies of elderly patients with diffuse gliomas are limited [
4]. This study included 140 patients with an age of ≥ 70 years. Statistical analyses reconfirms previous reports that age is one of the most important prognostic factors and performance status is independently associated with survival [
4,
21].
As the result according to 2016 WHO Classification, several characteristics were notable. First, grade II/III astrocytomas consisted of IDH-wt (94.1%) and IDH-mut (5.9%). Generally, the great majority falls into the IDH-mut category and IDH-wt astrocytomas are uncommon [
22]. Moreover, in oligodendroglial tumors, some AO did not retain both
IDH mutations and 1p/19q codeletion (22%). These tumors, histologically typical oligodendrogliomas, were diagnosed as AO, NOS after careful evaluation.
Arita et al. reported that almost all tumors harboring concurrent
IDH1/
2 mutations and total 1p/19q loss had
TERT promoter mutations [
23]. Indeed, in
TERT mutated tumors, all tumors with
IDH mutation harbored 1p/19q codeletion. Moreover, they proposed combined
IDH/
TERT classification [
12]. Also in this study, IDHwt/TERTmut patients expected the shortest survival in four subgroups.
Wiestler et al. reported that
MGMT promoter methylation was 35% in malignant astrocytoma in the elderly (> 65 years) [
24]. Our cohort had a relatively high frequency of
MGMT methylation (48.6%). Grade IV patients with
MGMT methylated tumors showed better survival compared to those with unmethylated tumors, but the difference did not reach statistical significance. This trend was also observed in previous reports [
4,
8].
TERT mutation status had a prognostic impact in this study. Together with MGMT methylation status, significant interaction between TERT and MGMT was observed. GB patients with TERT mutated and MGMT unmethylated had the poorest prognosis. Based on the results, a combination of IDH, TERT, and MGMT would refine clinically relevant classification of elderly diffuse gliomas.
Several treatment options have been recommended [
16]. For low-grade gliomas in the elderly, adjuvant treatments have never been discussed. In the cohort, non-aggressive resection tended to be undertaken. On the other hand, adjuvant RT + TMZ was conducted in the majority. Notably, there was no significant difference in survival time between 50 and 60 Gy and < 50 Gy RT groups, which is discussed in several studies [
6,
8,
25,
26]. TMZ monotherapy group resulted in shorter survival regardless of
MGMT status, as was inconsistent with other reports [
17].
TMZ concomitant with and adjuvant to RT is a widely used approach, but the role in elderly cases remains discussed [
27]. Arvold et al. stated that the addition of TMZ to RT was associated with a small survival gain [
28]. Franceschi et al. reported that RT + TMZ is effective only in methylated
MGMT tumors [
29]. On the other hand, in the phase 3 trial by Perry et al., the addition of TMZ to short-course RT was associated with significantly longer survival [
3]. In subgroup analyses, the benefit was also observed in unmethylated
MGMT cases [
3]. These results suggest that the addition of TMZ to RT confers a survival benefit regardless of
MGMT status.
In general, treatment outcomes are mostly consistent with previous reports [
4,
21,
30]. Although the optimal treatment remains controversial, maximum and safe resection followed by short course RT with concurrent and adjuvant TMZ is warranted in GB [
3].
As a multi-institutional retrospective cohort design, there are several limitations. Unlike a randomized study, selection bias on decision-making of treatment strategy could exist. Attending physicians may decide to deliver treatments considering the patients’ age, conditions and wishes, and thus a selection could affect the survival findings. Variation of treatment regimen at multiple institutions, such as radiation protocol and dose schedule, should also be considered. The limited number of patients could explain the absence of statistical power to detect differences between groups. Modest prognostic impact of molecular characteristics might be partly due to the limited follow-up period of the population.
In conclusion, we report characteristics and outcomes of elderly patients with diffuse gliomas in the Kansai Network. This community-based study elucidated the present status of real-world practice. Further investigation in a larger population would contribute to our better understanding of the pathogenesis of glioma in the elderly.