The occurrence of malignant gliomas increases with age. More than half of the patients with glioblastoma are older than 65 years. Thus, the elderly have become the population with the highest incidence of glioblastoma. The prognosis of glioblastoma worsens with age, and various studies have shown that advanced age is an independent risk factor for glioblastoma. For a long time, the treatment of glioblastoma in such a special group of patients has been conservative and without a general consensus, and clinical trials have always excluded elderly patients from the inclusion criteria, until the recent publication of the results of two phase III clinical trials, which made the treatment of elderly gliomas once again attracted people’s attention, this paper will discuss and In this paper, we will discuss and review the issues related to elderly gliomas in order to unify the understanding and provide useful references for clinical practice. At present, there is no uniform standard for the definition of elderly patients, and different researchers define the age of elderly patients differently. Most of the studies mainly set the age demarcation of old age as over 70 years old, and some studies define it as over 60 or 65 years old. Analysis of the reasons for the poor prognosis of elderly glioblastoma patients: firstly, elderly glioblastoma patients often suffer from poorer general conditions, multiple comorbidities, poorer tolerance to surgery, radiotherapy, and so on, and secondly, both the doctors and the patients often tend to be conservative in their treatment choices, and are not given adequate and appropriate treatment. Once again, the direct cause of patient’s death may not be tumor progression, but may also be comorbidities such as infection or thrombosis. 2. Molecular pathology and prognosis of elderly glioblastoma Compared with young patients, elderly glioblastoma also has its own molecular pathology characteristics, similar to young patients, and the prognosis of MGMT promoter methylation is also relatively good in elderly patients, and the recently published NOA-08 and Nordic studies have confirmed that MGMT promoter methylation can predict the response of elderly patients to temozolomide. IDH1 mutations are common in secondary glioblastomas and low-grade gliomas, and their incidence decreases with age; patients with glioblastomas with IDH1 mutations have a better prognosis, but unfortunately the incidence is less than 2% in elderly patients. In addition to this, molecular pathologic alterations in TP53 were associated with a poorer prognosis in elderly patients, whereas in contrast EGFR amplification was an indicator of a better prognosis in elderly glioblastoma patients. Both of these molecular alterations have opposite prognostic roles in older and younger patients. The above molecular pathologic characteristics of elderly patients are significantly different from those of relatively young patients, which may imply that elderly patients have different molecular pathway alterations from those of young patients, and therefore should be given due attention in diagnosis and treatment. Clinical manifestations The main manifestations of elderly glioblastoma patients are dementia, memory loss and personality change, etc., and these atypical manifestations often delay the diagnosis of patients’ conditions. The incidence of epilepsy in elderly patients is relatively low, partly because the majority of elderly patients have glioblastoma, and epilepsy is more common in WHO grade II to III gliomas. There is no consensus on the treatment of glioblastoma in the elderly. The reasons for this are the wide variety of general conditions and comorbidities in different patients, the different concepts of treatment for elderly patients by different physicians, and the lack of research supported by high evidence-based medical evidence. The role of surgery, radiotherapy and chemotherapy in elderly patients will be discussed below. (1) Surgery According to the Chinese Glioma Guidelines, safe maximal resection of tumors in adult glioblastoma patients significantly improves their prognosis. This principle also applies to elderly patients, but the definition of safe resection is more difficult and complex given the surgical risks and comorbidities present in the elderly. A small randomized trial of elderly patients showed that overall or near-total resection prolonged median survival by 3 months compared with biopsy alone. A case-control study from Johns Hopkins University also found that total resection improved median survival over biopsy alone, and Ewelt et al. reported median survival of 13.9 months for total resection, 7 months for partial resection, and 2.2 months for biopsy. However, due to the heterogeneity of the general condition of the elderly, how to grasp the surgical pointers is a hot topic of clinical discussion. Studies have shown that patients with KPS <80, chronic obstructive pulmonary disease, motor dysfunction, speech dysfunction, cognitive impairment, and tumors larger than 100 px have significantly less survival benefit when treated with surgery. Patients with less than one risk factor had a postoperative survival of 9.2 months, whereas patients with 4-6 risk factors had a postoperative survival of only 4.4 months. Therefore, patients with more than two risk factors may be considered for biopsy only. (2) Radiation therapy Radiation therapy is one of the standard components of treatment for adult glioblastoma, but the ability of elderly patients to tolerate the toxic side effects of radiation therapy and to prolong survival is an important issue for clinicians to consider. A French randomized study (ANOCEF) included 85 high-grade patients over 70 years of age with a KPS score of 70 or higher. Patients were divided into two groups, one receiving radiotherapy with a total of 50.4 Gy in 28 fractions and the other receiving only supportive symptomatic therapy. The median survival was 4.2 months and 7.3 months in the supportive therapy and radiotherapy groups, respectively, which was a significant difference. This study demonstrated that radiotherapy is well tolerated and effective in elderly patients. The standard radiotherapy duration of 6 weeks is a heavy burden for elderly patients due to the fact that many of them have limited mobility. Therefore, radiotherapists have attempted to reduce the duration of radiotherapy in patients by using short courses of hypofractionated therapy.Roa et al. studied elderly patients over the age of 60 years with a KPS score of 50 or more, and there was no significant difference in survival between the two groups when a total of 40 Gy of hypofractionated radiotherapy over 3 weeks was used compared with the standard 60 Gy of radiotherapy.24 Therefore, a short course of hypofractionated radiotherapy in elderly patients who are still in fair general condition is also a feasible and convenient option. At present, the use of postoperative radiotherapy in patients with KPS scores below 50 and several poor prognostic indicators does not result in a significant survival benefit, and therefore the selection of radiotherapy for these patients should be made with caution. (3) Temozolomide therapy With the demonstration of the antitumor effects of temozolomide (TMZ) by the stupp regimen,30 the low-toxicity and effective characteristics of TMZ in glioblastoma have been accepted, and researchers have begun to focus on its role in elderly patients.The ANOCEF study group conducted a phase II clinical study that included elderly patients over 70 years of age with KPS scores less than 70 years old, divided into two groups. One group was treated with TMZ 150-200 mg/M2, a 5/28 regimen, and the other with supportive therapy only. Although the TMZ treatment group received an average of only 2 cycles of chemotherapy, compared to 3-4 months in the supportive treatment group, their survival still reached 6.3 months, and 1/3 of the patients improved their KPS score by at least 10 points. Moreover, the study found that patients with methylated MGMT promoters had significantly longer survival than unmethylated patients (7.8 months vs. 4.8 months, P=0.03). The incidence of toxic side effects of the drug was similar to that of adult patients (<70 years) in the stupp study. Because TMZ is easy to take and has lower toxic side effects compared to radiotherapy, it often replaces radiotherapy as an alternative treatment for patients with low KPS scores. In addition to TMZ, many cytotoxic drugs have been used in the treatment of glioblastoma, for example, nitrosoureas have gained some promising efficacy, but the effect of this kind of drug is limited in elderly patients and 1/3 of the patients have serious hematologic toxicity. 5, the choice of treatment options Because of the poor tolerance of radiotherapy in elderly patients, the type of treatment for elderly patients is often based on the personal judgment and experience of the attending physician, especially the choice of radiotherapy or chemotherapy can make the patient more benefit is not conclusive. That is, until the publication of two phase III clinical trials in elderly high-grade gliomas provided a partial answer. The German NOA-08 clinical trial11 enrolled 373 elderly patients with high-grade gliomas who were 65 years of age or older and had a KPS score of 60 or higher, and randomized them into two groups to receive either a total of 60 Gy (1.8-2.0 Gy per division) or a TMZ-enhanced density regimen (100 mg/m2/d, 7day on/7day off regimen). Mean survival was 9.6 and 8.6 months in the radiotherapy and TMZ-enhanced groups, respectively, and the study concluded that the TMZ density-enhanced group did not have worse overall survival than the radiotherapy group, but had a slightly higher incidence of side effects. Compared with patients in the radiotherapy group, MGMT-methylated patients treated with TMZ had significantly longer progression-free survival (HR 1.95, P=0.01) and a trend toward longer overall survival (HR 1.34, P=0.129). The opposite was true for non-methylated patients. From this study, it was concluded that MGMT-methylated patients would benefit more from the choice of TMZ, whereas non-methylated patients would benefit more from the choice of radiotherapy. The study35 included glioblastoma patients over 60 years of age, who were randomized into three groups: a standard TMZ regimen (5/28 regimen) treatment group, a hypofractionated radiotherapy group (a total of 34Gy, 3.4Gy x 10 sessions), and a standard radiotherapy group (60Gy, 2Gy x 30 sessions). The median survival of the three groups was 8.3, 7.5, and 6.0 months, respectively.There was a significant difference between the TMZ standard regimen group and the standard radiotherapy group (HR 0.7, P = 0.01), but there was no significant difference between the TMZ group and the low-fractionated radiotherapy group (HR 0.85; P = 0.24). For patients aged 70 years or older, survival was significantly longer for those who chose the standard TMZ regimen of treatment or low-fractionated radiotherapy than for those who received standard radiotherapy. This study similarly found that patients with MGMT promoter methylation treated with TMZ significantly prolonged survival, whereas MGMT promoter methylation status did not differ for patients treated with radiation therapy. From these two phase III clinical trials of elderly high-grade gliomas, it is concluded that MGMT promoter methylation status is an important predictor of treatment choice for elderly patients. For some elderly high-grade glioblastoma patients with better general conditions, some scholars have adopted the combined radiotherapy and chemotherapy treatment model. Several retrospective studies and meta-analyses have demonstrated that the combination of radiotherapy and chemotherapy provides a survival benefit in elderly patients, especially in those without comorbidities and with favorable prognostic factors (wide resection or high KPS score), but treatment-related neurological toxicities have been noted in up to about half of the patients. The recent completion of a phase III randomized clinical trial by the NCIC and EORTC comparing the impact of short course hypofractionated radiotherapy (40Gy, 15 fractions) ± synchronous and adjuvant temozolomide treatment on patient survival in the elderly over 65 years of age will give a satisfactory answer to this question. 6 Summary and recommendations Due to the complexity of the elderly population, with different underlying conditions such as general status and comorbidities, so far there is no uniform standard treatment protocol for the treatment of glioblastoma in the elderly, and discretion is needed according to the individual's different conditions. In general, for patients with better general condition, no comorbidities, and KPS score >80, overall resection + simultaneous radiotherapy + adjuvant chemotherapy (stupp regimen) can be considered. If the patient’s general condition is a little worse, or has more comorbidities, he/she can choose simple biopsy, and then radiotherapy or chemotherapy, and it is recommended to detect the methylation of MGMT promoter, and if there is methylation, then TMZ chemotherapy will be chosen, and if there is there is no methylation then choose radiotherapy, and the radiotherapy regimen can choose a short course and low division regimen, which has the same efficacy, reduces the patient’s back and forth, and improves the patient’s quality of life and adherence. If the patient’s general condition is poor and the KPS is less than 50, symptomatic supportive therapy including hormone can be chosen.