The present study represents one of the largest series of non-selected very elderly glioblastoma patients reported so far. We identified adjuvant irradiation and chemotherapy as favorable independent factors for the overall survival in very elderly patients.

Although glioblastoma is common in elderly patients, standard therapy has long been defined only for patients under 65 or under 70 years of age. Additionally, the age cut-off for several studies on therapy for glioblastoma in the elderly is set at 65 years [3, 5, 10,11,12,13]. Different prospective and randomized trials documented the benefit of complete surgical resection if at the same time new perioperative deficits can be avoided [14,15,16,17]. Based on the EORTC-22,981/26,981 / NCIC CE3 trail, standard adjuvant therapy is an adjuvant and concomitant radio-/chemotherapy with temozolomide [2]. For MGMT promoter methylated glioblastomas, intensification of temozolomide chemotherapy by additional administration of CCNU might be beneficial [18]. Interestingly, there were no relevant differences in the distribution of MGMT promoter methylation status in our elderly cohort compared to other studies with a younger patient cohort [3,4,5]. Based on the (EORTC)-22,981/26,981 / National Cancer Institute of Canada (NCIC) CE3 study, it was assumed that standard therapy is too aggressive for elderly patients, and less aggressive adjuvant therapy concepts were addressed in prospective studies [19].

The NOA-08 trial compared temozolomide chemotherapy alone (100 mg/m2 temozolomide, one week on / one week off protocol) with radiotherapy alone (30 × 1.8-2.0 Gy ad 60 Gy) in glioblastoma patients with a KPS > 50 and an age > 65 years. The study established the MGMT promoter methylation as therapeutic marker as temozolomide chemotherapy was associated with a longer event-free survival in MGMT promoter methylated glioblastoma as compared to radiation therapy alone. In contrast, in MGMT promoter unmethylated glioblastoma, radiation was beneficial [3]. The Nordic trial compared temozolomide chemotherapy alone (200 mg/m2; 5/28 day cycle), radiation therapy (30 × 2 Gy ad 60 Gy) and hypofractionated radiotherapy (10 × 3.4 Gy ad 34 Gy) in elderly glioblastoma patients ≥ 60 years. The study confirmed the role of the MGMT as therapeutic marker as the overall survival was not inferior in the temozolomide chemotherapy group compared to standard radiation therapy [5]. The CCTG CE.6/EORTC 26,062 − 22,061 phase III trial compared hypofractionated radiotherapy (40 Gy/15 fractions) alone with hypofractionated radiotherapy with concomitant and adjuvant temozolomide in newly diagnosed glioblastoma patients aged ≥ 65 years [4].

In our present analysis Kaplan-Meier analyses suggested that aggressive neurosurgical treatment with resection instead of biopsy alone was associated with favorable outcome referred to overall survival (OS). In contrast, our multivariate analysis showed no benefit in terms of the overall survival for a surgical resection. Again, although prospective and randomized trials have proven the benefit of a complete surgical resection if at the same time new perioperative deficits can be avoided [14,15,16,17], such an association has yet not been shown for elderly and geriatric patients. With reference to the ANOCEF trial from 2022, no advantage was demonstrated for tumor resection compared to biopsy alone in patients ≥ 70 years of age in terms of OS. However, there was a significantly better quality of life and PFS for patients following tumor resection [20]. Here, multimorbidity and geriatric limitations could certainly be risk factors for successful surgery. The benefit of a complete resection may not outweigh the increased risk from multimorbidity and geriatric limitations. However, with our data this remains speculative since co-morbidities weren’t systematically recorded. Further prospective and randomized studies assessing the role of surgical and novel adjuvant treatments in geriatric glioblastoma patients are needed.

Independent of the prospective studies on adjuvant therapy in elderly glioblastoma patients mentioned above, the impact of the adjuvant therapy has been analyzed in numerous retrospective studies [21,22,23,24,25,26,27,28,29,30,31]. Elderly patients in good pre- and postoperative clinical condition may have comparable survival rates as younger patients when treated according to standard of care [32]. However, a more aggressive therapy likely results in a higher frequency of side-effects and clinical deterioration. The predictive role of MGMT promoter methylation is well documented in various studies and should therefore be considered [32, 33].

In our cohort, the natural course of the disease proved to be devastating, especially when biopsy without adjuvant treatment was performed. A more aggressive therapy resulted in a better outcome as defined by a longer overall survival, albeit this also being short. However, it should be considered in this context that aggressive treatments can only be offered to patients with a good general condition, guided by the KPS. Our results may help clinicians to counsel their patients regarding the pros and cons of surgery and/or adjuvant therapy.

We acknowledge several limitations of our analysis: (1) All data are derived from a retrospective, single center study. (2) A standard geriatric assessment was neither established in the present study nor in recent prospective randomized trials [3]. Like the general condition as assessed by the KPS, however, geriatric burden most likely has an impact on the ability to cope with surgical and adjuvant therapy, on the quality of life and on the prognosis. Therefore, a high symptom burden in geriatric screening could be a valuable marker for therapy decisions. (3) In the present series, we analysed a homogenous cohort with elderly IDH-wildtype glioblastoma patients and aimed to minimize potential confounders by different brain tumours diagnoses. As a potential confounder, the patient cohort was heterogenous in respect to pre-therapeutic clinical performance and therapeutic protocols, making estimates regarding their effect on overall survival difficult. (4) Tumors were histopathologically classified by the 2016 version of WHO classification. Recently, a new version of the WHO classification was published. However, the differences between versions of the WHO classification can be regarded as rather small with regard to IDH wild-type glioblastomas. Moreover, new and more aggressive therapies of glioblastomas have been introduced, e.g. the adjuvant and concomitant temozolomide and CCNU chemotherapy for patients with MGMT promoter methylated glioblastoma [18] as well as the tumour-treating fields [34]. The impact of the therapies in the treatment of especially elderly patients remains yet unclear. (5) In the present analysis, we did not analyse the side effects, such as hemato-toxicity or treatment effects on neurocognition. (6) Moreover, we did not perform any assessment of quality of life, psycho-oncological and social burden on patients and their relatives. We cannot exclude that the identified prognostic markers might significantly impair patient’s quality of life. This issue might be addressed in further studies.