Glioblastoma is the most common and most aggressive primary cranial malignancy, and the incidence increases with age. In the United States, the median age at diagnosis of glioblastoma is 64 years, and there are approximately 6,000 cases per year of older patients aged >65 years who are first diagnosed. The median survival of patients with glioblastoma is approximately 15 months, and the prognosis is worse in older age groups. A retrospective analysis based on the US Surveillance, Epidemiology and Prognosis Program (SEER) database showed that the median survival of glioblastoma patients >65 years of age was only 4 months, regardless of treatment.
For younger patients, the current standard of care is maximum safety tumor resection + postoperative radiation therapy in the involved field + concurrent and adjuvant temozolomide chemotherapy. This radiotherapy regimen was proposed by a prospective controlled trial conducted by Stupp et al. that showed a 2.5-month prolonged median survival with the combination of radiotherapy compared to radiotherapy alone. Notably, the trial excluded patients with glioblastoma aged >70 years, and subgroup analysis suggested a survival benefit for the 60-65 year old subgroup receiving radiotherapy and no benefit from radiotherapy for the 65-70 year old subgroup.
There are few studies on the treatment of GBM in the elderly that are sufficient to provide clinical oncologists with evidence for optimal treatment. Because the efficacy of standard treatment regimens in older patients is uncertain, and because of toxicity avoidance concerns, conventional treatment of older patients is “undertreated”.
Based on current evidence-based evidence, the recommended treatment for pathologically confirmed GBM is as follows.
Surgery
Whether elderly patients with glioblastoma should undergo aggressive surgery has been controversial, as elderly patients may face poor surgical outcomes due to multiple complications, poor postoperative wound healing, and poor tolerance of perioperative stress. However, the conclusions of relevant studies are relatively consistent: older patients can still benefit from extensive tumor resection. Chaichana et al. retrospectively analyzed 80 patients with GBM >65 years of age, of whom 40 patients in the surgical group underwent >95% tumor resection, with improved overall survival (OS) compared to the biopsy-only group, and analysis of the subgroup >70 years of age still showed the superiority of surgery in improving OS. In a prospective study by Vuorinen et al, 30 patients aged >65 years with highly suspicious high-grade gliomas based on imaging were randomly assigned to either the decompression surgery group or the biopsy group, and although postoperative pathology suggested a confirmed diagnosis of GBM in only 75% of cases, with the remaining cases having pathological diagnoses of brain metastases, lymphoma, and cerebral infarction, an intent analysis showed that decompression surgery both improved OS while delaying neurological deterioration. A retrospective analysis by Stark et al. showed that complete resection of the primary tumor, radiotherapy and resection of recurrent tumors were independent favorable prognostic factors in GBM patients >60 years of age. A similar study by Hoffermann et al. suggested that a kps score <80 was a prognostic disadvantage in gbm, but advanced age per se was not a direct prognostic factor, and their study similarly suggested a survival benefit in the surgical group, but faced a higher risk of complications.
Similar to younger patients, greater surgical resection also improved the survival prognosis of older GBM patients. As molecular characterization of tumors plays an increasing role in GBM treatment decisions, surgeons will minimize biopsy alone in favor of obtaining enough tumor tissue to obtain molecular characterization.
Radiotherapy
Radiotherapy is an important adjunct to postoperative treatment of GBM, and in older patients, it is important to balance the benefits of radiotherapy with the toxicity associated with radiotherapy.
Kime-Guibert et al. compared the efficacy of best supportive care and involved field radiotherapy (50.4Gy/28f) in a prospective controlled study in which 50% of patients underwent biopsy only. The trial was closed early due to significantly prolonged survival in the radiotherapy group compared to the supportive care group, so the investigators concluded that radiotherapy was appropriate for treating elderly patients with high Kps scores. roa et al. attempted to explore the effect of different radiotherapy modalities on efficacy and cumulative toxicity of radiotherapy in 95 patients with GBM >60 years of age who were randomly assigned to either a large-split radiotherapy group receiving 40Gy/15f irradiation or a conventional-split group receiving 60Gy/ 30f irradiation. A single-center retrospective analysis by Arvold et al. suggested that the efficacy of macrofractionated radiotherapy was similar to conventional radiotherapy with the addition of temozolomide chemotherapy.
The application of radiotherapy in elderly GBM patients improved PFS and OS without affecting patients’ quality of life and cognitive function.
Chemotherapy
There are two major prospective studies on chemotherapy alone for the treatment of GBM in the elderly. Chinot et al. used temozolomide chemotherapy to treat GBM patients >70 years of age (Stupp regimen) with PFS and OS of 5 and 6.4 months, respectively, with acceptable toxic effects. However, MGMT status was not taken into account in this study. In contrast, temozolomide in the ANOCEF study was administered at 150-200 mg/m2/day, d1-5, in 28-day cycles. Despite a median chemotherapy cycle of only 1 cycle for all patients, the median OS was 6.25 months, a significant improvement over previous survival data with supportive therapy only. Subgroup analysis showed significantly improved OS in GBM with the presence of MGMT promoter methylation compared to those without methylation.
MGMT is a DNA repair enzyme that deregulates the alkylating effect of temozolomide thereby reducing antitumor efficacy. Approximately 40-50% of GBM have hypermethylation in the MGMT promoter region, and this group of patients can benefit from temozolomide chemotherapy. A large prospective, observational study by the German Glioma Network analyzed the relationship between MGMT status and prognosis in 233 elderly GBM patients and found no clinical benefit from alkylating agent chemotherapy in GBM without MGMT promoter methylation. For GBM with MGMT promoter methylation, both radiotherapy combined with alkylating agents and alkylating agent chemotherapy alone significantly prolonged PFS compared with radiotherapy alone.
Combination of radiotherapy and chemotherapy
In a prospective non-randomized study, Brandes et al. compared the efficacy of radiotherapy alone (24 patients), radiotherapy combined with procarbazine, lomustine and vincristine (PCV) chemotherapy (32 patients), and radiotherapy combined with temozolomide chemotherapy (23 patients) for GBM >65 years of age. Minniti et al. conducted two prospective trials, including a single-arm study that included 32 patients with GBM >70 years of age who received concurrent radiotherapy and adjuvant chemotherapy (Stupp regimen), with median PFS and OS of 7 months and 10.6 months, respectively. However, the study reported more severe hematologic and neurotoxicity in 28% and 40% of subjects. In the second, also a single-arm trial, 43 patients >70 years of age received large-split radiotherapy and adjuvant temozolomide chemotherapy, with median PFS and OS of 6.3 and 9.3 months, respectively, and 28% of subjects experienced hematologic toxicity of 3rd degree or greater. Despite the high incidence of toxic reactions in both studies, the investigators recommend both of these treatment options as treatment options for GBM in the elderly. Another retrospective study by this group suggested that large-split radiotherapy combined with concurrent and adjuvant chemotherapy was less toxic and comparable to conventional split-combination chemotherapy.
Radiotherapy vs. chemotherapy
A retrospective analysis by Glantz et al. of temozolomide chemotherapy alone versus radiation therapy alone in 86 GBM >70 years of age suggested no statistical difference in OS between the two modalities. Two other large phase 3 controlled clinical studies, the Nordic study in which patients with GBM >65 years of age were randomly assigned to the standard radiotherapy group (60 Gy/30f), the large split radiotherapy group (34 Gy/10f), or the temozolomide chemotherapy group (monthly treatment, 6 cycles), showed the worst prognosis in the standard radiotherapy group, with no significant difference in survival between the other two groups. The prognosis of those with MGMT methylation in the chemotherapy group was significantly better than that of those without methylation, which was not observed in the radiotherapy group. A non-inferiority study initiated by the German Neuro-Oncology Collaborative Group comparing standard radiotherapy (60 Gy/30f) with temozolomide chemotherapy (100 mg/m2 , d1-7, 2-week cycle until tumor progression) showed that chemotherapy was non-inferior to radiotherapy, but showed more side effects.
Conclusion
In elderly GBM patients, prolonging survival and maintaining a good quality of life are equally important, and treatment should be based on individual fitness and patient age. Surgical procedures can improve survival, and in older patients in good physical condition, extended resection can facilitate both genetic and molecular identification of the tumor and prolong survival. Cumulative field irradiation is also an effective treatment for GBM in the elderly, and the current controversy lies mainly in the mode of radiation therapy. Temozolomide, either alone or as adjuvant chemotherapy to radiotherapy, has been shown to improve overall survival. Notably, MGMT promoter methylation status is a reliable predictor of GBM efficacy for temozolomide treatment and should be used as a reference when selecting postoperative adjuvant chemotherapy.