Management of glioblastoma in older adults

INTRODUCTION — Approximately one-half of patients with glioblastoma are 65 years of age or older at the time of diagnosis. Among clinical factors affecting prognosis, older age and poor performance status have consistently been shown to be associated with shorter survival. The poorer prognosis of older adults and the relative lack of clinical trial data in this age group have led to uncertainty about optimal management. Treatment decisions in older adults can be additionally complicated by factors such as comorbid disease, polypharmacy, increased susceptibility to side effects, and social and economic vulnerability.

The available evidence and approach to older adults with glioblastoma will be reviewed here. The general approach to surgery, radiation therapy, and adjuvant chemotherapy for patients with malignant gliomas is discussed separately. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Temozolomide' and "Radiation therapy for high-grade gliomas".)

PROGNOSTIC FACTORS — Older adults with glioblastoma have a worse prognosis compared with younger patients [1]. In population-based studies, the median survival of patients 65 years of age and older with newly diagnosed glioblastoma is approximately six months [2-5]. Older adults also tend to receive less aggressive therapy, which may influence outcomes [5-8].

The most important prognostic factors affecting survival in patients with malignant glioma are age and performance status (table 1). In a retrospective study that included over 700 patients with glioblastoma diagnosed at 70 years of age or older, the median age at diagnosis was 75 years and the median Karnofsky Performance Status (KPS) was 70 [9]. Recursive partitioning analysis revealed four prognostic groups, with median overall survival stratified according to age and performance status as well as extent of resection:

●Subgroup I (gross total resection or partial resection, age <75.5 years) – 8.5 months

●Subgroup II (gross total resection or partial resection, age ≥75.5 years) – 7.7 months

●Subgroup III (biopsy, KPS ≥70) – 4.3 months

●Subgroup IV (biopsy, KPS <70) – 3.1 months

Molecular alterations also carry prognostic value in older adults, although certain markers, such as mutations in isocitrate dehydrogenase (IDH) and codeletion of 1p and 19q, become increasingly rare with advancing age. The most valuable molecular prognostic factor in older adults is methylation of O6-methylguanine-DNA methyltransferase (MGMT), which is present in approximately half of glioblastomas in patients over the age of 70 years and is associated with improved survival compared with unmethylated MGMT [10]. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'MGMT methylation status'.)

ROLE OF SURGERY — Observational studies in younger adults support the value of maximal safe resection in patients with malignant glioma for the purposes of preserving neurologic function and improving survival. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Extent of resection'.)

In older adults, maximal safe resection is likely beneficial as well, but factors such as medical comorbidities, effects of general anesthesia, and vulnerability to postoperative complications such as delirium weigh more heavily in the decision to operate. (See "Anesthesia for the older adult".)

Based on the available evidence, we suggest maximal surgical resection consistent with preservation of neurologic function rather than biopsy in older patients with glioblastoma. In appropriately selected patients, the goals of resection are to help relieve mass effect, reduce steroid requirements, delay neurologic decline, and facilitate successful delivery of radiation and/or temozolomide. Subtotal resection or stereotactic biopsy alone may be preferred, however, depending upon the location and size of the tumor, general health of the patient, and overall goals of care.

The evidence supporting surgery in older adults is largely observational. In the only completed trial, conducted in France by the ANOCEF cooperative group, 101 older adults (≥70 years) with a suspected operable glioblastoma were randomly assigned to either resection or biopsy [11]. Patients enrolled from 2008 to 2017 received postoperative radiation therapy, and those enrolled from 2017 to 2019 received radiation plus temozolomide. With median follow-up of 40 months, overall survival was similar between the resection and biopsy groups (9.4 versus 9.0 months, adjusted hazard ratio [aHR] 0.79, 95% CI 0.52-1.21). However, the resection group had modestly improved progression-free survival (5.0 versus 4.0 months, aHR 0.50, 95% CI 0.32-0.78) and slower decline in quality-of-life measures compared with the biopsy group. Wide confidence intervals for the survival outcome indicate that the trial was underpowered, and enrollment was slower than expected, which may limit generalizability.

Observational studies in older adults, including a meta-analysis and large population-based analysis using data from the Surveillance, Epidemiology, and End Results (SEER) database, have suggested that gross total resection and subtotal resection are associated with improved survival compared with biopsy alone or no surgical intervention [7,12-17]. In the SEER database study, gross total resection conferred a two- to three-month survival advantage over subtotal resection, even after adjusting for tumor size, location, and receipt of radiotherapy [13]. This effect was present in all age groups examined, although the magnitude of the benefit decreased with advancing age. A major limitation to the interpretation of observational studies, including meta-analyses of observational studies, is that they cannot completely control for factors that influence the decision to pursue surgery in the first place, and many of these factors are strongly associated with survival [18].

INITIAL TREATMENT

Selection of therapy — For older adults with glioblastoma, we suggest a treatment approach that depends primarily on the overall functional status of the patient postoperatively and molecular information about O6-methylguanine-DNA methyltransferase (MGMT) methylation status, if available in a timely manner after surgery (algorithm 1). The three major treatment options (concurrent chemoradiation with or without alternating electric field therapy, radiation alone, and temozolomide alone) are discussed individually below.

Combined-modality therapy is the standard of care for younger patients with glioblastoma, but with advancing age the benefits become more closely balanced with risks of toxicity and side effects. Single-modality therapy is often better tolerated and is a common approach in older patients with a low functional status. In such patients, subgroup analyses from randomized trials support the role of MGMT status in helping to select between radiation and temozolomide [19]. MGMT status is less helpful in patients with a good functional status who are candidates for concurrent chemoradiation, as both methylated and unmethylated patients appear to benefit from the addition of temozolomide to radiation therapy [20]. (See 'Efficacy' below.)

Careful assessment of the patient's overall clinical status and comorbidities is essential. A comprehensive geriatric assessment may be useful in this setting. (See "Comprehensive geriatric assessment for patients with cancer".)

Radiation with concurrent and adjuvant temozolomide — In patients >70 years of age with a good performance status (eg, Karnofsky Performance Status [KPS] ≥70), we suggest using hypofractionated radiation (eg, 40 Gy in 15 fractions) with concurrent and adjuvant temozolomide. The risks of toxicity with the addition of chemotherapy are more closely balanced with the potential for improved survival in older patients compared with younger patients, however. Patients who are particularly concerned about side effects could reasonably choose single-modality therapy.

Older patients selected for combination therapy are also candidates for use of alternating electric fields in the postradiation setting, which have been shown to improve survival in a randomized trial of adults age 18 years and older with newly diagnosed glioblastoma when used in combination with standard radiation plus concurrent and adjuvant temozolomide [21,22]. The median age of the patients in the trial was 57 years (range 20 to 83 years). (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Alternating electric fields'.)

Efficacy — Support for combined-modality therapy in older patients with newly diagnosed glioblastoma is provided by results of a randomized trial of hypofractionated radiation (40 Gy in 15 fractions) with or without concurrent and adjuvant temozolomide [20]. Eligible patients were 65 years of age or older with an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2. The trial included 562 patients with a median age of 73 years (range 65 to 90). Results include the following:

●The addition of temozolomide to radiation resulted in improved survival compared with radiation alone (9.3 versus 7.6 months, hazard ratio [HR] 0.67, 95% CI 0.56-0.80). Progression-free survival was also improved (5.3 versus 3.9 months).

●MGMT was analyzed in 354 patients. Among patients with MGMT methylated tumors (n = 165), the addition of temozolomide improved overall survival by nearly six months (13.5 versus 7.7 months, HR 0.53, 95% CI 0.38-0.73). Temozolomide also appeared to improve survival in patients with MGMT unmethylated tumors (n = 189), but the magnitude of effect was smaller (10 versus 7.9 months, HR 0.75, 95% CI 0.56-1.01).

●Quality-of-life outcomes were similar for functional domains. Patients in the combined-therapy arm had more nausea, vomiting, constipation, and hematologic toxicity, including grade 3 or 4 thrombocytopenia (11 versus 0.4 percent), neutropenia (8 versus 1 percent), and lymphopenia (27 versus 10 percent).

Additional supporting data are derived from observational studies in older adults, which may be subject to selection bias [23,24]. In a pooled analysis of four phase II studies that included older patients (>65 years old) with newly diagnosed glioblastoma treated with standard or short-course radiotherapy plus concurrent and adjuvant temozolomide, median overall survival was 13 months, which compared favorably with outcomes in younger patients [23]. The rate of grade 3 or 4 toxicity ranged from 8 to 46 percent.

The landmark European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group (EORTC/NCIC) trial was limited to patients 18 to 70 years of age, but the five-year analysis of results included a breakdown of outcomes based upon age [25]. Within that study, 170 of the 573 patients (30 percent) were aged 61 to 70 years. For this older subset of patients, median overall survival using the combined-modality approach compared with radiation therapy alone was similar (median 10.9 versus 11.8 months). However, there was a statistically significant prolongation in overall survival with adjuvant temozolomide compared with radiation therapy alone due to an increased number of relatively long-term survivors (22 versus 6 percent at two years and 7 versus 0 percent at five years, respectively, HR 0.7, 95% CI 0.5-0.97).

At least one retrospective study has shown worse outcomes with combined therapy compared with radiation alone in older patients [26], and others have shown a diminishing benefit from the addition of temozolomide with advancing age [27], especially in patients with MGMT unmethylated tumors [28].

Radiation dose and schedule — While a standard six-week radiation treatment course is typically used in younger adults, there is growing experience with hypofractionated radiation therapy combined with daily temozolomide in older patients. The most commonly used regimen in this setting is 40 Gy in 15 fractions, delivered over three weeks.

This schedule was used in the randomized trial reviewed above [20] as well as in a prospective study in which 71 older adults (≥70 years of age) with a KPS ≥60 were treated with a short course of radiation (40 Gy in 15 fractions over three weeks) plus daily temozolomide followed by up to 12 cycles of adjuvant temozolomide [29]. The median overall survival was 12.4 months, with a two-year survival of 20 percent. Temozolomide was discontinued for toxicity in only six patients (8 percent), and health-related quality of life was maintained or improved until the time of progression in the majority of patients [30].

No randomized trials in adults >70 years old have compared hypofractionated radiation with the standard six-week course when given in combination with temozolomide [31], and nonrandomized comparisons are likely to be confounded by differences in KPS and other baseline prognostic factors, which influence treatment selection. In a meta-analysis of seven retrospective studies in nearly 1000 older adults (>65 years), hypofractionated radiation plus temozolomide was associated with similar progression-free survival compared with standard radiation plus temozolomide yet decreased overall survival (mean difference, 3.5 months) [32]. However, the nature of the pooled analysis did not allow for adjustment for KPS or any other covariables. In the largest individual study that included multivariable adjustment by propensity score matching, hypofractionated radiation therapy (40 Gy) with concurrent daily temozolomide was better tolerated than standard radiation therapy (60 Gy) with daily temozolomide and associated with similar survival (12.5 versus 12 months; adjusted HR 0.93, 95% CI 0.66-1.31) [33].

Toxicity — Concern about an increased risk of neurotoxicity has been raised by at least two prospective studies in older patients undergoing standard radiation therapy with concurrent temozolomide. In one study, 13 of 32 patients experienced neurologic deterioration during or immediately following radiation therapy; symptoms were reversed by corticosteroids in approximately half of these patients [34]. In another study using the same regimen, 27 of 48 patients developed grade 2 or 3 mental status deterioration during adjuvant temozolomide therapy, which the authors stated did not correlate with disease progression in most cases [35].

Adverse-event and quality-of-life data from the randomized trial reviewed above [20] suggest that temozolomide may be better tolerated in combination with a shorter, three-week course of radiation compared with standard radiation over six weeks. (See 'Efficacy' above.)

Older adults may also be at increased risk for hematologic toxicity compared with younger adults, with risk of grade 3 or 4 toxicity of approximately 20 to 30 percent [20,34,36]. Side effects and monitoring of temozolomide during combination therapy are discussed in more detail elsewhere. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Side effects and monitoring'.)

Radiation therapy alone — Radiation alone is an effective alternative to combined-modality therapy in older adults with malignant glioma who are not candidates for combined-modality therapy due to poor functional status or medical comorbidities. It is preferred over temozolomide alone in such patients whose tumors are known to be MGMT unmethylated (algorithm 1). (See 'Methusalem (NOA-08) trial' below.)

Efficacy — The survival benefit of radiation in older adults was demonstrated in a trial in which 85 patients, age ≥70 with either grade III or IV gliomas, were randomly assigned to best supportive care, with or without involved field radiation therapy (50.4 Gy in 1.8 Gy fractions) [37]. Progression-free and overall survival rates were significantly increased with radiation compared with best supportive care alone (15 versus 5 weeks and 29 versus 17 weeks, respectively). There was no impairment of quality of life or cognitive function associated with radiation.

Additional data relevant to the use of radiation therapy in older adults are discussed below in the context of two contemporary randomized trials. (See 'Temozolomide alone' below.)

Dose and schedule — The optimal dose and schedule of radiation for older patients remain uncertain, and many such patients are not able to tolerate the prolonged courses of radiation used in younger patients. While standard (prolonged) courses of radiation therapy are expected to have lower rates of normal tissue toxicity in the long term (ie, years after radiation treatment), this becomes less relevant in patients with a median survival of less than one year.

Available data suggest that a shorter course of radiation provides similar efficacy with lower short-term toxicity [37-41]. These hypofractionated regimens are particularly appropriate for older patients with a poor functional status.

This approach was illustrated by a trial in which 100 patients with glioblastoma aged ≥60 years were randomly assigned to treatment with 40 Gy in 15 fractions over three weeks or 60 Gy in 30 fractions over six weeks [38]. The shortened schedule of radiation produced a comparable survival (5.6 versus 5.1 months with the six-week radiation therapy course), and fewer patients required an increase in posttreatment corticosteroid dose (23 versus 49 percent).

In a subsequent randomized trial by the same group, an even shorter course of radiation therapy (25 Gy in 5 daily fractions) was found to be noninferior to 40 Gy in 15 daily fractions in 98 older (≥65 years) and/or frail (≥50 years and KPS 50 to 70) patients with glioblastoma [42]. Although the study was not powered as an equivalency study, all outcomes were similar in patients assigned to one week versus three weeks of radiation, including median progression-free survival (4.2 months in both groups), median overall survival (7.9 versus 6.4 months), and quality of life at one and two months after completion of treatment.

Temozolomide alone — For older patients who are not candidates for a combined-modality approach because of poor functional status or significant comorbidity, emerging data support the use of temozolomide chemotherapy as an alternative to radiation therapy, particularly in those patients with MGMT methylated tumors (algorithm 1).

Like radiation therapy, the use of chemotherapy in this population may also be subject to increased toxicity compared with a younger group with less comorbidity. (See "Systemic chemotherapy for cancer in older adults", section on 'Comorbidity and functional status'.)

Two randomized trials conducted exclusively in older patients provide partially overlapping data about the optimal approach to this population, and specifically the role of temozolomide alone as an alternative to radiation. In both the Methusalem (NOA-08) trial [12] and the Nordic Clinical Brain Tumor Study Group trial [43], a strategy of initial chemotherapy as monotherapy was compared with initial radiation alone. Neither trial included a combined temozolomide-plus-radiation arm.

Taken together, these trials suggest that hypofractionated radiation alone and temozolomide alone are both reasonable treatment options in older patients, and that temozolomide alone is more effective in patients with MGMT methylated tumors than in patients with MGMT unmethylated tumors.

Methusalem (NOA-08) trial — In the randomized Methusalem trial (NOA-08), 373 patients aged 65 years and older were treated with either single-modality treatment using radiation therapy or chemotherapy [12]. Chemotherapy consisted of temozolomide (100 mg/m²/day for 7 days, repeated every 14 days), while radiation therapy was to be given in 30 fractions of 1.8 to 2.0 Gy given over six to seven weeks (total dose 60 Gy). The schedule of temozolomide in this protocol differed significantly from the daily schedule now widely used in the treatment of glioblastoma.

Upon progression, patients received salvage therapy if possible, which generally consisted of radiation for those assigned to temozolomide and chemotherapy (temozolomide) for those originally managed with radiation. Approximately 90 percent of patients had glioblastoma and the remainder had anaplastic astrocytoma.

Key results included:

●Overall survival was similar in the two treatment arms (median 8.6 versus 9.6 months, HR 1.09, 95% CI 0.84-1.42), which met the prespecified definition of noninferiority.

●MGMT promoter methylation status was tested in 56 percent of the study subjects. In this subset analysis, 35 percent of patients were positive for promoter methylation. In a subset analysis based upon these results, the presence of MGMT promoter methylation was associated with significantly longer overall survival compared with those in whom this marker was absent (11.9 versus 8.2 months, HR 0.62, 95% CI 0.42-0.91).

●Temozolomide was associated with significantly more grade 2 or higher hematologic toxicity, liver enzyme abnormalities, and thromboembolic events. The impact on quality of life and neurocognitive function was not assessed.

●Patients whose tumors had MGMT promoter methylation appeared to respond preferentially to temozolomide (median event-free survival 8.4 months with temozolomide versus 4.6 months with radiation therapy). By contrast, those patients whose tumors did not contain MGMT promoter methylation did worse with temozolomide rather than initial radiation therapy (median event-free survival 3.3 versus 4.6 months).

Nordic Clinical Brain Tumor Study Group trial — The Nordic Clinical Brain Tumor Study Group trial enrolled 342 patients aged 60 years or older with newly diagnosed glioblastoma; the median age was 70 years [40]. In this trial, 291 patients were randomly assigned to one of three arms: two radiation schedules (standard [60 Gy in 30 fractions] or hypofractionated [34 Gy in 10 fractions]) or chemotherapy with temozolomide (200 mg/m² for five days with cycles repeated every 28 days). An additional 51 patients were randomly assigned to either temozolomide or hypofractionated radiation.

●In the three-arm randomization, overall survival was significantly longer with temozolomide compared with standard radiation therapy (median 8.3 versus 6.0 months, HR 0.70, 95% CI 0.52-0.93).

●For all patients given either temozolomide or hypofractionated radiation, the difference in overall survival was not significant (8.4 versus 7.5 months, HR 0.82, 95% CI 0.63-1.06).

●Treatment with temozolomide was associated with significantly longer overall survival in those patients whose tumor had MGMT promoter methylation compared with those without MGMT promoter methylation (9.7 versus 6.8 months, HR 0.56, 95% CI 0.34-0.93). MGMT promoter methylation status did not have a significant effect on the response to radiation.

SURVEILLANCE AFTER TREATMENT — Patient management decisions require an assessment of both initial response to treatment and subsequent evidence of progressive disease. Clinical and imaging follow-up is reviewed separately. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Follow-up and monitoring'.)

RECURRENT DISEASE — Recurrent or progressive disease occurs in the majority of patients within the first year after diagnosis and initial therapy. As in newly diagnosed older adults, performance status at the time of recurrence may be a stronger predictor of prognosis than age alone [44].

Treatment options for recurrent disease in patients with glioblastoma include additional surgery, systemic therapy with bevacizumab or second-line chemotherapy, and reirradiation. Of these, bevacizumab is the most widely used therapy in older adults who are candidates for further therapy at the time of progression. (See "Management of recurrent high-grade gliomas".)

Bevacizumab — Bevacizumab is a monoclonal antibody that binds circulating vascular endothelial growth factor (VEGF). It has demonstrated significant clinical activity in recurrent malignant glioma in phase II studies as monotherapy and in combination with chemotherapy agents such as irinotecan. While not yet proven to improve survival in patients with malignant glioma, bevacizumab is associated with a response rate of 30 to 40 percent, reduced steroid requirements, and six-month progression-free survival rates of 40 to 50 percent in those patients with recurrent glioblastoma. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.)

SUPPORTIVE CARE — Optimal supportive care is critical in the management of all older adults with glioblastoma, whether or not they elect to proceed with disease-modifying therapy [45].

Corticosteroids and antiseizure medications are commonly used in brain tumor patients for management of tumoral edema and seizures, respectively. Each of these classes of drugs can have increased toxicity in older adults. These issues are reviewed separately. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Seizures in patients with primary and metastatic brain tumors" and "Seizures and epilepsy in older adults: Treatment and prognosis".)

Patients with a very low functional status, including those who are nonambulatory and fully dependent for activities of daily living, have a very poor prognosis and are best managed with maximal supportive care alone. Many aspects of palliative care for older adults with malignant glioma are common to older adults suffering from a variety of advanced-stage illnesses, including management of urinary incontinence, delirium, and increased risk for falls. An approach to the management of these issues is discussed separately. (See "Overview of comprehensive patient assessment in palliative care".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●For older adults with glioblastoma, careful assessment of the patient's overall clinical status and comorbidities is essential. A comprehensive geriatric assessment may be useful in this setting. (See "Comprehensive geriatric assessment for patients with cancer".)

●For older patients with malignant glioma, we suggest maximal surgical resection consistent with preservation of neurologic function rather than biopsy as the initial step in management (Grade 2C). Subtotal resection or stereotactic biopsy may be required, however, depending upon the location and extent of the tumor, the general health of the patient, and the overall goals of care. (See 'Role of surgery' above.)

●A general approach to postoperative decision making in older patients with glioblastoma is presented in the algorithm (algorithm 1). (See 'Selection of therapy' above.)

•For patients up to 70 years of age with a good performance status and without serious comorbidity, we recommend standard radiation therapy with concurrent and adjuvant temozolomide (Grade 1B). Adjuvant temozolomide consists of six monthly cycles. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Selection of systemic therapy'.)

•For older patients (>70 years of age) with a good performance status and without serious comorbidity, we suggest hypofractionated radiation (eg, 40 Gy in 15 fractions) with concurrent and adjuvant temozolomide (six monthly cycles) rather than single-modality therapy (Grade 2B). The risks of toxicity with combination therapy are more closely balanced with the potential for improved survival with advancing age, however, and patients who are particularly concerned about side effects could reasonably choose single-modality therapy. (See 'Radiation with concurrent and adjuvant temozolomide' above.)

•For older patients who are not candidates for a combined-modality approach because of poor functional status or significant comorbidity, O6-methylguanine-DNA methyltransferase (MGMT) methylation status of the tumor is useful for decision making:

-For patients with MGMT unmethylated tumors, or those with an unknown MGMT methylation status, we suggest a short course of radiation (eg, 40 Gy in 15 fractions or 25 Gy in 5 fractions) rather than temozolomide alone (Grade 2B). (See 'Radiation therapy alone' above.)

-For patients with MGMT methylated tumors, we suggest temozolomide rather than radiation (Grade 2B). (See 'Temozolomide alone' above.)

●Recurrent or progressive disease occurs in the majority of patients with glioblastoma within the first year after diagnosis and initial therapy. Bevacizumab is the most widely used therapy in older adults who are candidates for further therapy at the time of progression. (See 'Recurrent disease' above.)

●Optimal supportive care is critical in the management of all older adults with glioblastoma, whether or not they elect to proceed with disease-modifying therapy. (See 'Supportive care' above.)