Glioblastoma in Elderly Population

Abstract

Glioblastoma (GBM) is the third most common primary intracranial tumor and the commonest primary malignant brain tumor in adults. The peak incidence is between 65 and 84 years old. The incidence of GBM increases starkly with age—from 1.3/100,000 between the ages of 35–44 to 15.3/100,000 between the ages of 75–84 years. Elderly patients with GBM have increased comorbidities, lower functional status, aggressive tumor biology, and an overall worse outcome as compared with their younger counterparts. Age is an independent and powerful prognosticator of GBM outcomes, even if the performance status is controlled. Elderly patients with GBM represent a vulnerable heterogeneous cohort. Surgical resection in elderly patients offers a better outcome and improved quality of life as compared with biopsy alone and nowadays can be safely tolerated by elderly patients in specialized centers. The standard of care treatment of glioblastoma based on the Stupp’s protocol excluded patients over the age of 70. Thus, the standard of care treatment in elderly patients with GBM remains controversial. Selected elderly patients with excellent performance status may be treated with Stupp’s protocol. Elderly patients with lower functional status may be treated with a hypofractionated treatment regimen with concomitant and adjuvant temozolomide. Frail patients with MGMT methylated tumor can be treated with temozolomide monotherapy alone. It is also not unreasonable to treat elderly frail patients with MGMT unmethylated GBM with hypofractionated RT alone. Thus, treatment of elderly patients with GBM needs a multidisciplinary approach based on the extent of the tumor, MGMT methylation status, performance status, and even the social situation unique to the elderly patient. This chapter seeks to bring a comprehensive and updated review on the treatment of glioblastoma in the elderly population.

1. Introduction

Glioblastoma (WHO grade 4) is the third most common primary intracranial tumor and the most common primary malignant brain tumors in adults [1]. While death rates for many common cancers are declining due to prevention (e.g. tobacco control policies) [2], cancer screening [3], and immunotherapy (i.e. lung cancer, melanoma) [4, 5] and other advances in chemotherapeutics, the prognosis for patients with glioblastoma remains dismal with an overall survival of 12–18 months. The standard of care treatment for glioblastoma is maximum safe resection, followed by combined radiotherapy and temozolomide chemotherapy, and then monthly temozolomide for 6 months [6]. In 2011, a medical device called tumor-treating field was approved to deliver low frequency electromagnetic field locally to the tumor site and was found to further improve the median overall survival by 4.9 months [7].

Though glioblastoma can affect people at any age, it preferentially occurs in older individuals, with a peak incidence between 65 and 84 years old. The 2021 WHO classification of the central nervous system tumors has mandated that the term glioblastoma be used to indicate only IDH wildtype (WT) astrocytoma, WHO grade 4, and not IDH-mutant astrocytoma, WHO grade 4 [8]. IDH-WT glioblastoma occurs de novo and its prognosis is much worse than IDH-mutant astrocytoma, WHO grade 4. IDH-mutant astrocytoma, WHO grade 4 were previously also called secondary glioblastoma, and were found in younger patients. The reality is that IDH-wildtype glioblastoma is mostly a disease of the elderly. Yet, there continues to be a lack of clarity and unresolved challenges in treatment of elderly glioblastoma patients leading to a stark contrast in survival outcomes of the elderly (median overall survival of 4 months) vs. non-elderly glioblastoma population (median overall survival 15 months) [9].

What are some unique challenges faced by elderly glioblastoma patients? Elderly patients whose initial symptoms are confusion, memory loss, fatigue or depression are often diagnosed late and have a longer lead time to radiological and pathological diagnosis as compared to patients who present with seizures [10, 11]. Stroke and transient ischemic attacks are common in the elderly population and many glioblastomas are initially misdiagnosed as sub-acute infarcts. This delay in precious lead times often results in a larger tumor size and a worse neurological state at the time of surgery and initiation of treatment. It is well known that patients who undergo resection or de-bulking over a biopsy have better survival outcomes. Yet, elderly GBM patients are more likely to get biopsy over resection due to their frailty, neurological symptom burden, co-morbidities, large tumor size and lower surgical risk tolerance by surgical team and patient families. Therefore, by the time the elderly patient is radiographically and pathologically diagnosed, their condition may have declined too far to be able to tolerate the standard 6 weeks of combined chemoradiotherapy. Their treatment is usually tailored to either hypofractionated chemoradiotherapy, hypofractionated radiotherapy (HFRT) alone or temozolomide alone [12] Even if they are able to get the standard of care 6 weeks concurrent chemoradiation and adjuvant temozolomide, the treatment toxicity is much higher as compared to the non-elderly GBMs [13] and often necessitate treatment discontinuation. The next issue is the uniqueness of tumor biology in elderly glioblastoma. Is it possible that the tumor itself is more aggressive than their non-elderly counterpart? Is the aged brain parenchyma more conducive to tumor growth? Does aging decrease systemic immune-surveillance in the elderly? Further, complex socio-economic factors come in play in regard to treatment access to the elderly. Patients often live by themselves, in assisted living facilities or nursing homes. The treatment of glioblastoma is fully outpatient, thus making it vital that a full-time caregiver be available so that the patient can access the healthcare system. This is often not the case for elderly patients, and it is a not uncommon for them to be diagnosed with GBM and be transitioned to hospice care at the time of initial hospitalization.

In the following book chapter, we closely examine each of the above issues and present the most up-to-date evidence on the unique aspects of glioblastoma in the elderly.

2. Epidemiology

The incidence of primary brain tumors increases with age [14]. Glioblastoma is the most common malignant brain tumor in the aging population and accounts for 58% of all gliomas in the elderly [15]. The definition of elderly itself is a contested topic. Some researchers consider age 65+ or even 60+ as elderly, while in general most will agree that the population over 70 is elderly. The incidence rate of glioblastoma progressively increases as we grow older—from 1.3/100,000 between the ages of 35–44, 3.6/100,000 between the ages of 45–54, 8.1/100,000 between the ages of 55–64 to the dramatically higher rate of 13/100,000 between the ages of 65–74 and 15.3/100,000 between 75 and 84 years of age [1]. According to a recent study, non-Hispanic whites make up the majority of that population, and males were 1.62 times more likely to be affected than females. The study also concluded that the incidence of glioblastoma remained stable in the past couple of years [16]. Incidence rates for glioblastomas were highest in supratentorial regions and lowest in extra-cranial regions like the spinal cord [1].

3. Signs and symptoms

In a study on 339 elderly GBM patient over the age 70, the most common presenting symptoms were confusion (38%), hemiparesis (35%), speech disturbance (34%) and seizure (29%) [17]. Another study on 189 elderly GBM patients found that patients most commonly presented with global symptoms of cognitive dysfunction, headache, dizziness and fatigue (66%), followed by loss of neurological function (58%), headache (33%) and seizure (32%) [11]. This study also found if behavioral change, memory impairment and confusion were the presenting symptoms, elderly patients had the shortest overall survival because these symptoms were misinterpreted as normal aging by patients’ families and even their healthcare teams. Patients who present with seizures had a significantly longer survival and tend to be younger [11, 18].

4. Prognostic factors

Age alone is a prognostic factor in GBM [19, 20, 21], as elderly patients usually have increased incidence of comorbidities, lower functional status [22, 23] and a unique tumor biology as compared to younger population [21]. In elderly patients with GBM, age and performance status form a complex interplay. The most common performance status assessment tool for primary brain tumors is the Karnofsky Performance Scale (KPS) [24]. A patient with a KPS of 70% is self-caring but is unable to carry on normal activity or do active work. Interestingly, a large study of over 48,000 patients with GBM over the age of 60, found that that even when performance status is good (KPS ≥ 70), overall survival is poorer with advancing age—15.2 months (age 60–69) vs. 9.6 months (age 70–79) vs. 6.8 months (age ≥ 80) [25]. A poor KPS < 70 has also been associated with a poorer overall survival as patients with a lower KPS usually cannot tolerate a more aggressive treatment (i.e., radical resection followed by chemotherapy and radiotherapy) [26].

5. Tumor biology

There are molecular, epigenetic, and genomic biomarkers unique to elderly GBMs which are associated with a worse prognosis [19, 20, 21, 26]. Elderly GBMs usually lack the isocitrate dehydrogenase (IDH) mutation, which is usually found in younger glioblastoma patients (currently, reclassified as IDH-mutant astrocytoma, WHO grade 4) and is associated with an improved prognosis [12, 27]. It is well established that methylation of DNA repair O(6)methylguanine-DNA methyltransferase (MGMT) is related to response to alkylating agents, and the lack of promoter methylation in this elderly group leads to a poor response to chemotherapy [12, 27, 28]. Fukai et al. in a cohort of 212 patients found that TERT promoter mutation, copy number alterations such as PTEN deletion and CDK4 amplification/gain, and co-amplification of MDM2 and CDK4 were more frequent in the older group (>70 years old) [20]. There was also a higher triple overlapping of PTEN, CDKN2A and EGFR in the older group, which is positively associated with tumor invasiveness and resistance to therapy [29, 30, 31].

As the central nervous system ages, markers of cellular senescence come to the fore [32, 33, 34]. One may assume that the senescent cells are growth-arrested and are the polar opposite of oncogenic cells which divide uncontrollably. However, these senescent cells release pro-inflammatory factors called secretory associated senescent phenotype (SASP) which exacerbate cancer. SASP factors such are TGF-beta, IL-6, IL-8, VEGF, matrix metalloprotein-2 (MMP-2) and MMP-9 play a role in diseases such as cancer, neuroinflammation and neurodegeneration [14, 35].

6. Preoperative assessment

Age alone, even in octogenarian and nonagenarian, should not be the criterion to exclude surgical resection [36, 37, 38, 39, 40, 41]. A comprehensive assessment using risk prediction tools for outcomes after a GBM resection in elderly patients is recommended. Patient’s performance status is commonly evaluated using KPS (100 = normal to 0 = dead) [24] or the ECOG scale (0 = fully active to 5 = dead) [36] A KPS value lower than 70 is associated with a poor prognosis [21, 38, 39] and is commonly used as a cut-off for patient enrollment for newly diagnosed glioblastoma trials. A more comprehensive appraisal using Comprehensive Geriatric Assessment (CGA) which takes in account an older patient’s functional status, comorbid medical conditions, cognition, psychological state, social support, nutritional status, and a review of the patient’s medications has demonstrated prognostic and predictive role for treatment eligibility [21, 42, 43, 44]. CGA is interdisciplinary and multidimensional evaluation that includes eight major criteria (Figure 1) to formulate a better plan to anticipate and address challenges in management of geriatric patients. Lombardi et al. in a retrospective study of 133 patients found a prognostic significance for CGA in elderly patients with GBM [43]. Cloney et al. applying The Canadian Study on Health and Aging Modified Frailty Index (CSHA-mFI) found that frailer patients, independently of age, KPS or cardiovascular risk, were less likely to undergo surgery, had a longer inpatient stay, had more post-operative complications and a shorter overall survival [45]. Thus, in this heterogeneous group a complete and thorough assessment should be performed. While CGA is mainstream in the practice of geriatric oncology, its use is not prevalent in assessment of elderly GBM patients and needs to be encouraged.

Figure 1.

Comprehensive geriatric assessment consisting in eight general topics: medical, functional, social, environmental, advanced care, spirituality and sexuality and intimacy. CGA has been advocated for elderly patients with cancer by The International Society of Geriatric Oncology.

7. Treatment overview

A radical total resection followed by combined temozolomide and standard fractionated radiotherapy (SFRT), followed by adjuvant temozolomide for six cycles, is the standard first line of treatment of glioblastoma. This treatment is based on the EORTC/NCIC study on in which 573 patients after biopsy or resection were treated with 6 weeks of focal radiotherapy (total 60 Gy in 30 fractions) vs. radiotherapy plus continuous daily temozolomide (75 mg/m² of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150–200 mg/m² for 5 days during each 28-day cycle) [6]. This seminal study found that the median survival in the radiotherapy only group was 12.1 months and was significantly improved to 14.6 months in the combined radiotherapy and chemotherapy group. It is noteworthy that this study excluded patients above the age of 70. Interestingly this study found that in patients >60 years, median survival was 11.8 months with radiotherapy alone vs. 10.9 months with combination therapy. However, this was an exploratory analysis, and no firm conclusion could be drawn from this subset.

The best treatment approach for elderly glioblastoma patients remains controversial [46]. Due to patient’s lower KPS, higher prevalence of risk factors, and the question of ability to tolerate combined standard of care 60Gy chemoradiotherapy, studies on elderly glioblastoma have focused on making the treatment regimens tolerable to patients. Patients with a poor performance status (i.e., KPS < 70) can benefit from temozolomide monotherapy (especially if MGMT promoter methylated) or radiotherapy alone [27, 28, 46, 47, 48, 49, 50]. The specific dose of radiotherapy adopted is usually different from standard protocol, as the standard radiotherapy dose of 60 Gy can be difficult to tolerate, especially when combined with temozolomide [28]. In this context, hypofractioned radiotherapy (HFRT) has shown not inferior to SFTR with less side effects [51]. Another important factor to consider is that drugs for symptomatic management such as corticosteroids and antiepileptic drugs as they are less tolerated in this group [47]. Thus, there is a need to tailor the therapy for each individual patient’s profile in this age group.

8. Surgical treatment

Some authors have questioned if age alone should be the criterion to decide whether elderly GBM patients, especially those who are 80+, should undergo a surgical resection. The surgical question on elderly GBM patients is two-pronged. First, can the elderly tolerate a major brain surgery or biopsy similar to their non-elderly counterparts? And second, does resection as opposed to biopsy only, confer a survival benefit in elderly patients similar to non-elderly patients? The hesitation for craniotomies on elderly GBM patients, hinges on the fact that octogenarians have an increased incidence of comorbidities and lower functional status, and therefore may not be good candidates for a major surgery [52]. The higher prevalence of metabolic, neurologic, cardiac comorbidities and a loss of reserve capacity seen in this age-group is associated with a lengthier hospitalization [53].

The first question on the safety and tolerance of brain surgery in elderly is answered by several retrospective studies. In a retrospective cohort study of 741 patients with surgically assessable brain tumors, of whom 570 patients were between the ages of 60 and 79 (senior) and 83 were aged 80 or above (elderly), pre- and post-operative change to modified Rankin score, surgical complications, length of stay, and 30-days readmission were performed [36]. No statistical significance was found comparing the elderly patients with their counterparts of senior and young (20–29 years) (surgical complication rates of 6, 7.2 and 4.5% respectively). Post-operative complications such as neurological deficits, infection, DVTs are similar to those described in younger patients [10, 54, 55]. Thus, it appears that surgical resection in elderly can be safely performed in specialized centers without overt risk as compared to the non-elderly population.

The second question on the benefit of surgical resection as opposed to biopsy stems from the fact that elderly GBMs inherently have a more aggressive biology [19, 21, 35] and that the survival benefit from a radical resection seen in younger GBM patients may not translate to elderly GBM patients. This answer was explored by Chaichana et al. in a retrospective study comparing biopsy in 40 elderly GBM (65 years and older) patients to resection in 40 matched elderly GBM patients [56]. Overall survival in the resection group (5.7 months) was significantly greater than the biopsy group (4 months). Surgical resection offers a better outcome and is associated with an improved quality of life [57, 58] than biopsy in elderly with GBM [26, 59, 60, 61, 62]. Gross total resection (GTR) is related to longer survival time, progression free survival and improved functional recovery without increased morbidity or mortality, when compared to subtotal resection [10, 63, 64].

9. Post-operative assessment

Length of stay (LOS) has been shown to be longer in the elderly who undergo surgery. There is a positive correlation with LOS and delirium in aged patient [65, 66]. In a study highlighting the incidence of delirium in the elderly, it was found that patients with advanced age had a higher rate of post-operative delirium (POD) and post-operative cognitive dysfunction (POCD) [67, 68]. A possible approach to dealing with POD in the elderly is to optimize pharmacologic intervention. Antipsychotic regimen and use of dexmedetomidine may reduce post-operative delirium and are possible options for pharmacologic interventions to reduce LOS [69, 70, 71]. Other factors that could influence the LOS difference between elder and younger groups are mechanical factors such as early ambulation and the use of physical therapy. Chiu et al. found that additional factors such as geriatric consultation, care giver education, and music therapy can also play an important role in decreasing LOS [72].

10. Radiotherapy

The importance of SFRT in the treatment of glioblastoma has been established more than a decade ago [6]. The time to initiate radiation treatment is between 3 and 6 weeks after surgery [6, 73]. The standard course of 60Gy divided in 30 fractions is widely used in management of glioblastoma, although it is associated with a higher incidence of radionecrosis [74], and may not be well-tolerated in elderly population [12]. Hypofractionated radiotherapy has been shown to be non-inferior to standard radiotherapy in elderly patients. A randomized phase III trial by the Nordic Clinical Brain Tumor Study Group, enrolled patients over 60 years of age in three arms—temozolomide only, standard course of radiotherapy (60 Gy, 30 fractions) or hypofractionated radiotherapy HFRT) (34 Gy, 10 fractions) [12]. There was no cut-off for performance status so that real-world scenario could be replicated. For patients aged 70 and older, outcomes were worse in the standard radiotherapy group. For temozolomide vs. hypofractionated radiotherapy, median survival was similar. Only 72% of patients in the standard radiotherapy group could complete their treatment as opposed to 94% patients in the hypofractionated group. If elderly patients had difficulty tolerating 6 weeks of radiation only, then it may be extrapolated that tolerance would be much worse if they were to receive the combined 6 weeks radiation plus concomitant temozolomide. However, this may not apply to fitter elderly patients with KPS 70 or more. A randomized trial of 695 patients testing tumor-treating fields (TTF) after standard chemoradiotherapy and adjuvant temozolomide included 134 patients aged 65 or older and KPS of 70 or higher [7]. In this group of relatively fit elderly patients, the median overall survival was 13.7 months in the adjuvant temozolomide group vs. 17.4 months in the adjuvant temozolomide plus TTF group. Though this study did not discuss the tolerability of standard chemoradiation in the elderly population, the median survival of over 12 months in the each of the elderly group suggests that elderly patients with a good KPS can in fact tolerate standard 6 weeks of chemoradiation.

HFRT schedules were developed in an effort to improve treatment tolerability and decrease the daily burden of radiotherapy treatment for elderly. In a pre-temozolomide era prospective study on 100 GBM patients, 60 years and older were treated with either HFRT (40 Gy in 15 fractions) vs. standard radiotherapy (60 Gy in 30 fractions) [75]. Overall survival was similar in HFRT group (5.6 months) as compared to the standard radiotherapy group (5.1 months). The Nordic study showed a longer survival in patients over 70 years when treated with temozolomide or HFRT as compared to standard radiotherapy [12]. Based on these studies, it appears that HFRT is at least non-inferior to standard radiotherapy in elderly patients. A small phase III prospective study on elderly and/or frail in which patients were randomized to either a very short-course RT (25 Gy in five fractions delivered over 1 week) or commonly used HFRT (40 Gy in 15 fractions delivered over 3 weeks) [51], and showed an overall survival of 7.9 months in the 1 week radiotherapy group and 6.4 months in the 3 weeks radiotherapy group. However, the 1-week short course radiotherapy for GBM is controversial, and not commonly utilized in mainstream practice.

11. Chemotherapy

The alkylating agent temozolomide is the drug of choice for glioblastoma. Traditional treatment protocol that combines temozolomide (75 mg/m²/day) with standard RT/HFRT after surgical resection followed by 200 mg/m² for 5 days with cycles repeated every 28 days for up to six cycles is the choice for patients with a good KPS (≥70) [21, 76]. Elderly glioblastoma patients who have a good KPS and reasonably controlled co-morbidities can be treated with the standard combined chemoradiation and adjuvant chemotherapy [7, 77]. No prospective study on elderly patients so far has compared standard chemoradiotherapy with hypofractionated chemoradiotherapy.

However, for fragile elderly patients who cannot tolerate the standard treatment, the use of temozolomide alone is non-inferior to standard radiation alone. A phase III randomized trial in patients older than 65 tested with dense temozolomide regimen to 6 weeks standard radiotherapy and found that temozolomide alone was non-inferior to radiotherapy alone [50]. This study also confirmed the role of MGMT as a predictive biomarker for chemotherapy monotherapy in these patients. The most common side effects described in this population are fatigue and thrombocytopenia [13]. Malmström et al., in the Nordic trial that included a arm of temozolomide found an overall survival (OS) significantly longer specially in patients above 70 years old with MGMT promoter methylated (9.7 vs. 6.8 months, compared to non- methylated). A phase III randomized trial of patients 65 years or older tested HFRT alone (40 Gy in 15 fractions) vs. HFRT concurrent with temozolomide, followed by adjuvant temozolomide [78]. The median overall survival was longer in the combined group than with radiotherapy alone (9.3 vs. 7.6 months). The benefit with combined treatment was much greater in the MGMT methylated GBMs. A non-significant survival benefit was also found in the MGMT unmethylated GBM patients. For MGMT unmethylated elderly GBM patients, RT only should be favored over temozolomide monotherapy [50].

Bevacizumab is not recommended for people with newly diagnosed glioblastoma due to high rates of adverse events and no improvement in overall survival [79, 80, 81]. In select cases, bevacizumab may be cautiously used to treat tumor-related edema and to avoid the side-effects of steroids.

12. Tumor-treating field

Tumor-treating field (TTF) is a device which is worn locally over the patient’s shaved scalp and is FDA approved for treatment of glioblastoma. It delivers low-intensity alternating electric field to the tumor and thus has an anti-mitotic effect on glioblastoma. A phase III randomized clinical trial showed that the overall survival was significantly longer in the chemoradiotherapy + adjuvant temozolomide + TTF group (20.9 months) as compared to chemoradiotherapy + adjuvant temozolomide group (16 months) [7]. This study enrolled 695 patients with glioblastoma over the age of 18 and included 134 patients aged 65 or older. Patients 65 years or older had significantly increased survival on addition of TTF vs. temozolomide alone (HR, 0.51; 95% CI, 0.33–0.77). Device side-effects are mild as compared to chemotherapy or radiation and usually consist of mild to moderate skin toxicity underneath the transducer arrays. TTF is a local therapy and needs to be worn daily for long-term, optimally for over 18 h a day. Elderly patients will often require lifestyle modification and caregiver support when using it. It can be an attractive antineoplastic therapy for elderly as it does not have systemic side-effects.

13. Conclusion

GBM is the GBM is the most common primary brain tumor in the elderly population. It has been shown that GBM has a unique more aggressive biology in aged patients. Molecular patterns have not been thoroughly elucidated yet and many of these factors are thought to have a negative impact to the prognosis in these patients. If well-tolerated, surgical treatment should aim at gross total resection, and comprehensive pre-operative assessment is recommended. An active post-operative care can reduce the length of stay in these patients and consequently, the risk of post-operative complications and the incidence of delirium. Selected elderly patients with good performance status and well-controlled co-morbidities may receive standard 6 weeks of combined chemoradiotherapy, adjuvant temozolomide and TTF or HFRT combined with temozolomide. In patients with unmethylated tumors and poor KPS patients, HFRT alone has been commonly indicated. Chemotherapy alone is an option for patients with a low performance status and whose tumor is hypermethylated. Elderly patients with GBM represent a special and vulnerable group. Treatment in the elderly and very elderly patients with glioblastoma requires an individualized plan with a multi-disciplinary team. Patient’s age, KPS, MGMT status, patient’s wishes, and even social factors should guide the overall treatment plan.