Managing elderly patients with glioblastoma presents a unique set of challenges, including a scarcity of available data, which limits evidence-based recommendations. Nearly half of patients with a new diagnosis of glioblastoma are over 65 years of age, a common cutoff point in the medical literature for identifying an elderly population. The current standard of care for glioblastoma patients younger than 70 years of age with satisfactory performance status is maximal safe resection, followed by radiation therapy of 60 Gy (delivered in 30 fractions over a 6-week period) with concurrent temozolomide chemotherapy, followed by adjuvant temozolomide. There is no consensus recommendation regarding the best available treatment for patients over age 70 with glioblastoma; however, multiple studies have shown molecular characterization of glioblastoma in this group-particularly MGMT promoter methylation status-to be valuable in treatment decision making. Results of the phase III CE6 study by the Canadian Cancer Trials Group challenge the existing treatment paradigms for glioblastoma in the elderly. This review discusses best practices for the treatment of glioblastoma in patients older than 65 years, and highlights management concerns in caring for this particular patient population.
Introduction
Glioblastoma, formerly also known as glioblastoma multiforme, is the most common primary malignant brain tumor in adults. Overall average survival is less than 15 months despite best available treatment, and survival is markedly reduced in the elderly population.[1] The 2-year survival rate of glioblastoma in patients 65 to 74 years of age is only 8.9%, and is 3.2% for patients older than 75. In the United States, the incidence of glioblastoma is 3.2 per 100,000 persons, and the median age at onset is 64 years. Nearly half of patients in the United States with a new diagnosis of glioblastoma are over age 65, which is a common age-based definition of “elderly.”[2]
Standard of care for glioblastoma in the general population
In the general population of individuals from 18 to 70 years of age with glioblastoma, Level 2 evidence supports maximum safe resection of tumor.[3] The extent of resection is an independent predictor of overall survival (OS).[3,4] The landmark randomized controlled trial by the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) established the current postsurgical standard of care for glioblastoma, with Level 1 evidence supporting radiation therapy (RT) concurrent with temozolomide chemotherapy, followed by adjuvant temozolomide.[5] The EORTC/NCIC trial demonstrated statistically significant improvement in OS with combined radiation and chemotherapy (14.6 months) over radiation therapy alone (12.1 months) for patients 18 to 70 years old with favorable performance status.[5] The addition of a portable medical device applied to the scalp that generates low-intensity alternating electric fields (Tumor Treatment Fields) was shown in a randomized open-label trial to increase progression-free survival (7.1 months vs 4.0 months; hazard ratio [HR], 0.62; 98.7% CI, 0.43–0.89) as well as OS (19.6 months vs 16.6 months; HR, 0.74; 95% CI, 0.60–0.96),[6] and was added to the US National Cancer Institute guidelines for the treatment of glioblastoma.
Concerns specific to the treatment of glioblastoma in elderly patients
Evidence-based recommendations for elderly patients with glioblastoma are limited, given that few randomized controlled trials have included patients over the age of 70. Further, existing studies did not use consistent chemotherapy regimens or RT protocols.[7] Subgroup analysis of the 5-year follow-up to the EORTC/NCIC study demonstrated declining benefit of combination therapy with increasing age.[8] However, the 2- to 5-year analysis showed benefit for combination therapy in patients over 60 years of age. In the group receiving combined treatment, 12.3% of patients over the age of 60 years were alive at 3 years, whereas in the RT-only treatment group only 2.3% had survived, suggesting a fourfold increase in survival percentage with combination therapy at the 3-year time point. While median OS did not increase for patients older than 60 who received this regimen, a subgroup of patients experienced improvement in long-term survival.[8] In the medical literature, there is disagreement over the recommended treatment for glioblastoma in elderly patients, with some authors supporting RT alone or single-agent chemotherapy with temozolomide, and others recommending combined RT with chemotherapy, following the protocol developed by the EORTC/NCIC after their landmark study. This review will discuss best-practice care in the treatment of glioblastoma patients older than 65 years of age, and highlight unique concerns regarding management of this malignancy in the elderly population.
Defining ‘elderly’
A standard definition of “elderly” in the neuro-oncology community has not been established; however, approximately 50% of patients with glioblastoma are age 65 years or older at the time of diagnosis. In the medical literature on glioblastoma, the term elderly commonly refers to patients older than 65 or 70 years of age. Most clinical trials have excluded patients older than 70; thus, high-level data are limited for this population. It remains unclear if the tumors of advanced-age patients harbor distinct molecular or epigenetic markers that have not yet been identified.[9] Multiple studies have shown performance status and comorbid conditions to be more indicative of survival and treatment tolerance than age.[10,11] Since the standard of care for younger glioblastoma patients has been clearly defined, this review will focus on patients beyond age 65.
Why Elderly Glioblastoma Patients Constitute a Distinct Clinical Population
Age is an independent prognostic factor for OS in glioblastoma. Data from the Central Brain Tumor Registry of the United States reveal that the 22.2% of glioblastoma patients between 45 and 54 years of age have an OS of 2 years, compared with 8.3% of patients between ages 65 and 74.[2] Other prognostic factors for survival include extent of resection, tumor size, performance status, and the presence of IDH1 mutation.[10,12,13] A recursive partitioning analysis of 437 glioblastoma patients older than 70 years based on age, performance status, and extent of resection resulted in four prognostic subgroups. Patients younger than 75.5 years of age who underwent resection of any extent had a median OS of 8.5 months, while patients older than 75.5 years of age undergoing gross total or partial resection had a median OS of 7.7 months. Patients undergoing biopsy only fared significantly worse: those with a Karnofsky Performance Status (KPS) ≥ 70 had a median OS of 4.3 months, whereas patients with a KPS < 70 undergoing the same procedure survived 3.1 months.[14]
Glioblastoma patients of advanced age are more likely to have a diagnostic biopsy, less likely to have maximal safe resection of their tumor, and often receive less aggressive treatment than their younger counterparts.[15,16] Further, a patient’s provider may have reservations about administering maximal therapy, since elderly patients typically have physiologic conditions that affect their ability to tolerate treatment. Older patients are often treated with polypharmacy and exhibit reduced organ reserves, manifested as myelosuppression, blunted immune response, or neurocognitive decline. Other explanations for poorer treatment outcomes in elderly patients include reduced social resources; caregiver limitations; provider-imposed treatment bias; and the possibility that glioblastoma has a distinct biology in the older patient that is demonstrated by reduced treatment tolerance and a reduced response to standard therapies.[9,17]
The Molecular Signature of Glioblastoma in the Elderly
Patients of advanced age may exhibit a distinct molecular tumor signature that has yet to be elucidated. Diagnostic biopsies in elderly patients often do not provide enough tissue for molecular characterization of the tumor. There is interest in the use of a biomarker or molecular signature to identify elderly patients likely to derive maximal benefit from specific treatments. Mutation of IDH1 has been proposed to have greater prognostic value than histologic grading in patients with high-grade glioma.[12] The presence of IDH1 mutation is indicative of a secondary glioblastoma, conveys a more favorable prognosis, and is implicated in tumorigenesis; investigation into IDH1 mutations as a therapeutic target in glioblastoma is underway.[13] IDH1 mutations are rare in the elderly population, and were identified in only 5 of 376 samples tested from the NOA-08 and Nordic trials combined.[18-20]
Subgroup analysis of data from the NOA-08 and Nordic trials suggested that MGMT promoter methylation was predictive of a favorable response to temozolomide; however, neither study was powered to answer this question with certainty.[19-21] MGMT is a DNA repair protein that blunts the effects of alkylating chemotherapy. Epigenetic silencing of MGMT identified by promotor hypermethylation downregulates DNA repair and is associated with improved survival in glioblastoma when treated with alkylating agents such as temozolomide.[22] Several groups have proposed that MGMT methylation status be used to identify elderly patients who may benefit from the addition of alkylating chemotherapy.[17,23-25] Understanding the molecular and epigenetic landscape of glioblastoma in the elderly has the potential to make it possible to personalize current treatment modalities, identify new therapies, and add prognostic value.[18]
Extent of Surgical Resection
Based on several observational studies, maximal resection with preservation of neurologic function is recommended for patients with newly diagnosed glioblastoma.[4] Retrospective studies have demonstrated improved survival with near-complete resection of enhancing tumor when compared with biopsy in patients over 65 years old with matched KPS, treatment, and tumor location.[26] Subgroup analyses of the Nordic and NOA-08 trials in addition to several nonrandomized studies have demonstrated improved median OS with debulking surgery in the elderly, compared with biopsy alone.[14,20,21] Definitive, prospective randomized trials demonstrating a survival benefit for maximal safe resection over biopsy in elderly patients with glioblastoma are lacking; however, there is an obvious need to obtain sufficient tissue for molecular analysis, since this has important implications for treatment stratification.
RT
External beam fractionated RT was the sole established therapy for glioblastoma in the general population for many years prior to the EORTC/NCIC study. Several studies have shown that RT benefits elderly patients with glioblastoma. A Surveillance, Epidemiology, and End Results Program database analysis of 2,836 glioblastoma patients over 70 years of age demonstrated that surgery combined with RT yields an OS of 8 months, compared with 4 months in patients treated with RT alone, and 3 months in patients managed with surgery alone.[27] A randomized trial in the pre-temozolomide era that included 85 patients 70 years of age and older with either grade III or grade IV gliomas demonstrated a survival benefit from RT to a total dose of 50.4 Gy in 28 fractions, compared with supportive care only. Patients had a 58% increase in median OS (29.1 weeks vs 16.9 weeks) without further compromise in health-related quality of life (QOL).[28]
A prior study showed noninferiority of hypofractionated RT (40 Gy in 15 fractions) when compared with standard RT (60 Gy in 30 fractions), with a median OS of 5.6 months and 5.2 months, respectively.[29] With hypofractionated RT, there are fewer fractions but the radiation dose is higher; the rationale for this approach is that hypofractionated therapy offers reduced treatment time for frail patients, with a limited reduction in total radiation dose to the tumor. The 2012 Nordic trial enrolled 342 glioblastoma patients over 60 years of age (median age, 70 years) to compare standard RT (60 Gy, delivered in 30 fractions) with a hypofractionated regimen (34 Gy, 10 fractions) and with chemotherapy with temozolomide. Treatment with hypofractionated radiation or single-agent temozolomide resulted in superior median OS compared with standard radiation at 60 Gy, with median OS times of 7.5, 8.3, and 6.5 months, respectively.[20] Patients in the 60-Gy RT treatment arm demonstrated reduced OS when compared with historical controls, but not all cancer centers assigned patients to this arm of the study. In particular, patients over age 70 benefited from hypofractionated RT when compared with standard RT at 60 Gy; 1-year survival rates more than doubled, at 18% vs 7%, respectively.[4] QOL data were not reported.
Chemotherapy
Temozolomide is an oral alkylating chemotherapy and the first-line chemotherapy for glioblastoma. Independent of age, patients with MGMT promotor methylation demonstrate an improved response to temozolomide.[22,24] Older patients with MGMT-methylated glioblastoma and poor functional status or significant comorbidity who are not candidates for combination therapy with radiation and chemotherapy might especially benefit from the use of single-agent temozolomide chemotherapy. Investigators of a single-arm prospective trial of temozolomide in patients over age 70 years with poor functional status (KPS ≤ 70) concluded that single-agent temozolomide had an acceptable toxicity profile. This study demonstrated a prolonged median OS when compared with historical controls, as well as an appreciable increase in performance status in one-third of the enrolled patients (Table 1).[15]
As previously described, the Nordic trial compared different radiation regimens with single-agent temozolomide and demonstrated no significant difference in OS for patients older than 70 years treated with single-agent temozolomide or hypofractionated RT at 34 Gy in 10 fractions.[20] Both temozolomide and hypofractionated RT were superior to standard RT (60 Gy in 30 fractions). Patients with MGMT promotor methylation treated with temozolomide demonstrated a 2.9-month increase in OS (9.7 months vs 6.8 months) when compared with MGMT-unmethylated patients. The NOA-08 randomized study used a different temozolomide dosing schedule of 100 mg/m2 for 7 days every other week, and compared that regimen against treatment with 60-Gy RT in patients with glioblastoma (89% of the study population) or anaplastic astrocytoma (11% of the study population) who were over 65 years of age and had a KPS > 60.[21] OS was similar in the two treatment arms. MGMT promoter methylation was again demonstrated to predict improved median OS in patients receiving temozolomide, but had no significant bearing on outcomes for the RT cohort.
The aforementioned studies reinforce the importance of obtaining molecular markers in elderly patients with glioblastoma. Patients with methylated MGMT or poor performance status, or those who are averse to undergoing RT, still might benefit from single-agent temozolomide. Glioblastoma patients without hypermethylated MGMT have a clear unmet need for more effective therapies (Table 2).
Combination Treatment: RT With Chemotherapy
The landmark EORTC/NCIC study demonstrated improved OS with combination RT and temozolomide chemotherapy for patients 18 to 70 years of age with favorable performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 2, compared with RT alone.[5] There is evidence to support that temozolomide enhances the efficacy of RT when used in combination therapy. Multiple retrospective reviews and prospective nonrandomized single-arm studies of RT with concurrent temozolomide chemotherapy followed by adjuvant temozolomide have been conducted in the elderly population, including evaluation of standard and hypofractionated RT regimens. In the EORTC/NCIC study, the benefit of combination therapy as measured by OS was reduced with increasing age. The 190 patients over age 60 experienced no significant improvement in median OS with combination therapy (10.9 months vs 11.8 months); however, the patients receiving combination treatment demonstrated greater long-term OS rates at 2 years (21.8% vs 5.7%, respectively), 3 years (12.3% vs 2.3%, respectively), 4 years (8.8% vs 2.3%, respectively), and 5 years (6.6% vs 0%, respectively).[8] In this study, the authors did not report on the impact of MGMT methylation on long-term survival of patients over 60 years of age.
KEY POINTS
- Radiation therapy with concurrent temozolomide followed by adjuvant temozolomide is recommended for patients over age 65 with favorable performance status.
- Patients with poor performance status and advanced cancer should receive palliative care early in the disease course, concurrent with active treatment, to limit symptoms and maximize quality of life.
- Molecular analysis, including evaluation of MGMT promoter methylation status, is often of value in selecting initial treatment for elderly patients with glioblastoma.
- Clinical trials in glioblastoma should include elderly patients, to establish consensus standard-of-care recommendations.
Perry et al recently published the preliminary results of the Canadian Cancer Trials Group (CCTG) CE6 study, a phase III randomized controlled trial of hypofractionated RT (40 Gy in 15 fractions) with or without concurrent and adjuvant temozolomide in glioblastoma patients over age 65.[30] This is the first randomized study demonstrating benefit from combination therapy with hypofractionated RT and temozolomide in elderly patients with glioblastoma, compared with hypofractionated RT alone (Table 1). Eligible patients were at least 65 years old with an ECOG score less than 2. A total of 562 patients were enrolled; patients were 65 to 90 years of age (median age, 73 years). In the enrolled group, 68% underwent partial or complete resection, and MGMT methylation status was available for 354 of these patients.
Results of this study suggest a significantly improved OS with RT plus temozolomide compared with RT alone (9.3 vs 7.6 months; P < .0001). Progression-free survival was also improved (5.3 months in patients randomized to chemoradiation therapy vs 3.9 months in patients treated with RT alone; P < .0001).[30] Benefit with combination therapy was most notable in MGMT-methylated patients, with a 5.8-month increase in median OS (13.5 months vs 7.7 months). Patients with unmethylated MGMT also seemed to benefit from the combined regimen; however, while the survival analysis showed a strong trend in this regard, the median OS outcomes fell slightly short of statistical significance (10.0 months vs 7.9 months; HR, 0.75; 95% CI, 0.56–1.01; P = .055) (see Table 2). QOL outcomes were similar for functional domains, but patients receiving temozolomide had more chemotherapy-related side effects, such as nausea, vomiting, and constipation. These results suggest that hypofractionated RT with concurrent temozolomide followed by adjuvant temozolomide should be considered in patients over age 70 with glioblastoma. Since there was no comparison arm with standard RT plus temozolomide, it remains unclear how the hypofractionated regimen compares with the standard of care used in younger patients. Further investigation is needed to compare outcomes of combination treatment with chemotherapy plus hypofractionated RT against the traditional 60-Gy regimen of the EORTC/NCIC study (Figure).
Translational Opportunities for Glioblastoma Treatment in the Elderly
Promising translational therapies for the treatment of glioblastoma are in development. It is not known how elderly patients will respond to, or tolerate, treatment with contemporary investigational agents for glioblastoma-which include molecular targeted therapies; immunotherapy; vaccine treatments; virus-based treatments; and advanced surgical techniques, such as laser interstitial thermal therapy, intraoperative enhanced tumor visualization employing 5-aminolevulinic acid fluorescence to enhance tumor visualization, and other novel technologies. Recent advances have altered our understanding of the molecular and epigenetic landscape of glioblastoma management, and have the potential to uncover distinct glioblastoma phenotypes in the elderly population, and in turn to better identify the most appropriate treatment for individual patients. Currently, however, meaningful molecular profiling of tumors typically requires more tissue than is routinely acquired by a standard needle biopsy.
Immunotherapy
Immunotherapy has shown promise in many systemic cancers, and a variety of immunotherapeutic approaches to the treatment of central nervous system tumors are now being studied. Importantly, however, translation of current immunotherapy strategies for use in elderly patients is met with concern about reduced functional reserve and the impairment of adaptive and innate immunity with advanced age (ie, immunosenescence). Ongoing clinical trials in glioblastoma are investigating therapy with checkpoint inhibitors, which essentially unmask the tumor to the immune system; these agents block immune inhibitory “checkpoint” signals, thought to be upregulated in glioblastoma, which prevent the immune system from identifying and destroying tumor cells. In a study of recurrent melanoma, safety and efficacy of the immune checkpoint inhibitor ipilimumab, a monoclonal antibody against the T-cell inhibitory effects of cytotoxic T-lymphocyte–associated antigen 4, were investigated in 193 patients over 70 years of age, with 27 of the patients older than 80 years. Treatment with ipilimumab was well tolerated and, in a pattern similar to that observed previously in a younger population of patients with melanoma, extended survival in these elderly patients.[31] Immunotherapy is being actively investigated as potential therapy for glioblastoma in multiple clinical trials (ClinicalTrials.gov identifiers: NCT02667587, NCT00045968, NCT02617589), and may hold promise for the management of patients of advanced age.
Supportive Care
Elderly patients with glioblastoma often suffer from significant symptom burden, and many studies in the medical literature report median OS times of less than 12 months. The new American Society of Clinical Oncology guideline on integration of palliative care into standard oncology care recommends that patients with limited survival and advanced cancer should receive active palliative care early in the disease course and concurrent with active treatment.[32] Neurologic symptom burden and behavioral health of the patient and caregivers should be monitored throughout the disease course, and the early involvement of palliative care services is recommended to decrease symptoms and to maintain QOL.[33] Despite the lack of prospective data on patients with brain tumors, evidence from studies of patients with advanced lung cancer demonstrated that early involvement of a palliative care team can improve patients’ QOL, symptom burden, and even survival.[34] The care of elderly patients with glioblastoma requires a multidisciplinary team approach and a personalized understanding of patients’ specific needs, including prospective integration of support services to maintain and improve QOL at all stages of the disease and to integrate proactive advanced care planning.
Conclusion
The treatment of glioblastoma in elderly patients presents unique management challenges. Further research is needed to shed light on the molecular and epigenetic landscape of glioblastoma in patients of advanced age-most importantly in terms of questions and concerns related to treatment efficacy, tolerance of available therapies, and the distinct supportive care needs of this population. Data from the CCTG’s CE6 trial support the combination of hypofractionated RT with temozolomide in patients older than 65 years of age harboring MGMT methylation, with questionable benefit in those without MGMT methylation. There is a critical need for a randomized controlled trial comparing the current standard of care in glioblastoma against both the EORTC/NCIC protocol and the use of combination therapy with hypofractionated RT and temozolomide in elderly patients affected by this malignancy.
Financial Disclosure:Dr. Walbert serves on the advisory board of Novocure. Dr. Snyder has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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