Radiation therapy for older patients with brain tumors
© The Author(s). 2017
Received: 21 March 2017
Accepted: 13 June 2017
Published: 19 June 2017
The incidence of brain tumors in the elderly population has increased over the last few decades. Current treatment includes surgery, radiotherapy and chemotherapy, but the optimal management of older patients with brain tumors remains a matter of debate, since aggressive radiation treatments in this population may be associated with high risks of neurological toxicity and deterioration of quality of life. For such patients, a careful clinical status assessment is mandatory both for clinical decision making and for designing randomized trials to adequately evaluate the optimal combination of radiotherapy and chemotherapy.
Several randomized studies have demonstrated the efficacy and safety of chemotherapy for patients with glioblastoma or lymphoma; however, the use of radiotherapy given in association with chemotherapy or as salvage therapy remains an effective treatment option associated with survival benefit. Stereotactic techniques are increasingly used for the treatment of patients with brain metastases and benign tumors, including pituitary adenomas, meningiomas and acoustic neuromas. Although no randomized trials have proven the superiority of SRS over other radiation techniques in older patients with brain metastases or benign brain tumors, data extracted from recent randomized studies and large retrospective series suggest that SRS is an effective approach in such patients associated with survival advantages and toxicity profile similar to those observed in young adults. Future trials need to investigate the optimal radiation techniques and dose/fractionation schedules in older patients with brain tumors with regard to clinical outcomes, neurocognitive function, and quality of life.
KeywordsBrain tumors Elderly Radiotherapy Chemotherapy Radiosurgery
Cancer is most frequently diagnosed among individuals aged 65 years and older [1–3], and the number of older patients with cancer will increase in the future as result of increasing life expectancy of the population . As for other cancers, the incidence of either malignant or benign brain tumors has been increasing in the elderly population , representing an important aspect of public health.
Radiotherapy (RT) given alone or in combination with systemic therapy is a cornerstone of the multidisciplinary management of brain tumors and remains an attractive option for older patients . Advances in radiation planning and dose delivery have improved the safety and efficacy of RT, although irradiation of brain tumors is particularly challenging in older patients because of the potential increased radiation-induced toxicity secondary to comorbidities, impaired functional status and neurocognitive function. In addition, older patients are under-represented in randomized controlled clinical trials and clinicians need to extrapolate data from studies done with a much younger cohort. However, treating older patients is not the same as treating patients in their 50s or 60s. The clinical behavior of some tumors changes with age. Some become more aggressive due to a high prevalence of unfavorable genomic changes or resistance to chemotherapy. For these reasons, treatment paradigms for older patients with brain tumors are not well defined.
The purpose of this review is to summarize the published literature on the clinical outcomes of RT for the most common brain tumors in the elderly population, and to address important issues such as optimal radiation dose and fractionation, combining RT with systemic therapy, quality of life and neurocognitive function after RT, and future research priorities for this population.
A literature search was conducted in MEDLINE PubMed evaluating older people with brain tumors. The search focused on randomized, prospective and retrospective studies published in English. The literature search was performed using a combination of medical subject headings (MeSH) (“brain tumors/radiotherapy” or “gliomas” or “brain metastases” or “lymphomas” or “meningiomas” or “pituitary adenomas” or “acoustic neuromas” or “older” or “elderly”) and free text terms (“toxicity” or “radiosurgery” or “fractionated stereotactic radiotherapy” or “chemotherapy” or “chemoradiation”). Relevant prospective and retrospective studies published from 1990 to 2017 were included. Studies published in languages other than English or not involving human subjects were not reviewed. There was no definitive age cutoff used for defining older patients. A total of 312 potentially relevant studies were identified, including 47 prospective/randomized studies and 265 retrospective studies. The results of the literature research were used and included if appropriate.
General aspects of radiation treatment in older patients
The aging process is characterized by a decrease in the function of various organ systems, as well functional, cognitive, emotional, and socioeconomic changes [6, 7]. It is also associated with an increased incidence of comorbidities and geriatric syndromes. Common geriatric syndromes include delirium, gait imbalance, malnutrition, and incontinence that can complicate treatments and may increase patient morbidity . When considering the appropriate therapy for an older patient with cancer, a baseline assessment of these multiple factors can be useful to determine if a patient is fit or frail [9–11]. Fit older adults have few comorbidities, no functional deficits, any or few geriatric syndromes, and generally may be considered appropriate for the same therapies used in younger adults. In contrast, frail patients have difficulty of maintaining functional independence, multiple chronic conditions and geriatric syndromes that make them more vulnerable to toxicities from therapy. In order to help cancer specialists to determine the best treatment for their older patients, the U.S. National Comprehensive Cancer Network, the European Society of Breast Cancer Specialists, the International Society of Geriatric Oncology (SIOG), and the European Organization for the Research and Treatment of Cancer have recommended the use of a comprehensive geriatric assessment (GA) in older patients with cancer [12–16].
A GA is a multidisciplinary diagnostic process that evaluates the risk of adverse outcomes of death and functional decline in older cancer patients. A comprehensive GA includes the evaluation of functional status, cognitive function, nutritional status, comorbidities, polipharmacy, and socioeconomic status in every older cancer patient with the aim of developing the optimal treatment plan. Several systematic reviews have showed that GA is beneficial in improving outcome and reducing the risk of adverse outcomes [17–19].
Domains of geriatric assessment and examples of instruments used for each domain
Commonly used instruments
Timed up and go 
Self-reported number of falls
Short Physical performance battery 
Activities of daily living (ADLs)
Instrumental activities of daily living (IADLs)
Mini Mental State Examination
Montreal cognitive Assessment
Blessed Orientation Memory Concentration Test
Clock Drawing Test
Memorial Delirium Assessment Scale
Charlson Comorbidity Index (CGI)
Cumulative Illness Rating Scale-Geriatrics (CIRS-G)
Geriatric depression scale
hospitalized anxiety and depression scale
patient health questionnaire
Body mass index
Mini Nutritional Assessment Short Form
Medication Appropriateness index
Lubben Social Network Scale
A full comprehensive GA takes an average between 30 and 120 min and this may limit its use in all older cancer patients in a busy clinical practice. Thus, several screening tests have been developed and implemented in daily practice. The most widely used screening instruments are the G8 , the abbreviated comprehensive geriatric assessment (aCGA) , the Groningen frailty indicator (GFI) , and the vulnerable elders survey-13 (VES-13) . In general, those older adults who scored above the cutoff of the screening instruments should receive a complete GA.
In summary, GA is a critical process that can help to identify fit, vulnerable, or frail older cancer patients. Its use should be implemented in clinical practice to help oncologists to guide cancer treatment decision-making and improve function and quality of life of older patients. GA models need to be incorporated in future clinical trials in order to validate their effectiveness in older patients with brain cancer treated with RT and/or chemotherapy.
Glioblastoma (GBM) is the most common primary brain tumor in adults, with an incidence rate among elderly patients of 70 years and older of 17.5 per 100,000 person-years, and a relative risk of 3–4 times compared with young adults .
RT is frequently used in older patients with GBM. Its superiority over supportive care alone has been demonstrated in a French multi-institutional randomized trial of 85 elderly patients aged 70 years and older . The median survival and progression-free survival times were 29.1 and 14.9 weeks in patients treated with RT (50 Gy given in daily fractions of 1.8 Gy) plus supportive care, and 16.9 and 5.4 weeks for those treated with supportive care alone (p = 0.002), respectively. As compared with supportive care, RT did not cause further deterioration in KPS, quality of life and cognitive function.
Selected published studies on radiotherapy or chemotherapy in older patients with high.grade gliomas/glioblastomas
Type of study
RT dose Gy/fractions
Median PFS months
Median OS months
Bauman GS et al. 
Ford JM et al. 
4 (11% at 1 year)
Hoegler DB et al. 
McAleese JJ et al. 
65-70 ≥ 70
37% at 6 months 41% at 6 months
Chinot O et al. 
5 (15% at 1 year)
6.4 (25% at 1 years)
Roa W et al. 
≥60 ≥ 60
Keime-Guiber F et al. 
≥70 ≥ 70
Gallego Perez-Larraya et al. 
4 (6.5% at at 1 year)
6 (11.4% at 1 year)
Malmstrom et al. 
100 98 93
>60 > 60
60/30 34/10 no
no no TMZ°
NA NA NA
6 (17% at 1 year) 7.5 (23% at 1 year) 8.3 (27% at 1 year)
Wick et al. 
>65 > 65
no TMZ °°
4.7 (9.3% at 1 year) 3.3 (12% at 1 year)
9.6 (37.4% at 1 year) 8.6 (34.4% at 1 year)
Roa et al. 
≥65 ≥ 65
In a recent Canadian study of 98 frail and/or elderly patients with GBM randomized to receive two different hypofractionated radiation schedules, Roa et al.  observed median overall survival times of 7.9 months (95% CI, 6.3 to 9.6 months) in patients who received 25 Gy in five daily fractions and 6.4 months (95% CI, 5.1 to 7.6 months) in those receiving 40 Gy in 15 daily fractions over 3 weeks (p = 0.9), with a similar median progression-free survival times of 4.2 months in both groups. With a median follow-up time of 6.3 months, the quality of life between groups at 4 weeks and 8 weeks after treatment was not different.
The main concern about the use of a radical course of RT in older patients with GBM is the potential high incidence of radiation-induced neurological toxicity and deterioration of quality of life. Roa et al.  reported no significant differences in KPS scores over time between standard RT and hypofractionated RT, although 49% of patients treated with standard RT required an increase in corticosteroid dosage as compared with 23% of patients who received short-term RT (p = 0.02). Similarly, in the Nordic study no significant differences were observed in physical, role, emotional, social, and cognitive functioning, and global health status between patients receiving standard RT or hypofractionated RT . However, data should be interpreted with caution because of the low number of completed questionnaires. In a prospective series of 43 elderly patients aged 70 years and older with GBM who received hypofractionated RT given at the dose of 30 Gy in 6 fractions over 2 weeks followed by adjuvant TMZ, no negative effects of treatment on KPS and health-related quality of life scores were observed . Analysis of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QOL) C-30 questionnaires showed that global health status and several functioning scales, including physical, role, emotional, social, and cognitive functioning, did not deteriorate in the majority of patients until tumor progression. An improved functional status has been reported by others using other hypofractionated schedules [45, 48].
The use of chemotherapy as an alternative to RT in older patients with malignant gliomas has been addressed in a few prospective and randomized studies [49, 51–53] (Table 2). In the German Neuro-oncology Working Group (NOA) phase 3 trial (NOA-08), 373 patients older than 65 years with histologically confirmed anaplastic astrocytoma or GBM, and a KPS score ≥ 60, were randomly assigned to receive dose-dense TMZ (1 week on, 1 week off schedule, 100 mg/m2 given on days 1–7) or standard RT . Median event-free survival time was 3.3 months for patients treated with TMZ and 4.7 months for those treated with standard RT (hazard ratio 1.15, 95% CI 0.92–1.43, p = 0.03), respectively. Median survival was 8.6 months for patients treated with TMZ and 9.6 months for those treated with standard RT (hazard ratio 1.09, 95% CI 0.84–1.42, p = 0.03), respectively, indicating that chemotherapy was non-inferior to standard RT. Analysis of health-related quality of life scales showed no significant differences between groups; however, grade 2–4 adverse events were more frequent in the TMZ group. A striking finding of the study was the predictive role of O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation status on survival outcomes. MGMT promoter methylation was associated with longer survival (median 11.9 months vs 8.2 months; hazard ratio 0.62, 95% CI 0.42–0.91, p = 0.014) and longer event-free survival (median 5.7 months vs 3.5 months; hazard ratio 0.5, CI 0.36–0.68, p < 0.001) than unmethylated status. The presence of MGMT promoter methylation was associated with better event-free survival time only in patients who received TMZ, but not in patients who received RT, whereas the opposite was true for patients with unmethylated tumor.
In the Nordic study , no survival differences were observed amongst patients aged 60–70 years who received standard RT, hypofractionated RT or TMZ; however, for patients older than 70 years median overall survival was better with TMZ and hypofractionated RT than with standard RT (9.0 and 7.0 months vs 5.2 months, p < 0.0001 and p = 0.02). Data for health-related quality of life, including cognitive functioning and global health status, were generally better in patients who received TMZ than in those who received RT; however, because of the low number of completed questionnaires results need to be interpreted with caution. As for the NOA-8 trial, the study confirmed the predictive value of MGMT promoter methylation. Amongst patients treated with TMZ, median overall survival was 9.7 months for those with methylated tumors and 6.8 for those with unmethylated tumors (p = 0.02). In contrast, MGMT methylation status did not affect survival in patients treated with RT (8.2 months in methylated vs 7.0 months in unmethylated tumors, p = 0.81).
Selected studies on combined radiochemotherapy in older patients with glioblastoma
Type of study
RT dose Gy/fractions
median PFS months
median OS months
Brandes et al. 
24 32 22
≥65 ≥ 65 ≥ 65
59.4/33 59.4/33 59.4/33
no PCV TMZ
5.3 (8.3% at 1 year) 6.9 (15.6% at 1 year) 10.7 (47.4% at 1 year)
11.2 (31.6% at 1 year) 12.7 (56.2% at 1 year) 14.9 (72.5% at 1 year)
Minniti G et al. 
6.7 (16% at 1 year)
10.8 (37% at 1 year)
Brandes et al. 
9.5 (35% at 1 year)
13.7 (31.4% at 2 years)
Minniti G et al. 
6.3 (12% at 1 year)
9.3 (35% at 1 year)
Minniti et al. 
6 (20% at 1 years
12.4 (58% at 1 year)
Perry et al. 
>65 > 65
4.7 (9.3% at 1 year) 3.3 (12% at 1 year)
9.6 (37.4% at 1 year) 8.6 (34.4% at 1 year)
The use of hypofractionated RT using a dose of 40 Gy given in 15 daily fractions in association with concomitant and adjuvant TMZ has been evaluated in a phase 2 trial in 70 patients aged 70 years and older with newly diagnosed GBM . The median overall survival time and 1-year survival rate were 12.4 months and 58%; respective progression-free survivals were 6 months and 20%. MGMT promoter methylation was the most significant favorable prognostic factor for survival. The 1-year and 2-year survival rates were 81 and 20% in MGMT methylated tumors, and 32 and 0% in MGMT unmethylated tumors, respectively (p = 0.0001). The treatment was well tolerated and was consistently associated with improvement or stability in most of health-related quality of life scales . Global health, social functioning, and cognitive functioning scores improved significantly between baseline and 6-month follow-up.
Results of the intergroup EORTC 26062-22061-NCIC Clinical Trials Group (NCI-CTG) CE6 randomized trial comparing the same regimen of hypofractionated RT (40 Gy in 15 fractions) to hypofractionated RT plus concomitant and adjuvant TMZ in 562 patients older than 65 years old with newly diagnosed GBM have been recently published . RT plus TMZ significantly improved overall survival time (9.3 vs 7.6 months, p < 0.0001) and progression-free survival (5.3 vs 3.9 months, p < 0.0001) over RT alone. MGMT methylation status was the strongest prognostic factor for survival. Amongs 165 patients with methylated MGMT status, overall survival was 13.5 months and 7.7 months in RT + TMZ group and RT group, respectively (p = 0.0001); in unmethylated patients, respective overall survival was 10.0 months and 7.9 months (p = 0.055). Analyses of quality of life assessed by the EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30) and the EORTC brain module (QLQ-BN20) showed that nausea and constipation were worse during chemoradiotherapy than during RT alone, but changes in the scores of all other symptom and function domains were similar in the two groups. In a large retrospective study of 243 older patients with GBM of 65 years or older who received standard RT or short-course RT plus concomitant and adjuvant temozolomide, the two treatments resulted in similar survival benefits of about 12 months, although short-course RT was associated with lower risks of neurological deterioration.
In summary, RT remains an essential treatment options in older patients with newly diagnosed GBM. An abbreviated course of RT may provide survival benefits similar to those reported with radical RT, maintaining an acceptable quality of life and potentially avoiding the long-term toxicity of more aggressive treatments. TMZ may represent a reasonable treatment option in older patients with MGMT promoter methylated tumors that is associated with survival benefit similar or even better than that reported with standard RT. In contrast, TMZ produces no benefit in patients with unmethylated tumors, and its use as initial treatment is not recommended. Recent studies have clearly demonstrated that the addition of concomitant and adjuvant TMZ to an abbreviated course of RT is a safe and more effective treatment for older patients with GBM as compared with RT alone, suggesting that chemoradiation can be considered the standard therapeutic option for this population.
Primary central nervous system lymphoma
The incidence of primary central nervous system lymphoma (PCNSL), a lymphoproliferative disorder that may affect the brain, eyes, spinal cord or leptomeninges in absence of systemic involvement, is 3–4% of all primary brain tumors . PCNSL has a predilection for the elderly population, with a median age at diagnosis of 55 years and a peak incidence in the sixth and seventh decades of life [69, 70]. Whole brain radiation therapy (WBRT) was historically the modality of choice to treat PCNSL until the early 1990s. PCNSL responds relatively quickly to RT, and the complete disappearance of enhancing tumor masses is frequently observed. However, local recurrence and intracranial progression at distant brain sites occurs within few months, and the reported survival outcome of patients treated by radiation alone is relatively poor [71, 72].
A combination of chemotherapy and WBRT has been evaluated in several studies in order to improve the disappointing survival observed after WBRT alone. High-dose methotrexate (hd-MTX) is currently the cornerstone of treatment of PCNSL with or without consolidation WBRT [73–75]; RT is typically given at 36–45 Gy in 1.6–1.8 Gy/fraction, with the aim to delay progression and improve survival. The superiority of combination of hd-MTX and radiation over radiation alone has been observed in several studies [76–78], even if a formal comparison has never been carried out; however, combined modality therapy appears to be associated with an increased risk of neurotoxicity, and its use has been questioned particularly in older patients [79, 80]. In a study of 31 patients with PCNSL treated with hd-MTX, WBRT, and high-dose cytarabine, Abrey et al.  observed an incidence of severe late treatment-related toxicity in nearly one third of patients, with those of 60 years and older of age at higher risk (p < 0.0001).
Selected prospective studies on radio/chemotherapy in older patients with primary central nervous system lymphoma (PCNSL)
Type of study
Median PFS months
Median OS months
O’Neill et al. 
single arm phase II
CHOP and HD-ARAC
50,4 Gy WB
6.2, 25% at 1 year
8, 14% at 2 year
Fritsch et al. 
single arm phase II
31% at 3 years
31% at 3 years
Ghesquières et al. 
multicenter phase II
61-70 > 70
20 Gy WB 30 Gy boost
61-70, 2% at 5 years >70, 11% at 5 years
61-70, 31% at 5 years >70, 17% at 5 years
Hoang-Xuan et al. 
multicenter phase II
hd-MTX, lomustine, procarbazine, intrathecal MTX and ARA-C
40% at 1 year
Illerhaus G et al. 
multicenter phase II
hd-MTX, procarbazine, CCNU
50 Gy WB for not responders
15.4 (33% at 5 years)
Laack et al. 
multicenter phase II
41.4 Gy WB 9 Gy boost
3.4, 32% at 6 months
5.5, 37% at 6 months
Roth P et al. 
multicenter phase II (G-PCNSL-SG-1)
4 (16.1 for complete responders)
While these studies indicate that WBRT can be withheld and a radiological surveillance policy adopted for older patients who achieve complete remission, RT should be considered for those with residual disease after chemotherapy or in patients whose medical comorbidity precludes chemotherapy. An alternative approach to standard WBRT in older patients is represented by the use of low-dose consolidative RT, in the effort of maintaining the potential benefit of radiation while limiting the risk of neurotoxicity [89, 90]. In a phase II study conducted at Memorial Sloan Kettering, 52 patients were treated with WBRT, using 23.4 Gy in 1.8 Gy fractions after hd-MTX, rituximab, vincristine and procarbazine, and 2 cycles of consolidative high-dose Ara-C. Results, with rigorous neurocognitive testing, showed very good disease control (35% of patients relapsed) with minimal neurotoxicity . In another retrospective series of 33 patients with PCNSL who received consolidation WBRT after HD-MTX, Ferreri et al.  observed no significant difference in disease control between patients who received WBRT doses ≥40 Gy or doses of 30–36 Gy (relapse rate, 46 vs. 30%; 5-year failure-free survival, 51 vs. 50%; p = 0.26). Currently, the randomized phase II study RTOG 1114 is exploring the effects of rituximab, methotrexate, procarbazine, vincristine and cytarabine with and without low-Dose WBRT for PCNSL. A few series suggest that the use of partial brain irradiation may be considered in patients with a single tumor [72, 91]; however, in current clinical practice WBRT remains the standard technical approach (including optic nerves and with a lower limit at C1-C2).
In summary, most studies support the use of chemotherapy-only treatments for elderly patients given the high risks of neurotoxicity associated with radiotherapy. Despite the concerns about the detrimental neurocognitive effects of WBRT in the elderly population with PCNSL, it should not be forgotten that WBRT maintains an important palliative role in patients achieving partial response, or who are not candidate for hd-MTX based chemotherapy. Patients unfit for a protracted course of RT can be offered low-dose WBRT or a course of hypo-fractionated RT (e.g. 30 Gy/10 fractions). For very elderly patients who are too confused to undergo RT safely, palliative management with steroids alone may be the preferred option.
Brain metastases occur in up to 40% of patients with cancer, and treatment options include supportive care, surgery and RT. WBRT has classically been the standard treatment for patients with brain metastases with a reported median survival of 3–6 months . Older age has been reported as an unfavorable prognostic factor for survival [93–95]; using recursive portioning analysis (RPA) the Radiation Therapy Oncology Group (RTOG) has analyzed 1200 patients treated with WBRT enrolled in three consecutive RTOG trials conducted between 1979 and 1993, describing three prognostic classes defined by age, KPS, and disease status . The reported survival for patients of 65 years and over (RPA class II and III) was less than 5 months, with the worst outcome observed in patients with a KPS < 70 (RPA class III). In addition, the use of WBRT has been associated with the risk of neurocognitive deterioration [96–99], and this is of concern especially in older patients.
SRS has been increasingly used in the initial management of patients with brain metastases. The rationale for this approach is to achieve local control while avoiding the risk of the detrimental neurocognitive effects of WBRT. Although no prospective trials have been specifically addressed the clinical outcomes of SRS in older patients with brain metastases, data extracted from three randomized studies comparing the use of WBRT plus SRS versus SRS alone in patients of all ages show no significant survival differences between younger and older patients [99–103]. Aoyama et al.  reported 132 patients with 1 to 4 brain metastases randomized to receive WBRT plus SRS or SRS alone. The use of SRS alone resulted in a similar survival and risk of neurologic death as compared with WBRT plus SRS, with no significant differences between patients < 65 years and those ≥ 65 years. In another randomized trial of 213 patients with 1 to 3 brain metastases treated with SRS or SRS plus WBRT between February 2002 and December 2013, Brown et al.  reported similar median overall survival times of 7.4 months for patients who received SRS plus WBRT and 10.4 months for those receiving SRS alone (hazard ratio 1.02; 95% CI, 0.75–1.38; p = 0.9). Analysis by age, extracranial disease status, and number of brain metastases revealed no survival benefit in any group. Similar overall survival times in the range of 6 to 12 months without a clinically significant neurocognitive decline have been reported in few retrospective series of older patients with brain metastases treated with SRS [104–106].
Interestingly, the recently proposed diagnosis-specific graded prognostic assessment (DS-GPA) score offers different patterns of diagnosis-specific prognostic factors and seems more appropriate than RPA Classes in predicting the outcome that can be expected from the various treatment options in the elderly population . According to the DS-GPA scores, number of metastases and/or KPS, but not age, are significant prognostic factors for survival in several types of cancer, including breast cancer, renal cell cancer, gastrointestinal cancer, and melanoma.
The main reason for using SRS alone is that WBRT may be associated with a decline in quality of life [108, 109] and neurocognitive function [98, 99, 101, 103]. In 58 patients with 1 to 3 metastases randomly assigned to receive WBRT plus SRS or SRS alone, Chang et al.  observed that patients treated with SRS plus WBRT were significantly more likely to show a decline in learning and memory function at 4 months than patients assigned to receive SRS alone. In another randomized trial comparing the cognitive function in patients treated with SRS alone or SRS plus WBRT, Brown et al.  observed significantly less cognitive deterioration at 3 months after SRS alone as compared with SRS plus WBRT (difference, −28.2%; 90%CI, −41.9% to −14.4%; p < .001). In addition, overall quality of life was higher at 3 months after SRS alone (mean change from baseline, −0.1 vs −12.0 points; mean difference, 11.9; 95%CI, 4.8–19.0 points; p = 0.001).
Two recent studies have evaluated the protective effects of memantine and IMRT planning for hippocampus sparing on cognitive function among patients receiving WBRT for brain metastases [110, 111]. In the phase III RTOG 0614, 508 adult patients were randomized to receive WBRT with placebo or memantine (20 mg/d) for 24 weeks . The study failed to demonstrate a significant less decline in delayed recall in the memantine arm (p = 0.059), possibly due to the low number of analyzable patients at 24 weeks; however, patients receiving memantine had better cognitive function over time as compared with those receiving WBRT alone; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed. In the RTOG 0933 single-arm phase II study of 113 patients who received WBRT with hippocampal sparing for brain metastases, results of cognitive function and health-related QOL, assessed by the Hopkins Verbal Learning Test–Revised Delayed Recall and the Functional Assessment of Cancer Therapy–Brain subscale (FACT-BR), respectively, were compared with those observed in prespecified historical control of patients treated with standard WBRT (30 Gy in 10 fractions) . Among 42 patients who were analyzable at 4 months, mean relative decline in delayed recall from baseline to 4 months was 7.0% (95% CI, −4.7 to 18.7%), being significantly lower than historical control (p < .001); no decline in QOL scores was observed. Based on these results, a randomized phase III trial exploring the use of memantine and WBRT with or without hippocampal avoidance in patients with brain metastases has been activated (https://clinicaltrials.gov/ct2/show/NCT02360215).
In summary, data extracted from randomized trials and retrospective studies suggest that SRS is a reasonable approach to older patients with a limited number of brain metastases with both survival benefit and toxicity profile similar to those observed in young adults. Future randomized studies need to investigate the advantages of such approach in the elderly in terms of survival and quality of life over other treatment options.
Incidence of benign tumors, including meningiomas, acoustic neuromas and pituitary adenomas increases with age . Meningiomas constitute the most common non-glial brain tumor histological type and accounts for approximately 12–20% of all primary intracranial tumors. The risk for developing meningioma grows with age and increases dramatically after the age of 65, reaching a peak at the seventh decade of life. An incidence of 8.5 per 100,000 persons per year has been recorded among elderly people, which is significantly higher compared to 1–2.8 cases per 100,000 persons per year estimated for the general population [4, 112]. While surgery has traditionally been the mainstay of treatment of symptomatic and fast growing tumors in all age groups, RT is frequently employed after incomplete resection, recurrent tumors, or for patients at risk of severe morbidity with a reported excellent local control and low toxicity .
In general, large published series including patients of all ages with a meningioma treated with either SRS or fractionated stereotactic RT (FSRT) reported no differences in local control and treatment-related toxicity between younger and older patients [114–121]. Two retrospective studies have assessed the outcome of FSRT in older patients with meningiomas [122, 123]. In a series of 121 patients treated with FSRT (55.8 Gy in 1.8 Gy fractions), hypofractionated stereotactic RT (25-35Gy in 5–7 fractions) or SRS (15–18 Gy), Fokas et al.  reported a similar local control of about 95% at 5 years, with no new neurologic deficits, radiation necrosis or radiation-induced secondary malignancies. In another study of 100 patients aged 65 or older (median age 71 years) treated with FSRT (56.5 Gy), hypofractionated stereotactic RT (36.3 Gy in 5–7 fractions) or single-fraction SRS (17.6 Gy), Kaul et al.  observed a 5-year local control of 91.1%, with no grade 2 or 3 neurological toxicity. No study have specifically addressed the outcome of RT in older patients with either secreting or nonsecreting pituitary adenomas, and acoustic neuromas; however, data reported in large retrospective studies and systematic reviews show similar local control and toxicity between young and older patients after either SRS or FSRT [124–142]. Single-fractions doses of 13–16 Gy and 20–28 Gy are usually employed for non-functioning and secreting pituitary adenomas [124, 125, 129–134], respectively, and of 12–14 Gy for acoustic neuromas [135, 137, 139–142]. Hypofractionated RT and FSRT using doses of 21–25 Gy in 3–5 fractions and 45–54 Gy in 25–30 daily fractions of 1.8 Gy, respectively, are frequently employed for large tumors involving the optic pathway or compressing the brainstem [126–128, 133–136, 138].
RT remains an effective treatment in elderly patients with brain tumors. For large malignant gliomas, randomized studies comparing standard RT versus hypofractionated RT show similar survival benefit, although short-term courses of RT are associated with a better safety profile. Decisions regarding the choice between RT and TMZ chemotherapy should be based on the assessment of MGMT promoter methylation status. Patients with methylated tumors receive the most significant survival benefit from treatment with TMZ; by contrast, chemotherapy produces no benefit in patients with unmethylated tumors, suggesting that RT is a better option in these patients. An abbreviated course of RT plus TMZ has recently emerged as a safe treatment associated with improved survival over RT alone.
SRS alone represents a feasible approach for older patients with a limited number of brain metastases, with reported survival and risk of neurologic death similar to those observed for younger patients. This approach allows omitting or the delaying the use of WBRT in older patients, who are usually more sensitive to the negative impact of cranial irradiation on neurocognitive function and quality of life. Similarly, the use of stereotactic techniques, either SRS or FSRT, has permitted the delivery of safe radiation doses in older patients with skull base tumors, leading to excellent long-term tumor control with minimal side effects and preservation of quality of life. The choice of stereotactic technique is usually based on size and location of tumor. In clinical practice, SRS is recommended for small-to-moderate tumors (<2.5-3 cm) that do not involve radiosensitive structures, such as optic chiasm and brainstem; hypofractionated SRT or FSRT would be a better treatment option when a single-fraction dose carries an unacceptable risk of toxicity.
Future studies need to evaluate the impact of different radiation techniques on survival, neurocognitive outcome and quality of life in older patients with brain tumors, as well their comparison with regimens incorporating RT and/or chemotherapy. A rigorous assessment of tolerance of different brain structures, including optic chiasm, cranial nerves, brainstem, and hippocampus to different radiation dose/fractionation schedules in older population is a research priority for radiation oncologists.
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- DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64:252–71.PubMedView ArticleGoogle Scholar
- Smith RA, Manassaram-Baptiste D, Brooks D, Cokkinides V, Doroshenk M, Saslow D, et al. Cancer screening in the united states, 2014: a review of current American cancer society guidelines and current issues in cancer screening. CA Cancer J Clin. 2014;64:30–51.PubMedView ArticleGoogle Scholar
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.PubMedView ArticleGoogle Scholar
- Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the united states in 2005–2009. Neuro Oncol. 2012;14 Suppl 5:v1–49.PubMedPubMed CentralView ArticleGoogle Scholar
- Minniti G, Goldsmith C, Brada M. Radiotherapy. Handb Clin Neurol. 2012;104:215–28.PubMedView ArticleGoogle Scholar
- Carreca I, Balducci L, Extermann M. Cancer in the older person. Cancer Treat Rev. 2005;31:380–402.PubMedView ArticleGoogle Scholar
- Alvis BD, Hughes CG. Physiology considerations in geriatric patients. Anesthesiol Clin. 2015;33:447–56.PubMedPubMed CentralView ArticleGoogle Scholar
- Hoffe S, Balducci L. Cancer and age: general considerations. Clin Geriatr Med. 2012;28:1–18.PubMedView ArticleGoogle Scholar
- Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol. 2012;13:e437–44.PubMedView ArticleGoogle Scholar
- Ferrat E, Paillaud E, Caillet P, Laurent M, Tournigand C, Lagrange JL, et al. Performance of four frailty classifications in older patients with cancer: prospective elderly cancer patients cohort study. J Clin Oncol. 2017;35:766–77.PubMedView ArticleGoogle Scholar
- Huisingh-Scheetz M, Walston J. How should older adults with cancer be evaluated for frailty? J Geriatr Oncol. 2017;8:8–15.PubMedView ArticleGoogle Scholar
- Extermann M, Aapro M, Bernabei R, Cohen HJ, Droz JP, Lichtman S, et al. Task force on CGA of the international society of geriatric oncology. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the international society of geriatric oncology (SIOG). Crit Rev Oncol Hematol. 2005;55:241–52.PubMedView ArticleGoogle Scholar
- Biganzoli L, Wildiers H, Oakman C, Marotti L, Loibl S, Kunkler I, et al. Management of elderly patients with breast cancer: updated recommendations of the international society of geriatric oncology (SIOG) and European society of breast cancer specialists (EUSOMA). Lancet Oncol. 2012;13:e148–60.PubMedView ArticleGoogle Scholar
- Hurria A, Wildes T, Blair SL, Browner IS, Cohen HJ, Deshazo M, et al. Senior adult oncology, version 2.2014: clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2014;12:82–126.PubMedView ArticleGoogle Scholar
- Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, et al. International society of geriatric oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32:2595–603.PubMedPubMed CentralView ArticleGoogle Scholar
- Pallis AG, Gridelli C, Wedding U, Faivre-Finn C, Veronesi G, Jaklitsch M, et al. Management of elderly patients with NSCLC; updated expert’s opinion paper: EORTC elderly task force, lung cancer group and international society for geriatric oncology. Ann Oncol. 2014;25:1270–83.PubMedView ArticleGoogle Scholar
- Magnuson A, Allore H, Cohen HJ, Mohile SG, Williams GR, Chapman A, et al. Geriatric assessment with management in cancer care: current evidence and potential mechanisms for future research. J Geriatr Oncol. 2016;7:242–48.PubMedPubMed CentralView ArticleGoogle Scholar
- Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol. 2007;25:1824–31.PubMedView ArticleGoogle Scholar
- Chen CC, Kenefick AL, Tang ST, McCorkle R. Utilization of comprehensive geriatric assessment in cancer patients. Crit Rev Oncol Hematol. 2004;49:53–67.PubMedView ArticleGoogle Scholar
- Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–8.PubMedView ArticleGoogle Scholar
- Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994;49:M85–94.PubMedView ArticleGoogle Scholar
- Avlund K, Schultz-Larsen K, Kreiner S. The measurement of instrumental ADL: content validity and construct validity. Aging (Milano). 1993;5:371–83.Google Scholar
- Jolly T, Jolly TA, Deal AM, Nyrop KA, Williams GR, Pergolotti M, et al. Geriatric assessment-identified deficits in older cancer patients with normal performance status. Oncologist. 2015;20:379–85.PubMedPubMed CentralView ArticleGoogle Scholar
- Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.PubMedView ArticleGoogle Scholar
- Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–99.PubMedView ArticleGoogle Scholar
- Kawas C, Karagiozis H, Resau L, Corrada M, Brookmeyer R. Reliability of the blessed telephone information-memory- concentration test. J Geriatr Psychiatry Neurol. 1995;8:238–42.PubMedView ArticleGoogle Scholar
- Shulman KI. Clock-drawing: Is it the ideal cognitive screening test? Int J Geriatr Psychiatry. 2000;15:548–61.PubMedView ArticleGoogle Scholar
- Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The memorial delirium assessment scale. J Pain Symptom Manage. 1997;13:128–37.PubMedView ArticleGoogle Scholar
- Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.PubMedView ArticleGoogle Scholar
- Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the cumulative illness rating scale. Psychiatry Res. 1992;41:237–48.PubMedView ArticleGoogle Scholar
- Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res. 1982–1983;17:37–49.Google Scholar
- Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.PubMedView ArticleGoogle Scholar
- Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Colasanti V, Marianetti M, Micacchi F, Amabile GA, Mina C. Tests for the evaluation of depression in the elderly: a systematic review. Arch Gerontol Geriatr. 2010;50:227–30.PubMedView ArticleGoogle Scholar
- Kaiser MJ, Bauer JM, Ramsch C, Uter W, Guigoz Y, Cederholm T, MNA-International Group, et al. Validation of the mini nutritional assessment short-form (MNA-SF): a practical tool for identification of nutritional status. J Nutr Health Aging. 2009;13:782–88.PubMedView ArticleGoogle Scholar
- Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drugtherapy appropriateness. J Clin Epidemiol. 1992;45:1045–51.PubMedView ArticleGoogle Scholar
- Gallagher P, Ryan C, Byrne S et al. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment): Consensus validation.Google Scholar
- Lubben J. Assessing social networks among elderly populations. Fam Community Health. 1988;11:42–52.View ArticleGoogle Scholar
- Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32:705–14.PubMedView ArticleGoogle Scholar
- Soubeyran P, Bellera C, Goyard J, Heitz D, Curé H, Rousselot H, et al. Screening for vulnerability in older cancer patients: the ONCODAGE prospective multicenter cohort study. PLoS One. 2014;9:e115060.PubMedPubMed CentralView ArticleGoogle Scholar
- Overcash JA, Beckstead J, Moody L, Extermann M, Cobb S. The abbreviated comprehensive geriatric assessment (aCGA) for use in the older cancer patient as a prescreen: scoring and interpretation. Crit Rev Oncol Hematol. 2006;59:205–10.PubMedView ArticleGoogle Scholar
- Bielderman A, Van Der Schans CP, van Lieshout MR, de Greef MH, Boersma F, Krijnen WP, Steverink N. Multidimensional structure of the Groningen frailty indicator in community-dwelling older people. BMC Geriatr. 2013;13:86.PubMedPubMed CentralView ArticleGoogle Scholar
- Saliba D, Elliott M, Rubenstein LZ, Solomon DH, Young RT, Kamberg CJ, et al. The vulnerable elders survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc. 2001;49:1691–99.PubMedView ArticleGoogle Scholar
- Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Association of French-speaking neuro-oncologists. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;356:1527–35.PubMedView ArticleGoogle Scholar
- Bauman GS, Gaspar LE, Fisher BJ, Halperin EC, Macdonald DR, Cairncross JG. A prospective study of short course RT in poor prognosis glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1994;29:835–39.PubMedView ArticleGoogle Scholar
- Ford JM, Stenning SP, Boote DJ, Counsell R, Falk SJ, Flavin A, et al. A short fractionation radiotherapy treatment for poor prognosis patients with high grade glioma. Clin Oncol (R Coll Radiol). 1997;9:20–4.View ArticleGoogle Scholar
- Hoegler DB, Davey P. A prospective study of short course radiotherapy in elderly patients with malignant glioma. J Neurooncol. 1997;33:201–14.PubMedView ArticleGoogle Scholar
- McAleese JJ, Stenning SP, Ashley S, Traish D, Hines F, Sardell S, et al. Hypofractionated radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls. Radiother Oncol. 2003;67:177–82.PubMedView ArticleGoogle Scholar
- Chinot OL, Barrie M, Frauger E, Dufour H, Figarella-Branger D, Palmari J, et al. Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations. Cancer. 2004;100:2208–14.PubMedView ArticleGoogle Scholar
- Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22:1593–98.View ArticleGoogle Scholar
- Gállego Pérez-Larraya J, Ducray F, Chinot O, Catry-Thomas I, Taillandier L, Guillamo JS, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: An ANOCEF phase II trial. J Clin Oncol. 2011;29:3050–55.PubMedView ArticleGoogle Scholar
- Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Nordic Clinical Brain Tumour Study Group (NCBTSG), et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13:916–26.PubMedView ArticleGoogle Scholar
- Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.PubMedView ArticleGoogle Scholar
- Roa W, Kepka L, Kumar N, Sinaika V, Matiello J, Lomidze D, et al. International atomic energy agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. 2015;33:4145–50.PubMedView ArticleGoogle Scholar
- Minniti G, De Sanctis V, Muni R, Rasio D, Lanzetta G, Bozzao A, et al. Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. J Neurooncol. 2009;91:95–100.PubMedView ArticleGoogle Scholar
- Brandes AA, Vastola F, Basso U. A prospective Study in glioblastoma multiforme. Cancer. 2003;3:657–62.View ArticleGoogle Scholar
- Combs SE, Wagner J, Bischof M, Welzel T, Wagner F, Debus J, et al. Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients. Int J Radiat Oncol Biol Phys. 2008;70:987–92.PubMedView ArticleGoogle Scholar
- Minniti G, De Sanctis V, Muni R, Filippone F, Bozzao A, Valeriani M, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol. 2008;88:97–103.PubMedView ArticleGoogle Scholar
- Brandes AA, Franceschi E, Tosoni A, Benevento F, Scopece L, Mazzocchi V, et al. Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer. 2009;115:3512–18.PubMedView ArticleGoogle Scholar
- Gerstein J, Franz K, Steinbach JP, Seifert V, Fraunholz I, Weiss C, et al. Postoperative radiotherapy and concomitant temozolomide for elderly patients with glioblastoma. Radiother Oncol. 2010;97:382–86.PubMedView ArticleGoogle Scholar
- Minniti G, Salvati M, Arcella A, Buttarelli F, D'Elia A, Lanzetta G, et al. Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol. 2011;102:311–16.PubMedView ArticleGoogle Scholar
- Barker CA, Chang M, Chou JF, Zhang Z, Beal K, Gutin PH, et al. Radiotherapy and concomitant temozolomide may improve survival of elderly patients with glioblastoma. J Neurooncol. 2012;109:391–97.PubMedPubMed CentralView ArticleGoogle Scholar
- Minniti G, Lanzetta G, Scaringi C, Caporello P, Salvati M, Arcella A, et al. Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma. Int J Radiat Oncol Biol Phys. 2012;83:93–9.PubMedView ArticleGoogle Scholar
- Niyazi M, Schwarz SB, Suchorska B, Belka C. Radiotherapy with and without temozolomide in elderly patients with glioblastoma. Strahlenther Onkol. 2012;188:154–59.PubMedView ArticleGoogle Scholar
- Behm T, Horowski A, Schneider S, Bock HC, Mielke D, Rohde V, Stockhammer F. Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients. Clin Neurol Neurosurg. 2013;115:2142–46.PubMedView ArticleGoogle Scholar
- Minniti G, Scaringi C, Baldoni A, Lanzetta G, De Sanctis V, Esposito V, et al. Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide. Int J Radiat Oncol Biol Phys. 2013;86:285–91.PubMedView ArticleGoogle Scholar
- Perry JR, Laperriere N, O'Callaghan CJ, Brandes A, Menten J, Phillips C, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376:1027–37.PubMedView ArticleGoogle Scholar
- Eby NL, Grufferman S, Flannelly CM, Schold Jr SC, Vogel FS, Burger PC. Increasing incidence of primary brain lymphoma in the US. Cancer. 1988;62:2461–65.PubMedView ArticleGoogle Scholar
- Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg. 1988;68:835–53.PubMedView ArticleGoogle Scholar
- Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med. 1993;119:1093–104.PubMedView ArticleGoogle Scholar
- Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neuroncol. 1999;43:241–47.View ArticleGoogle Scholar
- Shibamoto Y, Sumi M, Takemoto M, Tsuchida E, Onodera S, Matsushita H, et al. Analysis of radiotherapy in 1054 patients with primary central nervous system lymphoma treated from 1985 to 2009. Clin Oncol. 2014;26:653–60.View ArticleGoogle Scholar
- DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol. 1992;10:635–43.PubMedView ArticleGoogle Scholar
- De Angelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ, Radiation Therapy Oncology Group Study 93–10. Combination chemotherapy and radiotherapy for primary central nervous sytem lymphoma: radiation therapy oncology group study 93–10. J Clin Oncol. 2002;20:4643–48.View ArticleGoogle Scholar
- Hoang-Xuan K, Bessell E, Bromberg J, Hottinger AF, Preusser M, Rudà R, European Association for Neuro-Oncology Task Force on Primary CNS Lymphoma, et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association of Neurology. Lancet Oncol. 2015;16:e322–32.PubMedView ArticleGoogle Scholar
- Glass J, Gruber ML, Cher L, Hochberg FH. Pre-irradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg. 1994;81:188–95.PubMedView ArticleGoogle Scholar
- Reni M, Ferreri AJ, Guha-Thakurta N, Blay JY, Dell'Oro S, Biron P, et al. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys. 2001;51:419–25.PubMedView ArticleGoogle Scholar
- Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, Van't Veer M, Hansen M, Soubeyran P, European Organization for Research and Treatment of Cancer Lymphoma Group, et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European organization for research and treatment of cancer lymphoma group phase II trial 20962. J Clin Oncol. 2003;21:4483–88.PubMedView ArticleGoogle Scholar
- Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol. 1998;16:859–63.PubMedView ArticleGoogle Scholar
- Correa DD, Shi W, Abrey LE, Deangelis LM, Omuro AM, Deutsch MB, et al. Cognitive functions in primary CNS lymphoma after single or combined modality regimens. Neuro Oncol. 2012;14:101–8.PubMedView ArticleGoogle Scholar
- Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010;11:1036–47.PubMedView ArticleGoogle Scholar
- O’Neill BP, O’Fallon JR, O'Fallon JR, Colgan JD, Earle JD, Krigel RL, et al. Primary central nervous system non-Hodgkin’s lymphoma: survival advantages with combined initial therapy? Int J Radiat Oncol Biol Phys. 1995;33:663–73.PubMedView ArticleGoogle Scholar
- Fritsch K, Kasenda B, Nikkhah G, Prinz M, Haug V, Haug S, et al. Immunochemotherapy with rituximab, methotrexate, procarbaziine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 2011;22:2080–85.PubMedView ArticleGoogle Scholar
- Ghesquières H, Ferlay C, Sebban C, Perol D, Bosly A, Casasnovas O, et al. Long-term follow-up of an age-adopted C5R protocol followed by radiotherapy in 99 newly disgnosed primary CNS lymphomas: a prospective multicentric phase II study of the groupe d’Etude des lymphomes de l’Adulte (GELA). Ann Oncol. 2010;21:842–50.PubMedView ArticleGoogle Scholar
- Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, European Organization for Research and Treatment of Cancer Brain Tumor Group, et al. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003;21:2726–31.PubMedView ArticleGoogle Scholar
- Illerhaus G, Marks R, Muller F, Ihorst G, Feuerhake F, Deckert M, et al. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol. 2009;20:319–25.PubMedView ArticleGoogle Scholar
- Laack NN, Ballman KV, Brown PB, O’Neill BP, North Central Cancer Treatment Group. Whole-brain radiotherapy and high-dose methylprednisolone for elderly patients with primary central nervous system lymphoma : results of North Central Cancer Treatment Group (NCCTG) 96-73-51. Int J Radiat Oncol Biol Phys. 2006;65:1429–39.PubMedView ArticleGoogle Scholar
- Roth P, Martus P, Kiewe P, Möhle R, Klasen H, Rauch M, et al. Outcome of elderly patients with primary CNS lymphoma in the G-PNCSL-SG-1 trial. Neurology. 2012;79(9):890–6.PubMedView ArticleGoogle Scholar
- Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013;31:3971–79.PubMedView ArticleGoogle Scholar
- Ferreri AJ, Verona C, Politi LS, Chiara A, Perna L, Villa E, et al. Consolidation radiotherapy in primary CNS lymphomas: impact of different fileds and doses in patients in complete remission after upfront chemotherapy. Int J Rad Oncol Biol Phys. 2011;80:169–75.View ArticleGoogle Scholar
- Shibamoto Y, Hayabuchi N, Hiratsuka J, Tokumaru S, Shirato H, Sougawa M, et al. Is whole-brain irradiation necessary for primary central nervous system lymphoma? Patterns of recurrence after partial-brain irradiation. Cancer. 2003;97:128–33.PubMedView ArticleGoogle Scholar
- Scoccianti S, Ricardi U. Treatment of brain metastases: review of phase III randomized controlled trials. Radiother Oncol. 2012;102:168–79.PubMedView ArticleGoogle Scholar
- Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–51.PubMedView ArticleGoogle Scholar
- Lutterbach J, Bartelt S, Stancu E, Guttenberger R. Patients with brain metastases: hope for recursive partitioning analysis (RPA) class 3. Radiother Oncol. 2002;63:339–45.PubMedView ArticleGoogle Scholar
- Rades D, Evers JN, Veninga T, Stalpers LJ, Lohynska R, Schild SE. Shorter-course whole-brain radiotherapy for brain metastases in elderly patients. Int J Radiat Oncol Biol Phys. 2011;81:e469–73.PubMedView ArticleGoogle Scholar
- DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39:789–96.PubMedView ArticleGoogle Scholar
- Crossen JR, Garwood D, Glatstein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol. 1994;12:627–42.PubMedView ArticleGoogle Scholar
- Le Péchoux C, Laplanche A, Faivre-Finn C, Ciuleanu T, Wanders R, Lerouge D, Prophylactic Cranial Irradiation (PCI) Collaborative Group, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003–08004, RTOG 0212 and IFCT 99–01). Ann Oncol. 2011;22:1154–63.PubMedView ArticleGoogle Scholar
- Sun A, Bae K, Gore EM, Movsas B, Wong SJ, Meyers CA, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol. 2011;29:279–86.PubMedView ArticleGoogle Scholar
- Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483–91.PubMedView ArticleGoogle Scholar
- Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037–44.PubMedView ArticleGoogle Scholar
- Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952–26001 study. J Clin Oncol. 2011;29:134–41.PubMedView ArticleGoogle Scholar
- Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs RadiosurgeryWith whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316:401–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Noel G, Bollet MA, Noel S, Feuvret L, Boisserie G, Tep B, et al. Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases. Int J Radiat Oncol Biol Phys. 2005;63:1555–61.PubMedView ArticleGoogle Scholar
- Kim SH, Weil RJ, Chao ST, Toms SA, Angelov L, Vogelbaum MA, et al. Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer. 2008;113:834–40.PubMedView ArticleGoogle Scholar
- Minniti G, Esposito V, Clarke E, Scaringi C, Bozzao A, Lanzetta G, et al. Stereotactic radiosurgery in elderly patients with brain metastases. J Neurooncol. 2013;111:319–25.PubMedView ArticleGoogle Scholar
- Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2000;77:655–61.View ArticleGoogle Scholar
- Wong J, Hird A, Zhang L, Tsao M, Sinclair E, Barnes E, et al. Symptoms and quality of life in cancer patients with brain metastases following palliative radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:1125–31.PubMedView ArticleGoogle Scholar
- Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, et al. A European organisation for research and treatment of cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013;31:65–72.PubMedView ArticleGoogle Scholar
- Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, Radiation Therapy Oncology Group (RTOG), et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15:1429–37.PubMedPubMed CentralView ArticleGoogle Scholar
- Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32:3810–16.PubMedPubMed CentralView ArticleGoogle Scholar
- Claus EB, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M, Black PM. Epidemiology of intracranial meningioma. Neurosurgery. 2005;57:1088–95.PubMedView ArticleGoogle Scholar
- Brell M, Villà S, Teixidor P, Lucas A, Ferrán E, Marín S, et al. Fractionated stereotactic radiotherapy in the treatment of exclusive cavernous sinus meningioma: functional outcome, local control, and tolerance. Surg Neurol. 2006;65:28–33.PubMedView ArticleGoogle Scholar
- Feigl GC, Samii M, Horstmann GA. Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of gamma knife radiosurgery. Neurosurgery. 2007;61:281–86.PubMedView ArticleGoogle Scholar
- Kollová A, Liscák R, Novotný Jr J, Vladyka V, Simonová G, Janousková L. Gamma Knife surgery for benign meningioma. J Neurosurg. 2007;107:325–36.PubMedView ArticleGoogle Scholar
- Kondziolka D, Mathieu D, Lunsford LD, Martin JJ, Madhok R, Niranjan A, et al. Radiosurgery as definitive management of intracranial meningiomas. Neurosurgery. 2008;62:53–8.PubMedView ArticleGoogle Scholar
- Minniti G, Amichetti M, Enrici RM. Radiotherapy and radiosurgery for benign skull base meningiomas. Radiat Oncol. 2009;4:42.PubMedPubMed CentralView ArticleGoogle Scholar
- Minniti G, Clarke E, Cavallo L, Osti MF, Esposito V, Cantore G, et al. Fractionated stereotactic conformal radiotherapy for large benign skull base meningiomas. Radiat Oncol. 2011;12:6–36.Google Scholar
- Santacroce A, Walier M, Régis J, Liščák R, Motti E, Lindquist C, et al. Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurgery. 2012;70:32–9.PubMedView ArticleGoogle Scholar
- Combs SE, Adeberg S, Dittmar JO, Welzel T, Rieken S, Habermehl D, et al. Skull base meningiomas: Long-term results and patient self-reported outcome in 507 patients treated with fractionated stereotactic radiotherapy (FSRT) or intensity modulated radiotherapy (IMRT). Radiother Oncol. 2013;106:186–91.PubMedView ArticleGoogle Scholar
- Fokas E, Henzel M, Surber G, Hamm K, Engenhart-Cabillic R. Stereotactic radiation therapy for benign meningioma: long-term outcome in 318 patients. Int J Radiat Oncol Biol Phys. 2014;89:569–75.PubMedView ArticleGoogle Scholar
- Fokas E, Henzel M, Surber G, Hamm K, Engenhart-Cabillic R. Stereotactic radiotherapy of benign meningioma in the elderly: clinical outcome and toxicity in 121 patients. Radiother Oncol. 2014;111:457–62.PubMedView ArticleGoogle Scholar
- Kaul D, Budach V, Graaf L, Gollrad J, Badakhshi H. Outcome of elderly patients with meningioma after image-guided stereotactic radiotherapy: a study of 100 cases. Biomed Res Int. 2015;2015:868401.PubMedPubMed CentralView ArticleGoogle Scholar
- Pan L, Zhang N, Wang EM, Wang BJ, Dai JZ, Cai PW. Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg. 2000;93:10–3.PubMedGoogle Scholar
- Sheehan JM, Vance ML, Sheehan JP, Ellegala DB, Laws Jr ER. Radiosurgery for Cushing’s disease after failed transsphenoidal surgery. J Neurosurg. 2000;93:738–42.PubMedView ArticleGoogle Scholar
- Colin P, Jovenin N, Delemer B, Caron J, Grulet H, Hecart AC, et al. Treatment of pituitary adenomas by fractionated stereotactic radiotherapy: a prospective study of 110 patients. Int J Radiat Oncol Biol Phys. 2005;62:333–41.PubMedView ArticleGoogle Scholar
- Minniti G, Traish D, Ashley S, Gonsalves A, Brada M. Fractionated stereotactic conformal radiotherapy for secreting and nonsecreting pituitary adenomas. Clin Endocrinol (Oxf). 2006;64:542–48.View ArticleGoogle Scholar
- Kong DS, Lee JI, Lim DH, Kim KW, Shin HJ, Nam DH, et al. The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution. Cancer. 2007;110:854–60.PubMedView ArticleGoogle Scholar
- Sheehan JP, Pouratian N, Steiner L, Laws ER, Vance ML. Gamma Knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes. J Neurosurg. 2011;114:303–9.PubMedView ArticleGoogle Scholar
- Franzin A, Spatola G, Losa M, Picozzi P, Mortini P. Results of gamma knife radiosurgery in acromegaly. Int J Endocrinol. 2012;2012:342034.PubMedPubMed CentralView ArticleGoogle Scholar
- Starke RM, Williams BJ, Jane Jr JA, Sheehan JP. Gamma Knife surgery for patients with nonfunctioning pituitary macroadenomas: predictors of tumor control, neurological deficits, and hypopituitarism. J Neurosurg. 2012;117:129–35.PubMedView ArticleGoogle Scholar
- Sheehan JP, Starke RM, Mathieu D, Young B, Sneed PK, Chiang VL, et al. Gamma Knife radiosurgery for the management of nonfunctioning pituitary adenomas: a multicenter study. J Neurosurg. 2013;119:446–56.PubMedView ArticleGoogle Scholar
- Minniti G, Osti MF, Niyazi M. Target delineation and optimal radiosurgical dose for pituitary tumors. Radiat Oncol. 2016;11:135.PubMedPubMed CentralView ArticleGoogle Scholar
- Li X, Li Y, Cao Y, Li P, Liang B, Sun J, Feng E. Safety and efficacy of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas: A systematic review and meta-analysis. J Neurol Sci. 2017;372:110–16.PubMedView ArticleGoogle Scholar
- Hansasuta A, Choi CY, Gibbs IC, Soltys SG, Tse VC, Lieberson RE, et al. Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases. Neurosurgery. 2011;69:1200–9.PubMedView ArticleGoogle Scholar
- Kapoor S, Batra S, Carson K, Shuck J, Kharkar S, Gandhi R, et al. Long-term outcomes of vestibular schwannomas treated with fractionated stereotactic radiotherapy: an institutional experience. Int J Radiat Oncol Biol Phys. 2011;81:647–53.PubMedView ArticleGoogle Scholar
- Hasegawa T, Kida Y, Kato T, Iizuka H, Kuramitsu S, Yamamoto T. Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with gamma knife surgery. J Neurosurg. 2013;118:557–65.PubMedView ArticleGoogle Scholar
- Litre F, Rousseaux P, Jovenin N, Bazin A, Peruzzi P, Wdowczyk D, et al. Fractionated stereotactic radiotherapy for acoustic neuromas: a prospective monocenter study of about 158 cases. Radiother Oncol. 2013;106:169–74.PubMedView ArticleGoogle Scholar
- Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg. 2013;119(Suppl):195–99.PubMedGoogle Scholar
- Régis J, Carron R, Delsanti C, Porcheron D, Thomassin JM, Murracciole X, et al. Radiosurgery for vestibular schwannomas. Neurosurg Clin N Am. 2013;24:521–30.PubMedView ArticleGoogle Scholar
- Williams BJ, Xu Z, Salvetti DJ, McNeill IT, Larner J, Sheehan JP. Gamma Knife surgery for large vestibular schwannomas: a single-center retrospective case-matched comparison assessing the effect of lesion size. J Neurosurg. 2013;119:463–71.PubMedView ArticleGoogle Scholar
- Boari N, Bailo M, Gagliardi F, Franzin A, Gemma M, del Vecchio A, et al. Gamma knife radiosurgery for vestibular schwannoma: clinical results at long-term follow-up in a series of 379 patients. J Neurosurg. 2014;121(Suppl):123–42.PubMedGoogle Scholar