Stereotactic radiosurgery for brain metastases: a case-matched study comparing treatment results for patients 80 years of age or older versus patients 65–79 years of age

Clinical article

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Object

Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65–79 years old.

Methods

This was an institutional review board–approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998–2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65–79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate.

Results

Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9–7.0 months) than in Group B patients (6.9 months, 95% CI 5.0–8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921–1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268–2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438–1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152–2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8–19.6 months), 7.9 months (95% CI 5.2–10.9 months), and 2.8 months (95% CI; 2.4–4.6 months) in patients whose disease status was modified–recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001).

Conclusions

Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65–79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.

Abbreviations used in this paper:CI = confidence interval; HR = hazard ratio; KPS = Karnofsky Performance Status; MST = median survival time; PET = positron emission tomography; RPA = recursive partitioning analysis; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy.

Object

Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65–79 years old.

Methods

This was an institutional review board–approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998–2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65–79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate.

Results

Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9–7.0 months) than in Group B patients (6.9 months, 95% CI 5.0–8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921–1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268–2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438–1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152–2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8–19.6 months), 7.9 months (95% CI 5.2–10.9 months), and 2.8 months (95% CI; 2.4–4.6 months) in patients whose disease status was modified–recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001).

Conclusions

Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65–79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.

In a cross-national comparative study of 7 industrialized nations, the proportion of individuals 65 years of age or older reportedly ranged from 12.6% to 18.1% in 2000.35 Furthermore, the proportion of elderly persons has been estimated to possibly reach 20%–28% of the entire population in most industrialized countries by 2030. As life expectancy is increasing not only in industrialized countries but also worldwide, the incidence of cancer in the elderly is rising. At the same time, prolonged survival, even in elderly patients with systemic cancer, is expected owing to recently developed diagnostic technologies and improved therapeutic strategies. The longer cancer patients survive, the more frequently physicians encounter brain metastases. Little is known, however, regarding management of elderly patients with brain metastases. Therefore, clinicians are often uncertain as to the optimal treatment for these patients—that is, whole-brain radiotherapy (WBRT), surgery, stereotactic radiosurgery (SRS), radiotherapy, administration of anticancer agents, or combinations of these modalities, efficacies of which vary among patient subsets.

SRS has recently been reported to be effective for the treatment of brain metastases in older patients, with various studies reporting on its successful use in patients 65 years or older,19 70 years or older,17 and 75 years or older.13 Furthermore, an increasing number of patients with brain metastases, even patients older than 80 years, have been treated with SRS. Little information is, however, available on SRS for these older patients. Thus, using our own database, we reappraised whether the results of SRS treatment in patients 80 years or older differ from the results in patients 65–79 years old.

As aging of the population is proceeding very quickly in Japan, considerable numbers of symposia and panel discussions, not only at neurosurgery congresses but also at those for other medical specialties, are increasingly focusing on treatment of patients 80 years of age and older. Therefore, we used age 80 years as the cut-off point in this study. This means that the categorization applied herein was based on neither medical nor radiobiological evidence. Univariate analysis with age as a continuous variable for overall survival using our most recently revised database including 2552 brain metastasis patients treated with SRS alone yielded a hazard ratio (HR) of 1.009, 95% confidence interval (CI) of 1.006–1.013, and p < 0.0001 (unpublished data). This HR is very close to “1” and can thus be clinically interpreted as indicating that patient age has little, if any, impact on overall survival even though, due to the large patient number, the p value was very low.

Methods

Patient Population

This retrospective cohort study used our prospectively accumulated database at Katsuta Hospital Mito Gammahouse, which included, at the time of the study, 2552 consecutive cases. The study was approved by the institutional review board of Tokyo Women's Medical University. Patients in our series underwent SRS alone, not in combination with concurrent WBRT, for treatment of brain metastases during the 13-year period between July 1998 and June 2011. As all patients had been referred to us for SRS, in most cases the patient selections were made by the patients' primary physicians. Patient selection criteria may thus have differed among referring physicians. Therefore, in each case, one author (M.Y.) decided whether the patient could be treated with SRS. We did not treat patients with SRS if they had low Karnofsky Performance Status (KPS)12 scores due to systemic disease (< 70%), an uncooperative state due to poor neurocognitive function, meningeal dissemination, or an anticipated survival period of 3 months or less. Among the 2552 patients, we studied 1346 who were at least 65 years of age at the time of SRS. These 1346 patients were divided into 2 groups: 165 patients 80 years of age or older (Group A) and 1181 patients 65–79 years of age (Group B).

Table 1 summarizes clinical characteristics overall and for the 2 age groups. Because all patients had been referred to us for SRS by other facilities, the primary physicians responsible for each patient had decided the indications for both surgery and radiotherapy, and 217 (16.1%) of the 1346 patients had undergone surgical removal of brain metastases prior to SRS and 49 (3.6%) had undergone WBRT.

TABLE 1:

Summary of clinical characteristics of 1346 brain metastasis patients with age ≥ 65 years*

CharacteristicTotalAge Group (yrs)p Value
≥80 (Group A)65–79 (Group B)
no. of patients13461651181
age (yrs)
 mean738371
 median728271
sex: female448 (33.2%)50 (30.3%)398 (33.7%)0.43
no. of tumors
 mean6660.36
 median323
 range1–891–531–89
primary cancer sites
 lung958 (71.2%)117 (70.9%)841 (71.2%)0.93
 alimentary tract169 (12.6%)19 (11.5%)150 (12.7%)
 breast60 (4.4%)4 (2.4%)56 (4.7%)
 kidney51 (3.8%)4 (2.4%)47 (4.0%)
 others108 (8.0%)21 (12.7%)87 (7.4%)
primary cancer status: controlled331 (24.6%)31 (18.8%)300 (25.4%)0.07
extracerebral METs: no779 (57.9%)104 (63.0%)675 (57.2%)0.18
KPS ≥80%980 (72.8%)104 (63.0%)876 (74.2%)0.004
modified-RPA class
 I+IIa286 (21.2%)28 (17.0%)258 (21.8%)
 IIb425 (31.6%)46 (27.9%)379 (32.1%)0.08§
 IIc+III635 (47.2%)91 (55.2%)544 (46.1%)
neurological Sx: no636 (47.3%)70 (42.4%)566 (47.9%)0.21
prior surgery: yes212 (15.8%)17 (10.3%)195 (16.5%)0.04
prior WBRT: yes49 (3.6%)4 (2.4%)45 (3.8%)0.51
tumor volume (cm3)
 cumulative
  mean9.2510.479.080.16
  range0.01–126.20.12–67.230.01–126.2
 largest tumor
  mean6.647.816.480.07
  range0.01–94.20.06–65.00.01–94.2
peripheral dose (Gy)
  mean21.3121.2521.320.81
  range10.00–32.0015.00–25.0010.00–32.00

Values represent numbers of patients (%) unless otherwise specified. METs = metastases; Sx = symptoms.

The Student t-test was used for continuous variables and Fisher's exact test for pairs of categorical variables.

Lung vs non-lung.

Modified-RPA Classes IIb vs I+IIa and IIc+III.

Before SRS, the treatment strategy was explained in detail to each patient and at least one adult relative by the second author (M.Y.). Written informed consent was obtained from all patients. We have described our radiosurgical techniques in detail in previous reports.30,32 Briefly, standard SRS procedures were performed using a Leksell Gamma Knife Model B (Elekta AB) before June 2003 and thereafter a Leksell Gamma Knife Model C (Elekta AB). Regarding dose selection in cases involving elderly patients, we did not take patient age into consideration.

After SRS, all cases were routinely managed by referring physicians, with a recommendation for follow-up clinical and neuroimaging examinations at an approximately 2- to 3-month interval. However, in 449 (33.4%) of the 1346 patients, neuroimaging follow-up could not be performed due to early post-SRS death or marked deterioration of general condition. Approximately 50% of our 1346 patients came to our outpatient clinic periodically, while clinical and/or neuroimaging data were sent to us by post in about 25% of cases. The second author (M.Y.) called the remaining 25% of patients or their relatives by telephone to confirm the patients' conditions. For deceased patients, the day of death, cause of death, and detailed information on patient condition changes were requested by telephone.

Case Matching

As shown in Table 1, there was bias and a large difference in numbers of patients between Groups A and B. Therefore, a case-matched study was conducted by one of the authors (Y.S.), who did not participate in other aspects of this study and was blinded to final outcomes. Patient selection was performed by employing the propensity score matching method with a Greedy 5-To-1 Digit-Matching algorithm20 for 2 clinical factors, KPS score and prior surgery.

Clinical Outcomes

The primary end point was overall survival, and the secondary end points were neurological death, neurological deterioration, local recurrence of the treated tumor, repeat SRS for new lesions, and SRS-induced major complications. For each end point, failures were regarded as events and any others as censored. Overall survival time was defined as the interval between the first SRS and death due to any cause (progression of systemic metastases and/or brain metastases, other disease unrelated to cancer, accident, suicide, and so on) or the day of the last follow-up. Neurological death was defined as death caused by any intracranial disease, including tumor recurrence, carcinomatous meningitis, cerebral dissemination, and progression of other untreated intracranial tumors.

Local recurrence–free survival time was defined as the interval between the first SRS and the day when follow-up MRI demonstrated local recurrence (at the irradiated lesion). Generally, local recurrence criteria were increased size of an enhanced area on post-gadolinium T1-weighted MR images and enlarged tumor core on T2-weighted MR images.10 However, in 41 cases in which MRI alone was not sufficient to confirm recurrence,11C methionine positron emission tomography (PET) was used to distinguish tumor recurrence from necrotic lesions.16,18,27,31 Thus, all findings of recurrence on MRI and/or PET were regarded as events and any others as censored. Also, repeat SRS–free survival time was defined as the interval between the first SRS and the day the second SRS was performed for new lesions; all repeat SRS procedures for newly developed lesions were regarded as events and any others as censored. For patients developing new brain metastases after the first SRS, our approach is similar to that in patients with initially diagnosed brain metastases. As to tumor size, if follow-up MRI demonstrates tumors with diameters of 2–3 mm in the brainstem or optic apparatus, we perform repeat SRS without further observation. Otherwise, repeat SRS is usually postponed with close MRI follow-up until the tumor diameter exceeds approximately 1 cm.

Neurological deterioration–free survival time was defined as the interval between the first SRS and the day that any brain disease–caused neurological worsening manifested (that is, local recurrence, progression of new lesions, and SRS-induced complications). Decreases in KPS scores, in patients with scores of 20% or less, due to neurological worsening were regarded as events and any others as censored. Major complication-free survival time was taken as the interval between the first SRS and the day major SRS-induced complications occurred. Patients with major complications included those with Radiation Therapy Oncology Group (RTOG) neurotoxicity grades of 2 or worse and, even if the grade was either 0 or 1, those in whom surgical intervention was required based on sequential MRI follow-up demonstrating progressive enlargement of a cyst and/or a mass lesion with further observation thus being regarded as excessively high risk; all of these conditions were regarded as events and any others as censored.22

Statistical Analysis

Data were analyzed according to the intention-to-treat principle. For the baseline variables, summary statistics were constructed using frequencies and proportions for categorical data and medians and ranges for continuous variables. We compared patient characteristics using the Fisher exact test for categorical outcomes and t-tests for continuous variables, as appropriate. The Kaplan-Meier method was used for overall survivals.11

For time-to-event outcomes, the cumulative incidences of local recurrence, repeat SRS, neurological deterioration, and major complications were estimated employing competing risk analysis, because death is a competing risk for loss to follow-up (that is, patients who die can no longer become lost to follow-up).5,6,23 Also, to identify baseline and clinical variables associated with the 4 aforementioned outcomes, competing risk analyses were performed with the Fine-Gray generalization of the proportional hazards model accounting for death as a competing risk.3 Fine-Gray generalization makes use of the subdistribution hazard to model cumulative incidence, thereby quantifying the overall benefit or harm of an exposure.2

All comparisons were planned and the tests were 2-sided. A p value of less than 0.05 was considered to be statistically significant. All statistical analyses were performed by one of the authors (Y.S.) using SAS software version 9.3 (SAS Institute) and the R statistical program, version 3.0.0. Before statistical analyses, the database was cleaned by another author (Y.H.). These 2 authors were not involved in either SRS treatment or patient follow-up.

Results

Cohort Studies

The overall median survival time (MST) after SRS for the 2552 patients whose cases were recorded in our database was 7.4 months (95% CI 7.1–7.9 months). In the herein-reported subset (1346 patients ≥ 65 of age, none lost to follow-up), the median post-SRS follow-up time among censored observations (39 cases) was 41.9 months (range 1.2–145.5 months), and 1307 patients (97.1%) had died as of August 2013. The MST after SRS was 7.0 months (95% CI 6.4–7.4 months). Actuarial post-SRS survival rates were 54.8%, 31.1%, 13.0%, 7.4%, and 3.5% at the 6th, 12th, 24th, 36th, and 60th post-SRS month, respectively. Among the 1302 deceased patients, causes of death could not be determined in 30, but were confirmed in the remaining 1277 to be non-brain disease in 1149 (90.0%) and brain disease in 128 (10.0%).

Studies of Case-Matched Subset

As described above, after all of the propensity score matches had been performed, we compared baseline characteristics between the 2 groups. Ultimately, 330 patients (165 in each group) were selected. The p values after matching were over 0.05 for all clinical factors (Table 2).

TABLE 2:

Summary of clinical characteristics of 330 case-matched brain metastasis patients with age ≥ 65 years

CharacteristicsTotalAge Group (yrs)p Values*
≥80 (Group A)65–79 (Group B)
no. of patients330165165
age (yrs)
 mean778372
 median808271
sex: female97 (29.3%)50 (30.3%)47 (28.5%)0.81
no. of tumors
 mean6650.74
 median323
 range1–531–531–50
primary cancer sites
 lung228 (69.1%)117 (70.9%)111 (67.3%)0.55
 alimentary tract44 (13.3%)19 (11.5%)25 (15.2%)
 breast12 (3.6%)4 (2.4%)8 (4.8%)
 kidney13 (3.9%)4 (2.4%)9 (5.5%)
 others33 (10.0%)21 (12.7%)12 (7.3%)
primary cancer status: controlled74 (22.4%)31 (18.8%)43 (26.1%)0.15
extracerebral METs: no191 (57.9%)104 (63.0%)87 (52.7%)0.07
KPS ≥80%208 (63.0%)104 (63.0%)104 (63.0%)1.00
modified-RPA class
 I+IIa60 (18.2%)28 (17.0%)32 (19.4%)
 IIb98 (30.0%)46 (27.9%)52 (31.5%)0.54
 IIc+III172 (52.1%)91 (55.2%)81 (49.1%)
neurological Sx: no143 (43.3%)70 (42.4%)73 (44.2%)0.82
prior surgery: yes35 (10.6%)17 (10.3%)18 (10.9%)1.00
prior WBRT: yes11 (3.3%)4 (2.4%)7 (4.2%)0.54
tumor vol (cm3)
 cumulative
  mean10.2910.4710.110.77
  range0.02–74.020.12–67.230.02–74.02
 largest tumor
  mean7.767.817.70.91
  range0.02–65.00.06–65.00.02–53.7
peripheral dose (Gy)
  mean21.1621.2521.060.58
  range15.00–25.0015.00–25.0015.00–25.00

The Student t-test was used for continuous variables and Fisher's exact test for pairs of categorical variables.

Lung vs non-lung.

Modified-RPA Classes IIb vs I+IIa and IIc+III.

As shown in Fig. 1, although the post-SRS MST was shorter in Group A (5.3 months) than in Group B (6.9 months) patients, this difference was not statistically significant (HR 1.147, 95% CI 0.921–1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%, respectively), but these differences did not reach statistical significance (Table 3). Also, time-to-event outcome studies using competing risk analysis showed that cumulative incidences of neurological death and deterioration were slightly lower in Group A than in Group B. However, there were no significant differences between the 2 groups (HR 0.734, 95% CI 0.346–1.559, p = 0.42 and HR 0.662, 95% CI 0.341–1.285, p = 0.22) (Table 4).

Fig. 1.
Fig. 1.

Overall survival based on 330 case-matched patients divided into 2 age groups, ≥ 80 years (Group A) and 65–79 years (Group B), estimated using the standard Kaplan-Meier method.11

TABLE 3:

Summary of treatment results after SRS

VariableAge Group (yrs)p Value
≥80 (Group A)65–79 (Group B)
neurological death*9 (6.3%)18 (11.8%)0.11
neurological deterioration14 (8.5%)23 (13.9%)0.16
local recurrence†5 (5.2%)8 (7.2%)0.76
repeat SRS24 (14.6%)35 (21.2%)0.15
salvage WBRT2 (1.2%)5 (3.0%)0.45
salvage surgery1 (0.6%)1 (0.6%)1.00
SRS-related complications3 (1.6%)6 (3.6%)0.50

Based on 296 deceased patients (152 [92.1%] in Group B and 144 [87.3%] in Group A, p = 0.11) whose causes of death were determined (34 patients were excluded because causes of death were not available).

Based on 206 patients (111 [67.3%] in Group B and 95 [57.6%] in Group A, p = 0.09); 124 patients were excluded because neuroimaging results were not available.

TABLE 4:

Summary of time-to-event outcome studies using competing risk analysis

VariableCumulative Incidence (post-SRS mos)HR (95% CI)p Value
6122436
neurological death0.734 (0.346–1.559)0.42
 ≥80 yrs (Group A)0.0320.0440.0510.060
 65–79 yrs (Group B)0.0300.0800.1040.111
neurological deterioration0.662 (0.341–1.285)0.22
 ≥80 yrs (Group A)0.0480.0670.0730.073
 65–79 yrs (Group B)0.0480.1090.1330.139
local recurrence*0.830 (0.268–2.573)0.75
 ≥80 yrs (Group A)0.0000.0000.0060. 018
 65–79 yrs (Group B)0.0000.0000.0000.006
repeat SRS0.738 (0.438–1.242)0.25
 ≥80 yrs (Group A)0.0910.1270.1390.139
 65–79 yrs (Group B)0.1450.1760.1820.212
SRS-related complications0.616 (0.152–2.495)0.49
 ≥80 yrs (Group A)0.0120.0120.0180.018
 65–79 yrs (Group B)0.0120.0180.0300.030

Based on 207 patients (96 [58.2%] Group A and 111 [67.2%] Group B patients, p = 0.11); 123 patients were excluded because neuroimaging results were not available.

Post-SRS follow-up MRI studies were available for 206 patients (63%): 95 in Group A and 111 in Group B. The incidences of local recurrence were similar, 5.2% in Group A and 7.2% in Group B (p = 0.76) patients (Table 3). Also, there was no significant difference between the 2 groups in the cumulative incidence of local recurrence, estimated using competing risk analysis (HR 0.830, 95% CI 0.268–2.573, p = 0.75) (Table 4).

Regarding post-SRS salvage treatment, although rates of repeat SRS and WBRT were slightly lower in Group A than in Group B patients (14.6% vs 21.2% and 1.2% vs 3.0%), these differences did not reach statistical significance (Table 3). Also, a time-to-event outcome study using competing risk analysis showed that cumulative rates of repeat SRS were slightly lower in Group A than in Group B patients, although the difference was not statistically significant (HR 0.738, 95% CI 0.438–1.242, p = 0.25) (Table 4). One patient (0.6%) in each of the 2 groups underwent salvage surgery (p = 1.00) (Table 3).

As shown in Table 4, cumulative incidences of SRS-related complications estimated using competing risk analysis did not differ significantly between the 2 groups (HR 0.616, 95% CI 0.152–2.495, p = 0.49).

Among the Group A patients, the post-SRS MSTs were 11.6 months (95% CI 7.8–19.6 months), 7.9 months (95% CI 5.2–10.9 months), and 2.8 months (95% CI 2.4–4.6 months) for modified–recursive partitioning analysis (RPA) (Table 5) Classes I+IIa, IIb, and IIc+3, respectively (p < 0.001) (Fig. 2 upper).30,33,34 The corresponding post-SRS MSTs for Group B patients were 14.3 months (95% CI 8.7–21.3 months), 7.1 months (95% CI 4.8–9.2 months), and 3.9 months (95% CI 2.8–5.2 months) (p < 0.001) (Fig. 2 lower). In patients with modified-RPA Class I+IIa disease, MSTs were very similar in Groups A and B (7.9 and 7.1 months, HR 0.938, 95% CI 0.624–1.406, p = 0.76). In patients with modified-RPA Classes I+IIa and IIc+III disease, MSTs in Group A were shorter than those in Group B (11.6 vs 14.3 months and 2.8 vs 3.9 months), but these differences did not reach statistical significance (HR 1.327, 95% CI 0.767–2.292, p = 0.31 and HR 1.059, 95% CI 0.784–1.433, p = 0.71).

Fig. 2.
Fig. 2.

Overall survivals based on 165 case-matched patients ≥ 80 years of age (Group A) (upper) and 165 case-matched patients 65–79 years of age (Group B) (lower) according to 3 modified-RPA30,33,34 patient Groups, I+IIa, IIb, and IIc+III, estimated using the standard Kaplan-Meier method.11

TABLE 5:

Outline of modified-RPA system*

Modified-RPA ClassGrading Criterion
I+IIaoriginal RPA Class I & Subclass IIa (score of 0 or 1)
IIbSubclass IIb (score of 2)
IIc+IIISubclass IIc (score of 3 or 4) & original RPA Class III

As presented by Yamamoto et al.33 The values in parentheses after subclasses refer to scores on the subclassification system for RPA Class II, which are based on the sum of a patient's scores for each of the following: KPS score, 90–100 (0) vs 70–80 (1); tumor number, solitary (0) vs multiple (1); controlled primary tumor, yes (0) vs no (1); extracerebral metastases, no (0) vs yes (1).4

Discussion

Is SRS a Reasonable Treatment for Brain Metastases in Patients 80 Years or Older?

In general, most physicians consider patients with brain metastases who are over 65 years of age to be unfavorable candidates for aggressive treatment (surgery, WBRT, or SRS). However, during the 15-year-period of the present study, there have been several reports on treatment of patients with brain metastases in this age group (Table 6). Noel et al.19 reported, based on 117 brain metastasis patients who were 65 years of age or older and underwent Linac-based SRS, that post-SRS MST was 8 months and actuarial survival rates were 58% ± 5% and 13% ± 4% at the 6th and 24th post-SRS months. Minniti et al.17 reported, based on 102 patients with brain metastases who were 70 years of age or older and underwent SRS, that post-SRS MST was 13.2 and that the 1- and 2-year survival rates after SRS were 63% and 28%. The 1- and 2-year post-SRS local control rates in their study were 90% and 84%. Kim et al.13 reported, based on 44 patients with brain metastases who were 75 years of age or older and underwent SRS (57%) or SRS plus WBRT (43%), that the MST from the time of diagnosis of brain metastasis was 7.3 ± 1.65 months. These results support applying SRS more aggressively for patients with brain metastases who are 70 years and older, or even those 75 years and older. However, there is little information on SRS for patients with brain metastases who are 80 years of age and older.

TABLE 6:

Publications on elderly patients with brain metastases*

Authors & YearNo. of PatientsTreatment Modalities (no.)Survival
Hotta et al., 1999311; <70 yrs: 213; ≥70 yrs: 98surgery (20), surgery + radiation (36), radiation (163), other (92)<70 yrs: 3.8 mos MST; ≥70 yrs: 2.9 mos MST
Lutterbach et al., 2005916; <50 yrs: 206; 50 64 yrs: 435; ≥65 yrs: 275surgery + WBRT (257), WBRT (659)overall: 3.5 mos MST from 1st day of RT; <65 yrs: 3.8 mos MST; ≥65 yrs: 2.6 mos MST
Noel et al., 2005117 (≥65 yrs)SRS (79); SRS + WBRT (38)overall: 8.0 mos MST from day of SRS
Kim et al., 200844 (≥75 yrs)SRS (25); SRS + WBRT (19)overall: 7.3 mos MST from day of Dx; 1 tumor: 10.1 mos MST, ≥2 tumors: 6.6 mos MST
Rades et al., 2008164 (≥65 yrs, 1–2 tumors)WBRT (34); SRS (43); surgery + WBRT (41); surgery + WBRT + boost (46)1-yr survival from completion of RT: 17, 40, 27, & 61%, respectively.
Minniti et al., 2013102 (≥70 yrs)SRS (102)overall: 13.2 MST mos from day of Dx; 63% at 1 yr & 28% at 2 yrs from day of SRS
present study165 (≥80 yrs); 165 (65 79 yrs)SRS≥80 yrs: 5.3 mos MST from day of SRS; 65 79 yrs: 6.9 mos MST from day of SRS

Dx = diagnosis; RT = radiotherapy.

In our present case-matched study, the post-SRS MST difference, 1.6 months, between Groups A (5.3 months) and B (6.9 months) was not statistically significant. Furthermore, even among Group A patients, there are subsets in which longer survival can be expected (> 6 months or even ~ 12 months after SRS) (Fig. 2). It is generally recognized that the main goal in caring for a patient with brain metastasis, regardless of the patient's age, is amelioration of neurological symptoms and/or prevention of status deterioration by avoiding worsening of neurological symptoms and, eventually, neurological death. The present study clearly demonstrated Group A patients to have noninferior results in terms of both neurological deterioration and death as compared with Group B patients. Also, Group A patients were demonstrated to have noninferior results as compared with Group B patients in terms of local recurrence, repeat SRS required for new tumors, salvage WBRT and surgery, or SRS-related complications.

Is Dose De-Escalation Necessary in Elderly Patients?

There is no solid consensus regarding whether dose de-escalation is necessary in SRS treatment for elderly patients. In our recently published study based on 167 patients with brain metastases who survived at least 3 years after SRS, neither patient age nor radiosurgical dose was a significant predictor of long-term complications.31 Also, in our herein-reported cohort study based on 2552 patients, including some younger than 65 years of age, neither patient age (≥ 65 vs < 65 years, HR 1.166, 95% CI 0.707–1.924, p = 0.55) nor minimum doses (as continuous variables, HR 1.003, 95% CI 0.933–1.086, p = 0.93) impacted cumulative incidences of SRS-related complications. Therefore, dose de-escalation is considered to be unnecessary for elderly patients receiving SRS.

Is WBRT Necessary With SRS?

Controversy persists as to whether SRS+WBRT is superior to SRS alone for treating brain metastases, because when patients are treated with SRS alone, microscopic tumors will still grow, and salvage SRS or WBRT will be required soon after the initial SRS. Thus, WBRT has generally been advocated. However, WBRT can be expected to prevent new tumors arising within 6–8 post-WBRT months at the longest, as shown in Fig. 2 of the report by Aoyama et al.1 We should remember that considerable numbers of patients with brain metastases can survive more than 1 year, outliving the effects of WBRT. Tsao et al. conducted a meta-analysis using data from previously published randomized controlled trials comparing SRS alone vs SRS plus WBRT.26 They concluded that, although additional WBRT improved distal and local control, SRS alone should be considered a routine treatment option due to favorable neurocognitive outcomes, less risk of late side effects, and the absence of adverse effects on patient performance status.

Fortunately, we already live in an era when a metastatic lesion with a diameter of 2 mm or even slightly smaller can be detected using thin-slice, Gd-enhanced MR images.8 Hanssens et al.7 recently reported that SRS alone, based on high-resolution MRI, decreased the incidence of and increased the time until distant recurrences. In fact, although data on periods between SRS and the appearance of new lesions were not available, the present study showed that rates of repeat SRS for new lesions were relatively low, 14.6% and 21.1% in our Groups A and B (Table 3). Cumulative rates of repeat SRS for new lesions were particularly low in our Group A patients, being 9.1%, 12.7%, 13.9%, and 13.9% at the 6th, 12th, 24th, and 36th post-SRS months, respectively. As we recently reported elsewhere, based on our cohort study including all age groups, the rate of repeat SRS for new lesions was 30.5%. We can reasonably speculate that most physicians would not have recommended further aggressive treatment for considerable numbers of elderly patients with brain metastases, even if new lesions appeared on MR images, because of advanced age.

Weaknesses of the Present Study

The major weakness of a retrospective study might be that clinical factors are obviously heterogeneous. As our previous reports described these issues in detail, they are not repeated herein.29 Briefly, the characteristics of patients receiving a particular treatment regimen are considered to have a major influence on treatment selection. This is an important issue when estimating the effects of treatments or exposures on outcomes using observational data. One approach to reducing or eliminating the effect of treatment selection bias and confounding effects is to use propensity score matching, which allows one to design and analyze an observational (nonrandomized) study that mimics some of the characteristics of a randomized controlled trial. Therefore, in the present investigation, a case-matched study was also conducted by one of the authors (Y.S.), who did not participate in other aspects of this study and was blinded to final outcomes. Nevertheless, because this was a retrospective study, even if case matching were to be applied, biases in patient selection, original cancer treatments over time, follow-up (outcome, toxicity, and imaging), observers, and so on, could not be eliminated.

As clarified in the Patient Population section of Methods, another potential weakness might be that meticulous follow-up was lacking in approximately 25% of our cohort. However, most of these patients died rather early due to systemic disease progression before SRS-induced complications could have occurred. Furthermore, with respect to these complications, only patients with RTOG neurotoxicity Grade 2 or worse were counted in this study, because, if severe problems, not only those that were symptomatic but also those detectable only on MRI, occurred in SRS-treated patients, every physician, without exception, consulted us; however, some busy physicians actually forgot to report minor problems like RTOG neurotoxicity Grade 0 or 1 to us. Therefore, a potential weakness of this study is that some minor complications may not have been included.

How Should Candidates for SRS be Selected From Among Elderly Patients With Brain Metastases?

How to select good candidates for SRS alone, even from among patients 80 years of age or older, is a very important issue. As numerous factors (including the primary cancer site, systemic disease condition, neurological symptoms, numbers and sizes of brain metastases) impact outcomes, clinicians are often uncertain as to the optimal treatment—WBRT, surgery, SRS or radiotherapy, anticancer agent administration, or combinations of these modalities, efficacies of which vary among patient subsets. An improved prognostic index might resolve some of the uncertainty in making treatment decisions as well as guiding future research efforts. Although 5 prognostic grading indices for initially treated brain metastasis patients, RPA, Score Index for Radiosurgery (SIR),28 Basic Score for Brain Metastases (BSBM),14 Graded Prognostic Assessment (GPA)24 and modified RPA30,33,34 are well established, the RPA, SIR, and GPA incorporate age factors and therefore are not applicable to elderly patient subsets. The BSBM incorporates no brain metastasis–related factors—neither tumor number nor tumor size, both of which are widely accepted as major factors influencing patient survival periods. Sperduto et al. recently modified their GPA system to derive the Diagnosis-Specific GPA (DS-GPA).25 Their new system uses a different scoring method, which takes into account different primary tumor types. Six common types of primary cancer associated with brain metastases (non–small cell lung cancer, small cell lung cancer, breast cancer, melanoma, renal cell cancer, and gastrointestinal cancer) were scored to allow comparison of post-WBRT survival rates. However, among the 6 original tumor categories, DS-GPA can be used for elderly brain metastasis patients only with breast cancer or gastrointestinal cancer because age factors are incorporated. Although the database that was used in the present paper included approximately 80% of the patients whose data were used for deriving the modified-RPA system in our previous publication,33 we intended to prove, in the present study, that this system is potentially useful for selecting favorable candidates among a small subset of elderly patients who are 65 years of age or older, or even 80 years of age or older. A possible criticism of this system is that the subgroup designation of Class I+IIa may not be appropriate because there were no original RPA Class I patients. Since yet another new index for elderly patients with brain metastases might result in even greater uncertainty among clinicians, we used the modified-RPA system for the present study.

Conclusions

Our results suggest that carefully selected patients 80 years of age or older are not poor candidates for SRS as compared with those 65–79 years old. Particularly, among patients 80 years of age or older, those in modified-RPA Class I+IIa or IIb are considered to be favorable candidates for more aggressive treatment of brain metastases.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Yamamoto. Acquisition of data: Yamamoto, Watanabe, Kawabe. Analysis and interpretation of data: Yamamoto, Watanabe, Higuchi. Drafting the article: Yamamoto, Barfod. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Yamamoto. Statistical analysis: Sato, Higuchi. Study supervision: Yamamoto, Kasuya, Yamamoto, Matsumura. Edited English: Barfod.

References

  • 1

    Aoyama HShirato HTago MNakagawa KToyoda THatano K: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:248324912006

    • Search Google Scholar
    • Export Citation
  • 2

    Bakoyannis GTouloumi G: Practical methods for competing risks data: a review. Stat Methods Med Res 21:2572722012

  • 3

    Fine JPGray RJ: A proportional hazards model for the sub-distribution of a competing risk. J Am Stat Assoc 94:4965091999

  • 4

    Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

    • Search Google Scholar
    • Export Citation
  • 5

    Gooley TALeisenring WCrowley JStorer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18:6957061999

    • Search Google Scholar
    • Export Citation
  • 6

    Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:114111541988

  • 7

    Hanssens PKarlsson BYeo TTChou NBeute G: Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences. Clinical article. J Neurosurg 115:4995042011

    • Search Google Scholar
    • Export Citation
  • 8

    Hayashi MYamamoto MNishimura CSatoh H: Do recent advances in MR technologies contribute to better gamma knife radiosurgery treatment results for brain metastases?. Neuroradiol J 20:4814902007

    • Search Google Scholar
    • Export Citation
  • 9

    Hotta TKohno HTaniguchi EMagaki THidaka TNishimoto T: Treatment option for elderly patients with metastatic brain tumors. Jpn J Cancer Clin 45:114311481999

    • Search Google Scholar
    • Export Citation
  • 10

    Kano HKondziolka DLobato-Polo JZorro OFlickinger JCLunsford LD: T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 66:4864922010

    • Search Google Scholar
    • Export Citation
  • 11

    Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958

  • 12

    Karnofsky DABuechenal JHThe clinical evaluation of chemotherapeutic agents in cancer. MacLeod CM: Evaluation of Chemotherapeutic Agents New YorkColumbia University Press1949. 191205

    • Search Google Scholar
    • Export Citation
  • 13

    Kim SHWeil RJChao STToms SAAngelov LVogelbaum MA: Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer 113:8348402008

    • Search Google Scholar
    • Export Citation
  • 14

    Lorenzoni JDevriendt DMassager NDavid PRuíz SVanderlinden B: Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:2182242004

    • Search Google Scholar
    • Export Citation
  • 15

    Lutterbach JBartelt SMomm FBecker GFrommhold HOstertag C: Is older age associated with a worse prognosis due to different patterns of care? A long-term study of 1346 patients with glioblastomas or brain metastases. Cancer 103:123412442005

    • Search Google Scholar
    • Export Citation
  • 16

    Matsuo MMiwa KShinoda JKako NNishibori HSakurai K: Target definition by C11-methionine-PET for the radiotherapy of brain metastases. Int J Radiat Oncol Biol Phys 74:7147222009

    • Search Google Scholar
    • Export Citation
  • 17

    Minniti GEsposito VClarke EScaringi CBozzao ALanzetta G: Stereotactic radiosurgery in elderly patients with brain metastases. J Neurooncol 111:3193252013

    • Search Google Scholar
    • Export Citation
  • 18

    Nariai TTanaka YWakimoto HAoyagi MTamaki MIshiwata K: Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:4985072005

    • Search Google Scholar
    • Export Citation
  • 19

    Noel GBollet MANoel SFeuvret LBoisserie GTep B: Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases. Int J Radiat Oncol Biol Phys 63:155515612005

    • Search Google Scholar
    • Export Citation
  • 20

    Parsons LS: Reducing bias in a propensity score matched-pair sample using greedy matching techniques. SAS (http://www2.sas.com/proceedings/sugi26/p214-26.pdf) [Accessed June 18 2014]

    • Search Google Scholar
    • Export Citation
  • 21

    Rades DPluemer AVeninga TSchild SE: Comparison of different treatment approaches for one to two brain metastases in elderly patients. Strahlenther Onkol 184:5655712008

    • Search Google Scholar
    • Export Citation
  • 22

    Radiation Therapy Oncology Group: Cooperative Group Common Toxicity Criteria (http://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroupCommonToxicityCriteria.aspx) [Accessed June 18 2014]

    • Search Google Scholar
    • Export Citation
  • 23

    Satagopan JMBen-Porat LBerwick MRobson MKutler DAuerbach AD: A note on competing risks in survival data analysis. Br J Cancer 91:122912352004

    • Search Google Scholar
    • Export Citation
  • 24

    Sperduto PWBerkey BGaspar LEMehta MCurran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:5105142008

    • Search Google Scholar
    • Export Citation
  • 25

    Sperduto PWChao STSneed PKLuo XSuh JRoberge D: 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 77:6556612010

    • Search Google Scholar
    • Export Citation
  • 26

    Tsao MXu WSahgal A: A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer 118:248624932012

    • Search Google Scholar
    • Export Citation
  • 27

    Tsuyuguchi NSunada IIwai YYamanaka KTanaka KTakami T: Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible?. J Neurosurg 98:105610642003

    • Search Google Scholar
    • Export Citation
  • 28

    Weltman ESalvajoli JVBrandt RAde Morais Hanriot RPrisco FECruz JC: Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys 46:115511612000

    • Search Google Scholar
    • Export Citation
  • 29

    Yamamoto MIde MNishio SiUrakawa Y: Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment?. Int J Radiat Oncol Biol Phys 53:127912832002

    • Search Google Scholar
    • Export Citation
  • 30

    Yamamoto MKawabe THiguchi YSato YBarfod BEKasuya H: Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. Int J Radiat Oncol Biol Phys 84:111011152012

    • Search Google Scholar
    • Export Citation
  • 31

    Yamamoto MKawabe THiguchi YSato YNariai TBarfod BE: Delayed complications in patients surviving at least 3 years after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 85:53602013

    • Search Google Scholar
    • Export Citation
  • 32

    Yamamoto MKawabe TSato YHiguchi YNariai TBarfod BE: A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs ≥ 5 tumors. Clinical article. J Neurosurg 118:125812682013

    • Search Google Scholar
    • Export Citation
  • 33

    Yamamoto MSato YSerizawa TKawabe THiguchi YNagano O: Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically. Int J Radiat Oncol Biol Phys 83:139914052012

    • Search Google Scholar
    • Export Citation
  • 34

    Yamamoto MSerizawa TSato YKawabe THiguchi YNagano O: Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases. J Neurooncol 111:3273352013

    • Search Google Scholar
    • Export Citation
  • 35

    Yancik RRies LAG: Cancer in older persons: an international issue in an aging world. Semin Oncol 31:1281362004

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Article Information

Address correspondence to: Masaaki Yamamoto, M.D., Katsuta Hospital Mito GammaHouse, 5125-2 Nakane, Hitachi-naka, Ibaraki 312-0011, Japan. email: bcd06275@nifty.com.

Please include this information when citing this paper: published online July 25, 2014; DOI: 10.3171/2014.6.JNS132790.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Overall survival based on 330 case-matched patients divided into 2 age groups, ≥ 80 years (Group A) and 65–79 years (Group B), estimated using the standard Kaplan-Meier method.11

  • View in gallery

    Overall survivals based on 165 case-matched patients ≥ 80 years of age (Group A) (upper) and 165 case-matched patients 65–79 years of age (Group B) (lower) according to 3 modified-RPA30,33,34 patient Groups, I+IIa, IIb, and IIc+III, estimated using the standard Kaplan-Meier method.11

References

  • 1

    Aoyama HShirato HTago MNakagawa KToyoda THatano K: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:248324912006

    • Search Google Scholar
    • Export Citation
  • 2

    Bakoyannis GTouloumi G: Practical methods for competing risks data: a review. Stat Methods Med Res 21:2572722012

  • 3

    Fine JPGray RJ: A proportional hazards model for the sub-distribution of a competing risk. J Am Stat Assoc 94:4965091999

  • 4

    Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

    • Search Google Scholar
    • Export Citation
  • 5

    Gooley TALeisenring WCrowley JStorer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18:6957061999

    • Search Google Scholar
    • Export Citation
  • 6

    Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:114111541988

  • 7

    Hanssens PKarlsson BYeo TTChou NBeute G: Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences. Clinical article. J Neurosurg 115:4995042011

    • Search Google Scholar
    • Export Citation
  • 8

    Hayashi MYamamoto MNishimura CSatoh H: Do recent advances in MR technologies contribute to better gamma knife radiosurgery treatment results for brain metastases?. Neuroradiol J 20:4814902007

    • Search Google Scholar
    • Export Citation
  • 9

    Hotta TKohno HTaniguchi EMagaki THidaka TNishimoto T: Treatment option for elderly patients with metastatic brain tumors. Jpn J Cancer Clin 45:114311481999

    • Search Google Scholar
    • Export Citation
  • 10

    Kano HKondziolka DLobato-Polo JZorro OFlickinger JCLunsford LD: T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 66:4864922010

    • Search Google Scholar
    • Export Citation
  • 11

    Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958

  • 12

    Karnofsky DABuechenal JHThe clinical evaluation of chemotherapeutic agents in cancer. MacLeod CM: Evaluation of Chemotherapeutic Agents New YorkColumbia University Press1949. 191205

    • Search Google Scholar
    • Export Citation
  • 13

    Kim SHWeil RJChao STToms SAAngelov LVogelbaum MA: Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer 113:8348402008

    • Search Google Scholar
    • Export Citation
  • 14

    Lorenzoni JDevriendt DMassager NDavid PRuíz SVanderlinden B: Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int J Radiat Oncol Biol Phys 60:2182242004

    • Search Google Scholar
    • Export Citation
  • 15

    Lutterbach JBartelt SMomm FBecker GFrommhold HOstertag C: Is older age associated with a worse prognosis due to different patterns of care? A long-term study of 1346 patients with glioblastomas or brain metastases. Cancer 103:123412442005

    • Search Google Scholar
    • Export Citation
  • 16

    Matsuo MMiwa KShinoda JKako NNishibori HSakurai K: Target definition by C11-methionine-PET for the radiotherapy of brain metastases. Int J Radiat Oncol Biol Phys 74:7147222009

    • Search Google Scholar
    • Export Citation
  • 17

    Minniti GEsposito VClarke EScaringi CBozzao ALanzetta G: Stereotactic radiosurgery in elderly patients with brain metastases. J Neurooncol 111:3193252013

    • Search Google Scholar
    • Export Citation
  • 18

    Nariai TTanaka YWakimoto HAoyagi MTamaki MIshiwata K: Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:4985072005

    • Search Google Scholar
    • Export Citation
  • 19

    Noel GBollet MANoel SFeuvret LBoisserie GTep B: Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases. Int J Radiat Oncol Biol Phys 63:155515612005

    • Search Google Scholar
    • Export Citation
  • 20

    Parsons LS: Reducing bias in a propensity score matched-pair sample using greedy matching techniques. SAS (http://www2.sas.com/proceedings/sugi26/p214-26.pdf) [Accessed June 18 2014]

    • Search Google Scholar
    • Export Citation
  • 21

    Rades DPluemer AVeninga TSchild SE: Comparison of different treatment approaches for one to two brain metastases in elderly patients. Strahlenther Onkol 184:5655712008

    • Search Google Scholar
    • Export Citation
  • 22

    Radiation Therapy Oncology Group: Cooperative Group Common Toxicity Criteria (http://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroupCommonToxicityCriteria.aspx) [Accessed June 18 2014]

    • Search Google Scholar
    • Export Citation
  • 23

    Satagopan JMBen-Porat LBerwick MRobson MKutler DAuerbach AD: A note on competing risks in survival data analysis. Br J Cancer 91:122912352004

    • Search Google Scholar
    • Export Citation
  • 24

    Sperduto PWBerkey BGaspar LEMehta MCurran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:5105142008

    • Search Google Scholar
    • Export Citation
  • 25

    Sperduto PWChao STSneed PKLuo XSuh JRoberge D: 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 77:6556612010

    • Search Google Scholar
    • Export Citation
  • 26

    Tsao MXu WSahgal A: A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer 118:248624932012

    • Search Google Scholar
    • Export Citation
  • 27

    Tsuyuguchi NSunada IIwai YYamanaka KTanaka KTakami T: Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible?. J Neurosurg 98:105610642003

    • Search Google Scholar
    • Export Citation
  • 28

    Weltman ESalvajoli JVBrandt RAde Morais Hanriot RPrisco FECruz JC: Radiosurgery for brain metastases: a score index for predicting prognosis. Int J Radiat Oncol Biol Phys 46:115511612000

    • Search Google Scholar
    • Export Citation
  • 29

    Yamamoto MIde MNishio SiUrakawa Y: Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment?. Int J Radiat Oncol Biol Phys 53:127912832002

    • Search Google Scholar
    • Export Citation
  • 30

    Yamamoto MKawabe THiguchi YSato YBarfod BEKasuya H: Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. Int J Radiat Oncol Biol Phys 84:111011152012

    • Search Google Scholar
    • Export Citation
  • 31

    Yamamoto MKawabe THiguchi YSato YNariai TBarfod BE: Delayed complications in patients surviving at least 3 years after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 85:53602013

    • Search Google Scholar
    • Export Citation
  • 32

    Yamamoto MKawabe TSato YHiguchi YNariai TBarfod BE: A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs ≥ 5 tumors. Clinical article. J Neurosurg 118:125812682013

    • Search Google Scholar
    • Export Citation
  • 33

    Yamamoto MSato YSerizawa TKawabe THiguchi YNagano O: Subclassification of recursive partitioning analysis Class II patients with brain metastases treated radiosurgically. Int J Radiat Oncol Biol Phys 83:139914052012

    • Search Google Scholar
    • Export Citation
  • 34

    Yamamoto MSerizawa TSato YKawabe THiguchi YNagano O: Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases. J Neurooncol 111:3273352013

    • Search Google Scholar
    • Export Citation
  • 35

    Yancik RRies LAG: Cancer in older persons: an international issue in an aging world. Semin Oncol 31:1281362004

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