Neuro-Oncology Advances 1

2(1), 1–10, 2020 | doi:10.1093/noajnl/vdaa041 | Advance Access date 24 April 2020

Epidemiology of synchronous brain metastases

  

Raj Singh, Kelsey C. Stoltzfus, Hanbo Chen, Alexander V. Louie, Eric J. Lehrer, Samantha R. Horn,
Joshua D. Palmer, Daniel M. Trifiletti, Paul D. Brown, and Nicholas G. Zaorsky

Department of Radiation Oncology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
(R.S.); Department of Radiation Oncology, Penn State Cancer Institute, Hershey, Pennsylvania, USA (K.C.S., S.R.H.,
N.G.Z.); Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania, USA (K.C.S.,

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

S.R.H., N.G.Z.); Department of Radiation Oncology, London Health Sciences Centre, London, Ontario, Canada (H.C.);
Department of Radiation Oncology, Odette Cancer Centre—Sunnybrook Health Sciences Centre, Toronto, Ontario,
Canada (A.V.L.); Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York,
USA (E.J.L.); Department of Radiation Oncology, The James Cancer Hospital at the Ohio State University Wexner
Medical Center, Columbus, Ohio, USA (J.D.P.); Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida,
USA (D.M.T.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA (P.D.B.)

Corresponding Author: Nicholas G. Zaorsky, MD, Department of Radiation Oncology, Penn State Cancer Institute; Department of
Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA (nicholaszaorsky@gmail.com).

Abstract
Background. The objectives of this study were to characterize (1) epidemiology of brain metastases at the time of
primary cancer diagnosis, (2) incidence and trends of synchronous brain metastases from 2010 to 2015, and (3)
overall survival (OS) of patients with synchronous brain metastases.
Methods. A total of 42 047 patients with synchronous brain metastases from 2010 to 2015 were identified from the
Surveillance, Epidemiology, and End Results database. Descriptive analysis was utilized to analyze demographics
and incidence. The Kaplan–Meier method and a Cox proportional hazards model were utilized to evaluate potential
prognostic factors for OS.
Results. The majority of patients were diagnosed from age older than 50 (91.9%). Common primary sites included
lung (80%), melanoma (3.8%), breast (3.7%), and kidney/renal pelvis (3.0%). Among pediatric patients, common pri-
maries included kidney/renal pelvis and melanomas. The incidence was roughly 7.3 persons/100 000. Synchronous
brain metastases were associated with significantly poorer OS compared to extracranial metastases alone (hazard
ratio [HR] =1.56; 95% CI: 1.54–1.58; P < .001). Among patients with brain metastases, male gender (HR = 1.60 vs
1.52), age older than 65 years (HR = 1.60 vs 1.46), synchronous liver, bone, or lung metastases (HR = 1.61 vs 1.49),
and earlier year of diagnosis (HR = 0.98 for each year following 2010) were associated with significantly poorer OS.
Conclusions. The vast majority of brain metastases are from lung primaries. Synchronous brain metastases are
associated with poorer OS compared to extracranial metastases alone.

Key Points
• The incidence of synchronous brain metastases was 7.3/100 000; roughly 80% were from
lung primaries.
• Brain metastases are associated with poorer survival among those with extracranial
metastatic disease.
• Older age, male gender, and extracranial metastases are associated with poorer survival
among patients with brain metastases.

© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
2 Singh et al. Epidemiology of synchronous brain metastases

Importance of the Study

We sought to analyze modern incidences and and cancers of the kidney/renal pelvis and cu-
demographics of patients with synchronous taneous melanomas being common primary
brain metastases, examine the impact of brain sites among pediatric patients. Patients with
metastases on survival for patients with met- metastatic disease with brain metastases were
astatic disease, and evaluate potential factors noted to have poorer survival as compared to
associated with survival among patients with patients with extracranial metastases alone.
brain metastases in the United States utilizing Also, patients with brain metastases who were
the SEER database. From 2010 to 2015, we older than 65 years, of male gender, diagnosed
noted that there was no significant change in earlier in the time period studied, or also had

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

the incidence of brain metastases at primary liver, bone, or lung metastases had signifi-
cancer diagnosis, with a predominance of brain cantly poorer survival.
metastases (roughly 80%) from lung primaries

Brain metastases account for the majority of intracranial

tumors and constitute the disease course of anywhere
from 15% to 20% of adults and 5–10% of children with ma-
Materials and Methods
lignancies. Estimates of new diagnoses of brain metas- Data Acquisition
tases each year in the United States range anywhere from
roughly 30 000 to 40 000 patients.1–3 The most common Patients with brain metastases at the time of primary
primary sites in adults have previously been shown to be cancer diagnosis, diagnosed between 2010 and 2015
cancers of the lung, kidney, breast, and colon, in addition (2010 is when information on brain metastases began
to melanomas; in the pediatric population common pri- to be queried), were captured from the National Cancer
mary sites are generally thought to be sarcomas, germ Institute’s Surveillance, Epidemiology, and End Results
cell tumors, and neuroblastomas.1–5 The morbidity and (SEER) program. For the purposes of the analysis to com-
mortality associated with brain metastases are gener- pare demographics, patients without brain metastases
ally quite poor, with associated neurologic deficits either were also queried from the SEER database. SEER is a net-
from mass effect secondary to the tumors themselves or work of population-based incidence tumor registries that
therapy-related toxicities, and median overall survival covered 27.8% of the US population consisting of geo-
(OS) ranging from 3 to 15 months.6–9 graphically distinct regions of the United States at the time
Notably, the incidence of brain metastases has re- of data analysis.16 Prior reports have noted both strengths
portedly risen over the past few decades for a number and limitations of the SEER database, with strengths in-
of primary cancer sites, particularly among patients cluding a large cohort of patients available for analysis al-
with breast cancers,10 colorectal cancers,11 and non- lowing for generalizability to the US population as well as
small-cell lung cancer (NSCLC).12 However, these ob- quality control programs to minimize miscoding of patient
servations are limited to single-institution reports, information.16–18
smaller multi-institutional series, or patients enrolled SEER*Stat 8.3.5 was used for analysis. Patients diag-
on clinical trials.6,13 Previous studies have examined nosed by autopsy or death certificate alone were excluded
the epidemiology of brain metastases in Detroit and from the analysis. The SEER 18 registry (2000–2015) was
The Netherlands.14,15 There are currently no data on the used for the current analysis, including both the case
epidemiology of brain metastases among all cancer pa- listing and rate sessions.16 All incidence rates were age-
tients in the United States. adjusted to the 2000 US standard population and are re-
We sought to address this gap in the literature regarding ported per 100 000 persons. Additional analyses were
patients with synchronous brain metastases (defined conducted using Microsoft Excel 15.0.5 (Microsoft) and R
as patients diagnosed with brain metastases at primary Studio (R Studio Inc.).
cancer diagnosis) with 3 main aims. First, we aimed to
examine the demographics of patients with synchro-
nous brain metastases, with an emphasis on patient age, Statistical Analyses
gender, race, and primary cancer site. Second, we analyzed
recent trends in the incidence of synchronous brain metas- For all patients with brain metastases, demographics were
tases in the United States among the general population, categorized by age at diagnosis, race, sex, and primary
as well as by primary cancer site and age group at diag- site. Furthermore, patients with and without de novo brain
nosis. Finally, we sought to compare the OS of patients metastases were compared by age, sex, year of diagnosis,
with synchronous brain metastases to patients with extra- presence of non-brain metastases, race, T stage, N stage,
cranial metastases alone at primary cancer diagnosis as median follow-up duration, and primary cancer site. To
well as examine for any factors associated with OS among assess differences in these categories between patients
patients with brain metastases. with and without brain metastases, t-tests, chi-squared
 Singh et al. Epidemiology of synchronous brain metastases 3

Advances
Neuro-Oncology
tests, or log-rank tests for continuous, categorical, and information on other sites of metastatic disease or OS.
time to event variables, respectively, were used where ap- A total of 2 056 647 patients without brain metastases were
propriate. Additionally, trends in incidence rates over the also identified for means of comparing baseline demo-
study time period (2010–2015) were assessed by the pri- graphics. A summary of patient characteristics with syn-
mary cancer site. A weighted least-squares method was chronous brain metastases by age, race, sex, and cancer
used to calculate annual percentage changes (APCs) with site broken down by year and with overall statistics over
SEER*Stat. While all cancer sites were included in the anal- the time period studied can be found in Supplementary
ysis, only primary cancers with an incidence rate greater Table 1. With regard to age, the most common age group
than 0.05 per 100 000 persons from 2010 to 2015 are pre- in which a diagnosis of brain metastasis was made was
sented to simplify interpretation. A Bonferroni correction from 60 to 69 years old (33%), followed by 70–79 years
was applied to all analyses other than those stratified by old (24.5%), 50–59 years old (23.3%), older than 80 years
primary sites testing 9 hypotheses, which resulted in statis- (11.2%), and younger than 50 years (8.11%). Males com-
tical significance being set at P < .006. prised 52.5% of the cohort examined, with whites, blacks,

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

For the survival analysis, the population was defined and other races comprising 80.1%, 12%, and 7.8% of pa-
as all cases with de novo metastatic cancer (M1 by the tients, respectively. Additionally, we examined differences
American Joint Committee on Cancer 7th edition defini- in demographics between patients with synchronous brain
tion). The main exposure was the presence of synchronous metastases as compared to all other patients without brain
brain metastasis as a dichotomous variable and the main metastases, which is provided in Table 1. Patients with syn-
outcome was OS, which was estimated by the Kaplan– chronous brain metastases were more likely to be older,
Meier method. Median follow-up was estimated using male, non-white, and have more advanced T and N staging
the reverse Kaplan–Meier method.19 Kaplan–Meier curves (all P < .001).
were created to compare OS between metastatic patients We also examined the incidence of synchronous brain
with synchronous brain metastases (with or without other metastases by age at diagnosis for males and females
metastases at primary diagnosis) and patients with extra- separately, shown in Figure 1A and B and Figure 1C and
cranial metastases alone at primary cancer diagnosis (lung, D, respectively. Among male patients 1–4 years of age
liver, and/or bone with no brain metastasis). Univariate and female patients less than 1 year of age, tumors of the
Cox proportional hazards regressions were used to com- kidney and renal pelvis were the only primary site associ-
pare the hazards of death for patients with synchronous ated with brain metastases. Melanomas and lung cancers
brain metastases versus those with extracranial metas- were the most common primary sites from ages 10–14 and
tases alone. Potential confounders of age (continuous), sex 15–29 years old, respectively, in the male cohort. Similar
(dichotomous), race (categorical), year of diagnosis (cate- to male pediatric patients, melanomas were the most
gorical), T- and N-stage (categorical), and the presence of common primary sites among female patients aged 10–14.
other metastases (dichotomous) were adjusted for with a Cancers of the lung comprised the majority of primary
multivariable Cox regression model. Effect modification sites for both male and female patients aged 35 years and
for OS among patients with brain metastases by age, sex, older with brain metastases as the time of primary cancer
race, year of diagnosis, and the presence of other metas- diagnosis.
tases (bone, liver, or lung) was investigated by the addi-
tion of interaction terms to multivariable Cox regression
models. For lung and breast cancer patients, the effect of Trends in Incidences of Synchronous Brain
different cancer subtypes (either NSCLC or small-cell lung Metastases Stratified by Disease Site and Age
cancer [SCLC] as well as hormone receptor [HR] positive
Trends in brain metastases by the primary site over time
or negative and HER2-neu positive or negative) was also
can be found in Supplementary Table 2 and Figure 2. The
investigated with interaction terms. The proportional haz-
most common primary site was consistently lung (with
ards assumption was assessed using Schoenfeld residual
an incidence ranging from 5.596 to 5.954 per 100 000, or
tests and Log(HR) versus time plots for the overall and site-
roughly 80% of all brain metastases) from 2010 to 2015,
specific multivariable regression models. Results stratified
with melanoma (0.252–0.324 per 100 000; 3.8%) and breast
by primary site of origin were subject to Holm’s correction
(0.244–0.284 per 100 000; 3.7%) being the second and
for multiple testing, with a threshold for statistical signifi-
third most common sites, followed closely by cancers of
cance of .05 post-adjustment.20,21
the kidney and renal pelvis (0.206–0.22 per 100 000; 3.0%).
Upon examination of lung and bronchus by subtype, we
noted an incidence of roughly 4.0–4.3 persons per 100
000 among NSCLC patients and 0.92–0.99 persons per
Results
100 000 among SCLC patients (Supplementary Figure 2).
Patient Demographics Stratified by Age The incidence of synchronous brain metastases across all
and Gender primary sites ranged from roughly 7.1 to 7.4 persons per
100 000 and was relatively constant throughout the study
A flowsheet of how patients were selected for inclusion for time period among all sites. A similar trend was observed
analysis can be seen in Supplementary Figure 1. We identi- when looking at trends over time by the primary site.
fied a total of 42 047 patients with synchronous brain me- A nonsignificant decline in brain metastasis diagnosis from
tastases from 2010 to 2015 with 41 105 patients available all primary sites during the time period was noted (−0.59%
for survival analysis after the exclusion of those without APC; P = .09) with the majority of this decline accounted
4 Singh et al. Epidemiology of synchronous brain metastases

   increases in incidences of brain metastases among those

Table 1. Summary of Baseline Characteristics of Patients With Brain aged 35–39 (P = .004) and declines among those aged
Metastases as Compared to Patients Without Brain Metastases
45–49 (P = .002) and 50–54 (P = .003).
Brain No Brain P
Metastasis Metastasis
(N = 42 047) (N = 2 056 647) Survival of Patients With Metastatic Disease
Age, mean 64.99 (12.02) 64.22 (14.50) <.001a Based on Disease Site and Presence of
(standard devi- Synchronous Brain Metastases or Extracranial
ation) Metastases Alone
Sex
We first examined OS outcomes of patients with syn-
Female 19 989 (47.5%) 1 040 294 (51.6%) <.001b
chronous brain metastases based on the primary site.
Male 22 058 (52.5%) 1 016 353 (49.4%) Kaplan–Meier estimate survival curves for the 6 most

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

Year of diagnosis common primary cancer sites based on whether patients
2010 6699 (15.9%) 334 313 (16.3%) had brain or extracranial metastases alone can be found
2011 6734 (16.0%) 339 201 (16.5%) in Supplementary Figure 3, with additional Kaplan–Meier
curves for the next 6 most common sites in Supplementary
2012 6961 (16.6%) 339 801 (16.5%) <.001b
Figure 4. Of the 6 most common primary sites, patients
2013 7114 (16.9%) 342 544 (16.7%) with breast cancer and brain metastasis had the highest
2014 7306 (17.4%) 347 392 (16.9%) 1-year OS rate of 41.4% and a median OS of 8 months.
2015 7233 (17.2%) 353 395 (17.2%) One-year OS rates and median OS for other common sites
were as follows: melanoma (24.7%; 4.9 months), kidney
Race
and renal pelvis (23.7%; 3.9 months), and lung (20.3%;
 American Indian/ 249 (0.6%) 12 127 (0.6%)
3.9 months). Among patients with brain metastases, other
Alaska Native
common sites associated with higher 1-year OS rates in-
 Asian or Pacific 2998 (7.1%) 137 248 (6.7%) <.001b cluded prostate (48.7%) and testes (52.7%), with poorer
Islander
outcomes in patients with pancreas (7.5%), bladder (10.9%),
Black 5034 (12.0%) 221 846 (10.8%) and stomach (15.0%) cancers, compared to the respective
White 33 692 (80.1%) 1 658 355 (80.6%) cancer population with extracranial metastases. We also
Unknown 74 (0.2%) 27 071 (1.3%) examined OS based on SCLC and NSCLC histologies,
which can be seen in Supplementary Figure 5 as well as
T-stage
for breast cancer by receptor status, which is presented in
T0 1201 (2.9%) 6567 (0.3%)
Supplementary Figure 6. Of note, a significant difference
T1 4446 (10.6%) 811 899 (39.5%) in OS was noted for patients with NSCLC with or without
T2 9144 (21.7%) 478 510 (23.3%) <.001b brain metastases (P < .0001) but not among patients with
T3 8348 (19.9%) 337 164 (16.4%) SCLC (P = .68). Poorer OS was noted among all patients
with breast cancer with synchronous brain metastases of
T4 10 894 (25.9%) 160 678 (7.8%)
any hormonal receptor subtype (P < .0001).
TX 6999 (16.6%) 137 323 (6.7%) We also analyzed for potential differences between pa-
Missing 1015 (2.4%) 62 048 (3.0%) tients with metastatic disease either with or without syn-
Other T 0 (0%) 62 458 (3.0%) chronous brain metastases. Patients with synchronous
N-stage
brain metastases were found to be significantly younger,
have lower rates of lung, bone, or liver metastases at di-
N0 10 155 (24.2%) 1 433 217 (69.7%)
agnosis, were more likely to be white, and had more
N+ 26 937 (64.1%) 491 890 (23.9%) <.001b advanced T and N stage with significant differences in pri-
NX 3927 (9.3%) 69 316 (3.4%) mary site (P < .001) (Supplementary Table 4). With regard to
Missing 1028 (2.4%) 1370 (0.1%) OS, as given in Table 2, on univariate analysis the hazard
ratio (HR) for OS for patients with synchronous brain
M-stage <.001b
metastases was significantly higher (HR = 1.43 [95% CI:
M1 1033 (97.6%) 293 557 (14.3%) 1.41–1.44]; P < .001). Following multivariable analysis con-
M0 0 (0%) 1 701 063 (82.7%) trolling for potential confounders across all primary sites,
Missing 1014 (2.4%) 62 027 (3.0%) patients with synchronous brain metastases had signifi-
cantly poorer OS as compared to those with extracranial
aTwo-sample t-tests. metastases alone (HR = 1.56 [95% CI: 1.54–1.58]; P < .001).
bChi-squared tests. Figure 3 demonstrates differences in OS by the primary
   site for patients with metastatic disease either with or
without brain metastases (all P < .001). The most marked
for by brain metastases from lung cancers (−0.932% APC; differences in OS between patients with either synchro-
P = .07) with no significant changes in incidence noted of nous brain metastases or extracranial metastases alone
any primary site. In Supplementary Table 3, trends in age- were noted for cancers of the tongue, anus/anal canal/
adjusted incidences of synchronous brain metastases anorectum, and testis. Of the top 12 most common sites
by age at diagnosis are given, which noted significant with brain metastases, patients with breast cancer and
 Singh et al. Epidemiology of synchronous brain metastases 5

Advances
Neuro-Oncology
  
Absolute incidence among males by age shows lung as Relative incidence among males by age shows kidney/renal pelvis and melanoma
A most common histology B as common histology among younger patients and lung among older patients
100%
4000
90% Lung
3500
80% Melanoma
3000 70%

Count (relative)
Breast
2500 60%
Count

Kidney
2000 50%
Esophagus
40%
1500 Colon and
30%
rectum
1000 20%
Misc.
500 10%
Stomach
0 0%
s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Prostate
ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar
ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye Corpus and
00 -04 -09 -14 -19 -24 -29 -34 -39 -44 -49 -54 -59 -64 -69 -74 -79 -84 85+ 00 -04 -09 -14 -19 -24 -29 -34 -39 -44 -49 -54 -59 -64 -69 -74 -79 -84 85+ uterus, NOS
01 05 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 01 05 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

Age at Diagnosis Age at Diagnosis

C Absolute incidence among females by age

shows lung as most common histology
D Relative incidence among females by age shows kidney/renal pelvis and melanoma
as common histology among younger patients and lung among older patients
3500 100%
3000 90%
80%
2500
70%
2000 Count (relative) 60%
Count

50%
1500
40%
1000 30%
20%
500
10%
0 0%
rs s s s s s s s s s s s s s s s
rs rs rs s s s s s s s s s s s s s s s s s s s
a a a a ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar ar
ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye ye
00 -04 -09 -14 -19 -24 -29 -34 -39 -44 -49 -54 -59 -64 -69 -74 -79 -84 85+ 00 -04 -09 -14 -19 -24 -29 -34 -39 -44 -49 -54 -59 -64 -69 -74 -79 -84 85+
01 05 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 01 05 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Age at Diagnosis Age at Diagnosis

Figure 1. Incidence of brain metastases among males and females, by age, from SEER 2010 to 2015. (A) Absolute incidence among males by age shows
lung as the most common histology. (B) Relative incidence among males by age shows kidney/renal pelvis and melanoma as common histology among
younger patients and lung among older patients. (C) Absolute incidence among females by age shows lung as the most common histology. (D) Relative
incidence among females by age shows kidney/renal pelvis and melanoma as common histology among younger patients and lung among older patients.
  

  
A Incidence by primary site shows stable incidence over time B Total incidence per year shows stable incidence over time
8
7
2010 2011 2012 2013 2014 2015
7 Lung
6 Melanoma
6 Breast
Incidence rate per 100 000
Incidence rate per 100 000

5 Kidney
5 Esophagus
4 Colon and
4 rectum
Misc.
3
Stomach
3
Prostate
2
2 Corpus and
uterus, NOS
1
1

0
0
us in st vi
s us m us h
at
e S
ch Sk ea el ag tu eo ac st
O 2010 2011 2012 2013 2014 2015
n he Br P h ec n om o , N
ro t al op R lla St Pr r us
d
B of en Es an
d ce te Year of Diagnosis
an a R is U
om d on M d
ng an an ol an
Lu el y C us
M ne p
Ki
d or
C

Figure 2. Incidence of brain metastases by primary site. (A) Incidence by the primary site shows a stable incidence over time. (B) The total inci-
dence per year shows a stable incidence over time.
  

brain metastases had the poorest OS as compared to those [95% CI: 1.86–2.58]), rectal cancers (HR = 2.07 [95% CI:
with extracranial metastases alone (HR = 2.20 [95% CI: 1.68–2.55]), and melanomas (HR = 1.93 [95% CI: 1.79–
2.06–2.34]), followed closely by uterine cancers (HR = 2.19 2.08]). For breast cancer patients, the detrimental effect of
6 Singh et al. Epidemiology of synchronous brain metastases

   1.58–1.63]) compared to females (HR = 1.52 [95% CI: 1.49–

Table 2. Results of Univariate and Multivariate Cox Regression 1.54]; P for interaction < .001), patients aged 65 years or
Comparing the Hazards of Death of Patients With Extracranial
older (HR = 1.60 [95% CI: 1.58–1.63]; P < .001) compared to
Metastases Alone or With Brain Metastases
younger patients (HR = 1.46 [95% CI: 1.44–1.48]), and those
HR 95% CI P with lung, bone, or liver metastases (HR = 1.61 [95% CI:
1.59–1.64]; P < .001) versus those without (HR = 1.49 [95%
Univariate analysis
CI: 1.46–1.52]). Interestingly, patients diagnosed with syn-
 Brain metastasis vs 1.43 [1.41–1.44] <.001
chronous brain metastases in 2010 had significantly poorer
extracranial metas-
tases alone OS (HR = 1.62 [95% CI: 1.59–1.65]) versus those diagnosed
in 2015 (HR = 1.49 [95% CI: 1.46–1.53]; P < .001) with an es-
Multivariable analysis
timated improvement in OS over time (HR = 0.98 [95% CI:
 Brain metastasis vs 1.56 [1.54–1.58] <.001 0.98–0.99] for each year after 2010).
extracranial metas-
We also note that the effect of synchronous brain

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

tases alone
metastases on OS was not constant over time. The global
Male vs female sex 1.13 [1.12–1.14] <.001
Schoenfeld residual test for the multivariable Cox re-
 Year of diagnosis (per 0.98 [0.98–0.98] <.001 gression model for all sites was statistically significant
each year increase)
(P < .001). A plot of the logarithm of the HR for this model
Age (per each year 1.02 [1.02–1.02] <.001 as a function of time can be found in Supplementary
increase)
Figure 7. The detrimental effect of synchronous brain
T-stage metastases on OS reached a maximum approximately
   T0 vs T1 1.1 [1.06–1.14] <.001 3 months after diagnosis, followed by a rapid drop-off
   T2 vs T1 1.18 [1.16–1.20] <.001 until 10 months after diagnosis then tapered off more
slowly. The detrimental effect of brain metastases on OS
   T3 vs T1 1.12 [1.10–1.13] <.001
remained statistically significant at the .05 level until the
   T4 vs T1 1.31 [1.29–1.33] <.001 end of the follow-up period. On site-specific analysis, the
   TX vs T1 1.51 [1.48–1.53] <.001 Schoenfeld residual test was significant for only lung
N-stage cancer (P < .001), breast cancer (P < .001), and melanoma
(P = .042) after multiple testing adjustment. Log(HR)
   N+ vs N0 1.15 [1.14–1.17] <.001
versus time plots for all available disease sites can be
   NX vs N0 1.18 [1.17–1.20] <.001
found in Supplementary Figure 8.
Race
  American Indian/ 1.05 [1.00–1.11] .036
Alaska Native vs
white
Discussion
  Asian/Pacific Islander 0.86 [0.85–0.87] <.001
vs white Brain metastases have a significant impact in the disease
   Black vs white 1.08 [1.06–1.09] <.001 course of multiple cancer sites and are expected to have
   Unknown vs white 0.51 [0.46–0.57] <.001 a rising incidence given improved systemic therapies and
subsequently longer OS.10–12 As such, the importance of
 Coexisting lung/bone/ 1.15 [1.14–1.16] <.001
liver metastasis vs no understanding the epidemiology and trends of brain me-
lung/bone/liver me- tastases in the United States is paramount to guide fu-
tastasis ture studies and clinical trials. Based on our findings, the
majority of synchronous brain metastases across all age
HR, hazard ratio; CI, confidence interval.
groups appear to be from lung primaries (roughly 80%)
   with a stable incidence of roughly 7 persons per 100 000
individuals at initial presentation. In the pediatric popu-
synchronous brain metastases on OS was highest in HER2+ lation, melanomas in patients from 10 to 14 years of age
and HR− patients (HR = 2.47 [95% CI: 2.02–3.01]), followed as well as those of the kidney and renal pelvis appear to
by HER2− and HR+ patients (HR = 2.23 [95% CI: 2.01–2.47]), comprise the majority of primaries. Notably, we also found
triple-negative patients (HR = 2.00 [95% CI: 1.75–2.29]), and that patients with synchronous brain metastases had sig-
HER2+ and HR+ patients (HR = 1.93 [95% CI: 1.62–2.31]; nificantly poorer OS as compared to patients with extra-
P < .001). Differences in OS for lung primaries were not cranial metastases alone (HR = 1.56 [95% CI: 1.54–1.58]; P <
as marked but still quite significant (HR = 1.24 [95% CI: .001), with HRs for the most common sites ranging from an
1.22–1.25]) and were maintained on analysis of both SCLC HR = 1.24 (95% CI: 1.22–1.25) for lung cancers to 2.20 (95%
(HR = 1.15 [95% CI: 1.11–1.19]) and NSCLC (HR = 1.26 [95% CI: 2.06–2.34) for breast cancers. Patients who were male,
CI: 1.24–1.28]) histologies. Median OS examined by pri- elderly, and had synchronous liver, bone, or lung metas-
mary cancer site as well as whether patients had extracra- tases were noted to have a poorer OS.
nial metastases alone or brain metastases at diagnosis can Historical reports in both the United States and Scotland
be found in Table 3. have previously noted incidence rates ranging from 8.3
When examining for effect modifications in OS for pa- to 14.3 brain metastasis persons per 100 000 individ-
tients with synchronous brain metastases by other factors uals.22–25 Walker et al.24 noted a higher incidence of males
of interest, we noted poorer OS in males (HR = 1.60 [95% CI: with new brain metastases (9.7 males vs 7.1 females per
 Singh et al. Epidemiology of synchronous brain metastases 7

Advances
Neuro-Oncology
  
Adjusted Hazard Ratio
Site p-value [95% CI]
Tongue <0.001 4.40 [2.35, 8.23]
Anus, Anal Canal and Anorectum 0.012 4.03 [1.78, 9.14]
Testis <0.001 3.03 [2.31, 3.97]
Retroperitoneum 0.069 2.97 [1.36, 6.49]
Larynx 0.028 2.72 [1.44, 5.16]
Mesothelioma 0.001 2.44 [1.60, 3.71]
Thyroid <0.001 2.29 [1.77, 2.95]
Small Intestine 0.003 2.27 [1.47, 3.51]
Oral Cavity excl. Tongue 0.032 2.26 [1.33, 3.83]
Breast <0.001 2.20 [2.06, 2.34]
Uterus <0.001 2.19 [1.86, 2.58]
Cervix Uteri <0.001 2.11 [1.63, 2.72]
Rectum <0.001 2.07 [1.68, 2.55]

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

Rectosigmoid Junction <0.001 1.95 [1.43, 2.65]
Melanoma of the Skin <0.001 1.93 [1.79, 2.08]
Prostate <0.001 1.89 [1.61, 2.21]
Tonsil 0.430 1.83 [1.01, 3.34]
Colon <0.001 1.83 [1.64, 2.04]
Nasopharynx 0.217 1.68 [1.08, 2.61]
Biliary Tract 0.003 1.66 [1.27, 2.16]
Bone and Soft Tissue <0.001 1.64 [1.34, 2.00]
Ovary 0.001 1.62 [1.27, 2.06]
Vulva and Vagina 1.000 1.61 [0.69, 3.76]
Urinary Bladder <0.001 1.61 [1.33, 1.94]
Kidney and Renal Pelvis <0.001 1.61 [1.50, 1.72]
Oropharynx 1.000 1.59 [0.76, 3.33]
All Sites <0.001 1.56 [1.54, 1.58]
Salivary Gland 0.648 1.51 [0.95, 2.40]
Pancreas <0.001 1.50 [1.31, 1.70]
Hypopharynx 1.000 1.45 [0.64, 3.30]
Esophagus <0.001 1.41 [1.26, 1.57]
Stomach 0.004 1.28 [1.12, 1.47]
Lung and Bronchus <0.001 1.24 [1.22, 1.25]
Peritoneum, Omentum and Mesentery 1.000 1.19 [0.29, 4.85]
Liver 1.000 1.10 [0.91, 1.33]
Ureter 1.000 1.09 [0.43, 2.80]
Penis 1.000 0.37 [0.04, 3.10]

Brain Metastasis Better Brain Metastasis Worse

0.5 1.5 2.5 3.5 4.5 5.5

Hazard Ratio

Figure 3. Forest plots showing poorer overall survival (OS) among patients with brain metastases compared to extracranial metastases alone by
the primary site.
  

100 000 individuals) that was attributed to higher rates of We noted a significantly higher rate of synchronous
lung primaries among male patients. However, Counsell brain metastases associated with lung cancers (roughly
et al.25 found a similar incidence rate among both sexes 80%) similar to that of previous investigations utilizing
in their cohort. Similar to our findings, they also noted a the SEER database. Notably, previous analysis by Cagney
gradual increase in the incidence rate of brain metastases et al.27 reported that patients with NSCLC or SCLC had the
by increasing age until the age of 74, when a sharp de- highest rates of brain metastases at initial diagnosis. Their
cline was noted, which was thought to be secondary to no analysis also found that of patients with metastatic dis-
formal workup for brain metastases. ease at presentation, those with melanoma (28%), NSCLC-
Regarding primary cancer sites, a prior investigation by adenocarcinoma (26.8%), non-specified NSCLC or other
Barnholtz-Sloan et al.14 of the Metropolitan Detroit Cancer lung cancers (25.6%), SCLC (23.5%), NSCLC-squamous cell
Surveillance System also found lung cancers to be the carcinoma (15.9%), bronchioloalveolar carcinoma (15.5%),
most common primary cancer site, though not constituting and renal cancers (10.8%) had the highest incidence of
the majority of patients as in our study (19.9% of their co- brain metastases. Another prior analysis of the SEER da-
hort). Other common sites were melanoma (6.9%), breast tabase by Kromer et al.28 examined patients with synchro-
(5.1%), and colorectal cancers (1.8%). Similar to these find- nous brain metastases from 2010 to 2013 and similarly
ings, a report by Schouten et al.15 from The Netherlands noted the highest frequency among patients with cancers
noted a 5-year cumulative incidence of new brain me- of the lung and bronchus (10.8%), and notably with SCLC
tastases to be highest among patients with lung cancers noted to have the highest incidence among all histologies
(16.3%), followed by renal cancers (9.8%), melanomas (15.1%).
(7.4%), breast cancers (5%), and colorectal cancers (1.2%). Among the pediatric population, we noted that tumors
Another report by Berghoff et al.26 of 2419 patients with of the kidney and renal pelvis was the only primary site
brain metastases found that those with lung cancers com- for patients less than 1 year of age, with melanomas
prised the largest proportion of solid tumor types with syn- being the predominant site for older pediatric patients.
chronous brain metastases (47%). Prior studies have noted brain metastasis incidence rates
8 Singh et al. Epidemiology of synchronous brain metastases

  
Table 3. Number of Patients With or Without Synchronous Brain Metastases at Diagnosis by Primary Cancer Site and Associated Unadjusted
Median Survival Time in Months

Cancer Site All Cancer Patients (M0 and M1 Patients With Brain Metastasis M1 Patients Without Brain
M1) Diagnosed 2010–2015 at Diagnosis Metastasis at Diagnosis
N Median Survival, N (%) Median Survival, N (%) Median Survival,
Months (95% CI) Months (95% CI) Months (95% CI)
Lung and bronchus 308 561 10 (10-10) 33 668 (10.9%) 4 (4-4) 104 664 (33.9%) 4 (4-4)
Small cell 36 281 7 (7-7) 5558 (15.3%) 5 (4–5) 17 790 (49.0%) 5 (5-5)
Non-small cell 272 280 11 (11-11) 28 110 (10.3%) 4 (4-4) 86 874 (31.9%) 4 (4-4)
Melanoma 126 397 NR (NR-NR) 1595 (1.3%) 5 (4–5) 2918 (2.3%) 12 (11–12)

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

Breast 379 261 NR (NR-NR) 1562 (0.4%) 9 (7–10) 19 208 (5.1%) 28 (28–29)
HR+/HER2- 253 783 NR (NR-NR) 580 (0.2%) 12 (10–15) 9910 (3.9%) 34 (33–35)
HR+/HER2+ 36 458 NR (NR-NR) 225 (0.6%) 20 (15–29) 2543 (7.0%) 43 (41–46)
HR−/HER2+ 15 727 NR (NR-NR) 176 (1.1%) 10 (8–14) 1328 (8.4%) 34 (30–41)
HR−/HER2− 39 147 NR (NR-NR) 287 (0.7%) 5 (4–6) 2160 (5.5%) 13 (12–13)
Unknown 34 146 NR (NR-NR) 294 (0.9%) 2 (2–4) 3267 (9.6%) 14 (13–15)
Kidney 89 382 NR (NR-NR) 1253 (1.4%) 4 (4–5) 11 685 (13.1%) 9 (9-9)
Colon and rectum 223 842 70 (69-NR) 573 (0.3%) 4 (3–5) 41 724 (18.6%) 13 (13-13)
Esophagus 24 033 11 (10–11) 393 (1.6%) 3 (3–4) 6536 (27.2%) 5 (5-5)
Stomach 40 565 14 (14–15) 253 (0.6%) 3 (2–4) 12 126 (29.9%) 5 (5-5)
Prostate 316 724 NR (NR-NR) 220 (0.1%) 11 (9–14) 17 136 (5.4%) 26 (25–27)
Corpus and uterus, NOS 80 623 NR (NR-NR) 186 (0.2%) 3 (3–4) 6073 (7.5%) 12 (12–13)

NR, not reached at the end of follow-up; HR, hormone receptor; HER2, human epidermal growth factor receptor 2.
  
ranging from 1.5% to 2.5% among children with solid tu- brain metastasis diagnosis. One of the initial recursive
mors, most commonly germ cell tumors and sarcomas partitioning analyses was reported by Gaspar et al.13 and
(often Ewing’s sarcoma and osteosarcoma).2,3 Rates of examined 1200 patients with brain metastases from 3
brain metastases on prior reviews have been found to Radiation Therapy Oncology Group prospective trials
be as high as 13.5% (germ cell tumors), 6.5% (osteosar- from 1979 to 2003 that defined 3 prognostic Classes (1–3)
comas), 3.3% (Ewing’s sarcomas), and 1.9% (rhabdomyo- based on Karnofsky performance status score, age, and
sarcomas).29 The findings of our study may be different the presence or absence of extracranial metastases for
than prior reports as pediatric patients with sarcomas patients with brain metastases of any primary site. Since
may develop brain metastases later on in their disease that time, more recent seminal work by Sperduto et al.6
course rather than at initial diagnosis, which the SEER da- resulted in the development of diagnosis-specific graded
tabase would not have captured. prognostic assessments utilizing a large multi-institutional
With respect to prognosis for patients with brain metas- cohort of nearly 4000 patients from 1985 to 2007 specific
tasis, our work noted that patients with brain metastases to lung, melanoma, breast, renal cell, and gastrointestinal
from breast cancers had a higher 1-year OS rate (41%) and primaries. Similar to both of the prior mentioned studies
a median OS of 8 months as compared to other common that found that extracranial metastases conferred worse
primary sites such as melanoma, kidney and renal pelvis, prognosis among patients with lung cancer and brain me-
and lung (all with 1-year OS rates and median OS ranging tastases, we noted that patients with brain metastases of
from roughly 20% to 25% and 3.9 to 4.9 months, respec- ages of 65 years and older (HR = 1.60 vs 1.46) in addition
tively). These findings are similar to those of Cagney et al.27 to those with synchronous lung, bone, or liver metastases
who noted that breast cancer patients had higher median (HR = 1.61 vs 1.49) had poorer OS.
OS (10 months) as compared to other primary sites, with Regarding potential changes in prognosis over time, a re-
other favorable primary sites being prostate (12 months) port by Nieder et al.30 compared a recent series of 103 pa-
and bronchioalveolar carcinoma (10 months). Also, tients treated from 2005 to 2009 to a cohort of 103 patients
Berghoff et al.26 found in their brain metastasis cohort that treated in 1983–1989. A higher proportion of patients in the
patients with breast cancer had the longest median OS recent cohort were noted to have received, surgery, stere-
(8 months) as compared to patients with primaries of the otactic radiosurgery, and systemic therapies. Higher 1-year
lung or kidney (7 months), melanoma (5 months), or colon/ OS rates were found among the recently treated cohort
rectum (4 months; P < .001). (34% vs 15%; P = .03), but the authors noted this was likely
Other prior studies have utilized multi-institutional co- due to a higher proportion of patients having favorable
horts or patients on prior prospective trials to develop prognosis, with minimal OS improvements in patients with
a method to estimate patients’ prognosis following a poorer prognoses. Our study noted significantly improved
 Singh et al. Epidemiology of synchronous brain metastases 9

Advances
Neuro-Oncology
OS for patients with extracranial metastases alone versus earlier during the studied time period had poorer OS.
those with synchronous brain metastases, suggesting that Additional studies are warranted to further characterize the
the general prognosis of patients with brain metastases con- modern landscape of brain metastases in the United States
tinues to remain quite poor. However, we did find that pa- to examine the incidence of patients who develop brain
tients diagnosed more recently had improved OS (HR = 0.98 metastases following initial diagnosis, differential prog-
for each year following 2010). This may be due to the chan- nosis based on primary site, and an exploration of poorer
ging landscape of management of brain metastases, which OS noted among patients with synchronous brain metas-
is evolving to include multimodality approaches of surgery, tases as compared to extracranial metastases alone.
radiation therapy via either stereotactic radiosurgery or
whole-brain radiation therapy, as well novel systemic ther-
apies such as mutation-specific agents or immunotherapy
with improved penetration of the blood-brain barrier.31 Data Availability
There are some limitations to our study that merit atten-

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

The data utilized for this study are provided in the SEER
tion. First are limitations inherent to the use of the SEER
database (https://seer.cancer.gov/seerstat/), which is freely
database. Limitations with regard to epidemiologic studies
accessible to the public available via the National Cancer
include demographic differences (over-representation
Institute SEER program, thus making the study exempt
of foreign-born patients and urban inhabitants as well as
from institutional review board review.
non-white patients as compared to the standard US pop-
ulation).17,18 Other limitations inherent to analyses utilizing
the SEER database include a lack of information on the in-
completeness of patient-level data such as socioeconomic
Supplementary Data
status, additional comorbidities, tumor recurrences fol-
lowing initial diagnosis, or intent, dose, or duration of ei- Supplementary data are available at Neuro-Oncology
ther chemotherapy or radiation therapy, and potential for Advances online.
loss for information as patients move in and out of SEER
geographic areas.16–18 Another drawback of any epidemio-
logic study utilizing the SEER database is that patients are
logged into the database only at the time of initial diag- Keywords
nosis. As such, this precludes the inclusion of patients who
at initial diagnosis may have early or locally advanced dis- brain metastases | cancer | epidemiology | incidence |
ease but may have developed brain metastases later on in prognosis
their disease course, thus biasing our incidence value to
likely be an underestimate. Other relevant information was
also not available, such as the number and size of brain
metastases, whether patients were symptomatic or asymp- Funding
tomatic at diagnosis, local control of brain metastases fol-
N.G.Z. has startup funding from Penn State Cancer Institute
lowing treatment, and management of brain metastases
and is supported by the National Institutes of Health LRP 1 L30
following diagnosis. Also, given that screening for brain
CA231572-01. H.C. is an International Association for the Study
metastases is generally indicated for locally advanced lung
of Lung Cancer Foundation Awardee. N.G.Z. is also supported by
cancers, breast cancers, and melanoma, this may bias the
the American Cancer Society, CSDG-CCE 133738.
estimate of the relative proportion of these primary sites to
Competing Interests: N.G.Z. received personal fees from
be higher. Finally, as not all healthcare institutions partici-
Springer Nature, Inc. for his textbook Absolute Clinical Radiation
pate in SEER, there is the concern regarding the generaliz-
Oncology Review and Weatherby Healthcare, unrelated to the
ability of our findings, though SEER does comprise a large
submitted work. D.M.T. reports clinical trial research support
proportion (over 34%) of all patients in the United States.16
from Novocure and publishing fees from Springer Nature, Inc.
for projects unrelated to the submitted work. P.D.B. reports per-
sonal fees from UpToDate (contributor), outside the submitted
work. J.D.P. reports support from Varian Medical Systems and
Conclusions speaking fees from Depuy Synthes outside the current work.
The incidence of brain metastases from 2010 to 2015 was A.V.L. has received honoraria from Varian Medical Systems Inc.
relatively stable at 7/100 000 patients, with 80% from lung and AstraZeneca, unrelated to this submitted work. All other au-
cancers. Common primaries among pediatric patients in- thors report no competing interests.
cluded those of the kidney/renal pelvis and melanomas,
while those in those older than 40 years of age were
mostly from lung cancer. Patients with brain metastases
from breast cancers had higher OS as compared to other Authorship Statement. N.G.Z.: conceived idea for the project.
common primary sites. Significantly poorer OS was asso- R.S., K.C.S., H.C., E.J.L., and S.R.H.: conducted statistical ana-
ciated with synchronous brain metastases as compared to lyses. R.S. and K.C.S.: drafted manuscript. R.S., K.C.S., H.C.,
extracranial metastases alone. Among patients with brain A.V.L., E.J.L., S.R.H., J.D.P., D.M.T., P.D.B., and N.G.Z.: editing of
metastases, males, elderly patients, those with synchro- the manuscript. All authors: final approval of the manuscript.
nous lung, bone, or liver metastases, and those treated
10 Singh et al. Epidemiology of synchronous brain metastases

15. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain

metastases in a cohort of patients with carcinoma of the breast, colon,
References
kidney, and lung and melanoma. Cancer. 2002;94(10):2698–2705.
16. Surveillance, Epidemiology, and End Results (SEER) Program (www.
seer.cancer.gov) Research Data (1973–2012). National Cancer Institute,
1. Johnson JD, Young B. Demographics of brain metastasis. Neurosurg
DCCPS, Surveillance Research Program, Surveillance Systems.
Clin N Am. 1996;7(3):337–344.
17. Yu JB, Gross CP, Wilson LD, Smith BD. NCI SEER public-use data: appli-
2. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol
cations and limitations in oncology research. Oncology (Williston Park).
Rep. 2012;14(1):48–54.
2009;23(3):288–295.
3. Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic
18. Duggan MA, Anderson WF, Altekruse S, Penberthy L, Sherman ME.
brain tumors. Neurosurg Clin N Am. 2011;22(1):1–6, v.
The Surveillance, Epidemiology, and End Results (SEER) program and
4. Bouffet E, Doumi N, Thiesse P, et al. Brain metastases in children with
pathology: toward strengthening the critical relationship. Am J Surg
solid tumors. Cancer. 1997;79(2):403–410.
Pathol. 2016;40(12):e94–e102.

Downloaded from https://academic.oup.com/noa/article/2/1/vdaa041/5824813 by guest on 12 March 2024

5. Graus F, Walker RW, Allen JC. Brain metastases in children. J Pediatr.
19. Shuster JJ. Median follow-up in clinical trials. J Clin Oncol.
1983;103(4):558–561.
1991;9(1):191–192.
6. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded
20. Holm S. A simple sequentially rejective multiple test procedure. Scand J
prognostic assessment: an accurate and facile diagnosis-specific tool
Stat. 1979;6(2):65–70.
to estimate survival for patients with brain metastases. J Clin Oncol.
21. Bender R, Lange S. Adjusting for multiple testing—when and how? J
2012;30(4):419–425.
Clin Epidemiol. 2001;54(4):343–349.
7. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radio-
22. Nieder C, Spanne O, Mehta MP, Grosu AL, Geinitz H. Incidence
therapy versus observation after radiosurgery or surgical resection of
and prognosis of patients with brain metastases at diagnosis of
one to three cerebral metastases: results of the EORTC 22952-26001
systemic malignancy: a population-based study. Neuro Oncol.
study. J Clin Oncol. 2011;29(2):134–141.
2017;19(11):1511–1521.
8. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus
23. Percy AK, Elveback LR, Okazaki H, Kurland LT. Neoplasms of the cen-
whole-brain radiation therapy vs stereotactic radiosurgery alone for
tral nervous system. Epidemiologic considerations. Neurology.
treatment of brain metastases: a randomized controlled trial. JAMA.
1972;22(1):40–48.
2006;295(21):2483–2491.
24. Walker AE, Robins M, Weinfeld FD. Epidemiology of brain tu-
9. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs
mors: the national survey of intracranial neoplasms. Neurology.
radiosurgery with whole brain radiation therapy on cognitive function in
1985;35(2):219–226.
patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA.
25. Counsell CE, Collie DA, Grant R. Incidence of intracranial tumours in the
2016;316(4):401–409.
Lothian region of Scotland, 1989-90. J Neurol Neurosurg Psychiatry.
10. Crivellari D, Pagani O, Veronesi A, et al.; International Breast Cancer
1996;61(2):143–150.
Study Group. High incidence of central nervous system involvement in
26. Berghoff AS, Schur S, Füreder LM, et al. Descriptive statistical analysis
patients with metastatic or locally advanced breast cancer treated with
of a real life cohort of 2419 patients with brain metastases of solid can-
epirubicin and docetaxel. Ann Oncol. 2001;12(3):353–356.
cers. ESMO Open. 2016;1(2):e000024.
11. Sundermeyer ML, Meropol NJ, Rogatko A, Wang H, Cohen SJ. Changing
27. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of
patterns of bone and brain metastases in patients with colorectal
patients with brain metastases at diagnosis of systemic malignancy: a
cancer. Clin Colorectal Cancer. 2005;5(2):108–113.
population-based study. Neuro Oncol. 2017;19(11):1511–1521.
12. Mamon HJ, Yeap BY, Jänne PA, et al. High risk of brain metastases in sur-
28. Kromer C, Xu J, Ostrom QT, et al. Estimating the annual frequency of
gically staged IIIA non-small-cell lung cancer patients treated with sur-
synchronous brain metastasis in the United States 2010–2013: a
gery, chemotherapy, and radiation. J Clin Oncol. 2005;23(7):1530–1537.
population-based study. J Neurooncol. 2017;134(1):55–64.
13. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning anal-
29. Curless RG, Toledano SR, Ragheb J, Cleveland WW, Falcone S.
ysis (RPA) of prognostic factors in three Radiation Therapy Oncology
Hematogenous brain metastasis in children. Pediatr Neurol.
Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys.
2002;26(3):219–221.
1997;37(4):745–751.
30. Nieder C, Spanne O, Mehta MP, Grosu AL, Geinitz H. Presentation, pat-
14. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE.
terns of care, and survival in patients with brain metastases: what has
Incidence proportions of brain metastases in patients diagnosed (1973
changed in the last 20 years? Cancer. 2011;117(11):2505–2512.
to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin
31. Fecci PE, Champion CD, Hoj J, et al. The evolving modern management
Oncol. 2004;22(14):2865–2872.
of brain metastasis. Clin Cancer Res. 2019;25(22):6570–6580.