Abstract
Few population estimates of brain metastasis in the United States are available, prompting this study. Our objective was to estimate the expected number of metastatic brain tumors that would subsequently develop among incident cancer cases for 1 diagnosis year in the United States. Incidence proportions for primary cancer sites known to develop brain metastasis were applied to United States cancer incidence data for 2007 that were retrieved from accessible data sets through Centers for Disease Control and Prevention (CDC Wonder) and Surveillance, Epidemiology, and End Results (SEER) Program Web sites. Incidence proportions were identified for cancer sites, reflecting 80% of all cancers. It was conservatively estimated that almost 70 000 new brain metastases would occur over the remaining lifetime of individuals who received a diagnosis in 2007 of primary invasive cancer in the United States. That is, 6% of newly diagnosed cases of cancer during 2007 would be expected to develop brain metastasis as a progression of their original cancer diagnosis; the most frequent sites for metastases being lung and bronchus and breast cancers. The estimated numbers of brain metastasis will be expected to be higher among white individuals, female individuals, and older age groups. Changing patterns in the occurrence of primary cancers, trends in populations at risk, effectiveness of treatments on survival, and access to those treatments will influence the extent of brain tumor metastasis at the population level. These findings provide insight on the patterns of brain tumor metastasis and the future burden of this condition in the United States.
Keywords: cancer incidence, cancer surveillance, metastatic brain tumors
Few population estimates of brain metastasis in the United States are available. As indicated by Fox et al., such estimates have value in planning for patient care and in working toward measures to prevent or decrease the likelihood of metastatic disease.1 Surveillance to understand the pattern of brain metastases over time is also important because of the potential for cases to overwhelm specialty diagnostic and therapeutic resources.
Brain metastases have been estimated anywhere from 10 times more common to equal to the incidence of primary malignant tumors of the brain. The true incidence is likely to be somewhere between these extremes.2,3 Much of the variation in these estimates seems to be based on disparate data sources used and the different time lines underlying the estimates. The annual incidence of brain metastasis reflects the number of new diagnoses each year, whereas prevalence reflects the number of persons living with metastatic brain disease. Another approach is to estimate the number of metastasis that occurs in a series of patients with cancer over their remaining lifetime. The focus of this study is on the latter estimation.
Neoplasms that most commonly metastasize to the brain are lung and breast. Although this ranking varies by clinical series, substantial proportions of other cancer primary sites including gastrointestinal (GI), melanoma, germ cell, and renal tumors, also metastasize to the CNS. A common measure of metastasis has been the percentage of patients with cancer in a fixed cohort who develop brain metastasis. Estimates in the literature have reported as little as 5% and up to 40% of all patients with cancer experiencing brain metastasis.4 Some variation in these rates may be attributable to clinical factors, including stage and treatment. As treatments have changed over time and as survival rates for some primary cancer sites have correspondingly improved, the potential for brain metastasis occurrence may have also changed. Increases over time have been reported in Sweden.5
To estimate the number of brain metastases expected to occur over the remaining lifetime in a cohort of individuals with primary cancer newly diagnosed over a 1-year period, we applied current information in the literature on brain metastasis incidence proportions to population statistics on cancer incidence. This indirect measure of the occurrence of brain metastases provides some insight into the magnitude of the condition and the current and future burden of disease in the United States.
Materials and Methods
The population-based estimation of expected brain metastasis incidence involved 2 components: (i) the proportion of cases known to develop brain metastasis for a cancer site (incidence proportion [IP%]) and (ii) the number of newly diagnosed cases for that cancer site in the United States during 2007.
Brain Metastasis Incidence Proportion Estimates
Incidence proportions were selected for cancer sites on the basis of availability in the literature and on the likelihood of brain metastasis occurring after initial diagnosis of the primary cancer. Because some literature included multiple IP% estimates, some guidelines were used in selecting the IP% used for this effort. First, the most recent IP% (taking into account the additional guidelines below) was selected to reflect the most current treatment modalities in use. This was a reflection of the fact that treatment is known to influence survival and, consequently, may increase the chance of brain metastases occurrence.6 Second, where possible, IP% calculated from studies done on US populations were selected, because our intent was to estimate metastasis in the US population. Third, the IP% selected did not include estimates based on autopsy findings or estimates that included autopsy findings. This allowed us to provide estimates that were clinically relevant or, in other words, estimates of individuals who received a diagnosis of active brain metastases. Fourth, for certain sites, the IP% that were available were for the histology that reflected the largest proportion of cases in that site, rather than for all tumors that may be found in that site (i.e. epithelial ovarian cancer, testicular germ cell tumors). As such, we used the IP% for the most common histology available. Although an approximation, we did not have sufficient population detail to accurately estimate histology in each cancer site. Finally, we elected to use estimates that were based on all groups in the study sample/population, but some restrictions by age, race, or some other study characteristic may unknowingly bias the estimate. The IP% selected for each cancer site and the associated reference is shown in Table 1, along with the period used to estimate the IP%, the time interval between primary diagnosis and the development of the metastasis, and the clinical characteristics of the population on which the estimate is based.7–19
Table 1.
Primary cancer site referent study characteristics: period, duration from diagnosis to onset of brain metastasis, and population under evaluation
| Primary site | Study time period | Mean duration to brain metastasis onset | Study population |
|---|---|---|---|
| Lung and Bronchus7 | 1973–2001 | n/a | Metropolitan Detroit Cancer Surveillance System (population based with routine chart review) |
| Renal8 | 2005–2007 | 23 months | Metastatic RCC from 246 centers in 52 countries participating in open-labeled expanded access program of sunitinib. |
| Melanoma7 | 1973–2001 | n/a | Metropolitan Detroit Cancer Surveillance System (population based with routine chart review) |
| Breast (both genders)7 | 1973–2001 | n/a | Metropolitan Detroit Cancer Surveillance System (population based with routine chart review) |
| Non-Hodgkins Lymphoma9 | 1980–1996 | Treatment 5 months | Norwegian Radium Hospital |
| relapse 16 months | |||
| Colorectal10 | 1984–2006 | 25 months | Dartmouth Hitchcock Medical Center |
| Esophageal11 | 1993–2001 | 5.6 months | University of Texas MD Anderson Medical Center |
| Testis12 | 1975–1993 | n/a | 10 country cohort of 5862 patients |
| Urinary Bladder13 | 1962–2001 | 10 months | University of Kentucky Medical Center |
| Thyroid14 | 1936–1991 | 21 years | Royal Marsden Hospital London, UK |
| Hepatocellular (Liver)15 | 1995–2006 | 18.2 months | Yonsei University Health System, Seoul, Korea |
| Stomach16 | 1957–1997 | n/a | University of Texas, MD Anderson Cancer Center |
| Prostate17 | 1944–1998 | n/a | University of Texas, MD Anderson Cancer Center |
| Uterine18 | 1991–2003 | 2 months | London Regional Cancer Center |
| Ovarian19 | 1980–2000 | 46 months | Royal Marsden Hospital London, UK |
With the exception of colorectal and testis cancers, estimates are based on studies reflecting long intervals of case accrual with short intervals between diagnosis and development of the brain metastasis. As such, the IP% should be relatively stable, although an underestimate of the true occurrence. For example, the colorectal cancer estimate is based on experience from the period 1984–2006. With a mean time of 25 months between diagnosis and development of brain metastases, one would expect most brain metastases to have occurred and been counted in the 1984–2004 group, whereas the last 2 diagnosis years may be an underestimate. Averaged over the 22 years, this underestimate is likely to be modest.
Primary Cancer Site Incidence Sources
Incidence proportions (Table 1) were applied to United States cancer incidence data for the most recent year where information was fully available, diagnosis year 2007. These data were retrieved from the interactive data sets available through the Centers for Disease Control and Prevention (CDC Wonder) and the Surveillance, Epidemiology, and End Results (SEER) Program research data files.20,21 The final analytic data set included newly diagnosed cancers in 2007 from 50 states and the District of Columbia.
Selected Estimates by Race, Sex, and Age
Because primary cancers occur differentially by race, sex, and age, one would expect brain metastases to also vary by these demographic characteristics. Population-based incidence proportions for lung, renal, melanoma, breast, and colorectal sites by race, sex, and age group were available from a study on the Metropolitan Detroit Cancer Surveillance System (MDCSS) SEER population. Shown in Table 2, these IP% were derived from follow-up study of MDCSS cases diagnosed during 1973–2001.7 Of note, considerable variation exists among race, sex, and age group categories in the IP% estimates from the respective study. These IP% were applied to the 2007 US cancer incidence to generate estimates of expected brain tumor metastasis by demographic characteristics.
Table 2.
Incidence Proportions (IP%) of brain metastases for selected cancer sites by race, sex and age at diagnosis for 5 cancer primary sites
| Lung | Renal | Melanoma | Breast | Colorectal | |
|---|---|---|---|---|---|
| IP% | IP% | IP% | IP% | IP% | |
| Total | 19.9 | 6.5 | 6.9 | 5.1 | 1.8 |
| Race | |||||
| White | 19.4 | 6.8 | 7.1 | 4.6 | 1.8 |
| African American | 21.8 | 5.3 | 11.7 | 7.4 | 2.0 |
| Other | 21.7 | 3.9 | 8.9 | 5.6 | 0.9 |
| Sex | |||||
| Male | 18.9 | 6.6 | 8.7 | 4.9 | 1.9 |
| Female | 21.8 | 6.2 | 4.8 | 5.1 | 1.7 |
| Age | |||||
| 20–39 | 25.8 | 4.3 | 5.5 | 10.0 | 2.2 |
| 40–49 | 31.3 | 6.0 | 7.4 | 6.6 | 2.4 |
| 50–59 | 26.3 | 8.8 | 8.5 | 6.4 | 2.8 |
| 60–69 | 20.2 | 7.7 | 7.8 | 4.5 | 2.2 |
| 70+ | 12.9 | 4.1 | 5.5 | 2.4 | 1.2 |
Adapated from Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System published by the American Society of Clinical Oncology [Barnsholtz-Sloan JS, Sloan AE, Davis FG et al: 22(1) 2004; 2865–2872].
Results
The estimated number of brain metastases occurring in 1 year from each of 15 primary cancer sites is shown in Table 3. The total incidence for all primary cancer sites was 1 497 926 during the diagnosis year 2007. Of this count, 1 194 282 (80%) incident cases occurred in the 15 cancer sites where incidence proportion estimates were available and were used in the calculation of these annual brain metastasis incidence estimates.
Table 3.
Estimated incidence of brain metastasis by selected primary site United States cancer incidence, 2007
| Selected incidence proportion (IP) | Site incidence | Brain metastasis incidence | |
|---|---|---|---|
| Single Primary Site | IP% | N | N |
| Lung and Bronchus7 | 19.9 | 209 969 | 41 784 |
| Renal8 | 7.0 | 49 575 | 3470 |
| Melanoma7 | 6.9 | 59 700 | 4119 |
| Breast (both genders)7 | 5.1 | 208 973 | 10 658 |
| Non-Hodgkins Lymphoma9 | 4.2 | 60 230 | 2530 |
| Colorectal10 | 2.3 | 146 040 | 3359 |
| Esophageal11 | 1.7 | 15 542 | 264 |
| Testis12 | 1.2 | 7948 | 95 |
| Urinary Bladder13 | 1.0 | 65 800 | 658 |
| Thyroid14 | 0.9 | 35 944 | 323 |
| Hepatocellular (liver)15 | 0.9 | 19 161 | 172 |
| Stomach16 | 0.7 | 21 134 | 148 |
| Prostate17 | 0.6 | 230 979 | 1386 |
| Uterine18 | 0.6 | 41 916 | 251 |
| Ovarian19 | 0.5 | 21 371 | 107 |
| Total Estimate (15 Site Annual Incidence) | 1 194 282 | 69 325 |
Abbreviations: IP, Incidence proportion percentage; N, number.
As shown in Table 3, it was estimated that almost 70 000 new brain metastases would occur over the remaining lifetime of individuals who received a diagnosis in 2007 of primary invasive cancer in the United States. That is, 6% of patients with newly diagnosed cases of invasive cancer during 2007 in the United States would be expected to subsequently develop brain metastasis as a progression of their original cancer diagnosis; the most frequent sites for metastases were lung and bronchus and breast cancers. Substantial numbers of brain metastases are also expected to arise from melanoma, renal, colorectal, and primary non-Hodgkins lymphoma cases.
Table 4 shows expected brain metastasis for the application of IP% derived from the MDCSS study to US cancer incidence by race, sex, and age group. The brain metastasis estimates reflect the magnitude of the primary cancer site incidence in the respective demographic category. The estimated numbers of brain metastasis from all 5 sites combined will be expected to be higher among white individuals, female individuals, and older age groups.
Table 4.
Brain metastasis incidence estimates based on application of Metropolitan Detroit Cancer Surveillance System incidence proportion estimates [7] to annual incidence for 5 cancer sites, 2007
| Lung | Melanoma | Breast | Renal | Colorectal | 5 Site Total | |
|---|---|---|---|---|---|---|
| N | N | N | N | N | N | |
| Race | ||||||
| White | 35 441 | 3994 | 8127 | 2873 | 2207 | 52 641 |
| African American | 4614 | 39 | 1664 | 290 | 333 | 6939 |
| Other | 1328 | 278 | 550 | 72 | 61 | 2289 |
| Total | 61 870 | |||||
| Sex | ||||||
| Male | 18 274 | 2961 | 96 | 2022 | 1420 | 24 772 |
| Female | 24 695 | 1232 | 10 558 | 1174 | 1212 | 38 872 |
| Total | 63 644 | |||||
| Age | ||||||
| 20–39 | 289 | 385 | 988 | 79 | 74 | 1816 |
| 40–49 | 2962 | 630 | 2293 | 321 | 257 | 6463 |
| 50–59 | 8100 | 1031 | 3158 | 945 | 724 | 13 959 |
| 60–69 | 12 085 | 953 | 2245 | 1006 | 729 | 17 018 |
| 70+ | 14 022 | 1067 | 1562 | 738 | 874 | 18 263 |
| Total | 57 520 | |||||
Fig. 1 displays the expected lifetime brain metastasis incidence counts in the United States by individual year during 2003–2007. These estimates were calculated using the same IP% shown in Table 3 for each year. Therefore, the observed increases in the number of brain metastases counts are a function of increasing annual primary cancer incidence and aging of the underlying population, rather than changes in the IP%, which are essentially unknown.
Fig. 1.
Estimated lifetime metastases of the brain for selected primary cancer sites, by individual year of diagnosis in the United States, 2003–2007.
Discussion
The study findings estimate that about 70 000 expected new cases of brain metastasis are likely to occur during the remaining lifetime of those individuals who received a diagnosis of a primary cancer during 2007 in the United States. This is about 3 times the number of newly diagnosed primary malignant brain tumors each year and between the extreme estimates currently in the literature.2,3,22
These estimates, which use best available data, are still fairly crude reflections of what underlies the true pattern of brain metastases. It is likely that the true expected incidence of brain metastasis is an underestimate, because IP% was not available for every individual cancer site. About 20% of all primary site cancers diagnosed during 2007 could not be evaluated for expected metastasis and, therefore, were excluded. The total incidence for excluded primary sites was 303 644 (Supplemental Table). Basis for exclusion included newly diagnosed primary malignant brain and central nervous system tumor, rare tumor with limited clinical investigations on brain metastasis (e.g., endocrine tumors), or more common tumors having clinically limited or unknown incidence of brain metastasis (e.g., cancers of the oral cavity and pancreas and leukemias). On the basis of these reasons for exclusion, the underestimation is likely to be modest. We also recognize that the IP% may not be current with recent changes in treatment, imaging (including use of PET scanning), pathological classification, and published literature lagging behind clinical experience.
Fox et al. review the epidemiologic literature to date and discuss the limitations of cancer registries for making these estimates.1 However, by combining the best available clinical experience with the national population data on cancer incidence, we believe that these findings reflect reasonable estimates for the occurrence of brain metastasis in patients with newly diagnosed cancer over their lifetime in the United States. We also recognize that, by omitting autopsy series from our IP%, we have limited these estimates to reflect symptomatic cases and, therefore, those that are likely to appear in the health care system. As more refined clinical data become available over time, it may be possible to improve the quality of the IP% data for use in future estimations.
For some primary cancer sites, survival rates have improved over time. Although with improved survival, intuitively one might expect that patients who live longer may be at higher risk of developing brain metastases, this may not in reality be the case. Overall survival is dependent on the treatment for both the initial primary and any metastasis or complications that occur as part of the recurrence or progression. Data indicate that patients with lung primaries (small cell and non–small cell tumors) who receive prophylactic cranial irradiation are at a reduced risk of developing brain metastasis.23–29 Monitoring future patterns in brain metastasis from lung cancer is increasingly important, because not all eligible patients receive this prophylactic treatment.30 Disparities may be expected to emerge if these treatment patterns continue. In contrast, for colon cancers, the introduction of whole brain radiation therapy has resulted in a modest increase in overall survival, and the use of surgery for brain metastasis has resulted in a significant improvement in post-metastasis quality of life and survival.31 Reports also suggest that specific drug therapies may reduce the rate of brain metastasis following the development of primary renal cancer.8,32 In contrast, for esophageal cancer, adjuvant therapy has been shown to actually increase the propensity for brain metastasis to develop.33 These primary cancer-specific data indicate that further surveillance of brain tumor metastasis needs to be done on a primary tumor-specific basis and will be improved by incorporating clinical and treatment information.
Data from Sweden suggest an increase in brain metastasis in that population during 1987–2006 that was not observed in the Netherlands during 1986–1995, although more recent data from the Netherlands are needed to verify the trends in that country.5,34 More data on IP% based on cohorts of patients with cancer are needed over time to understand the time trends or estimate the true annual occurrence of brain metastasis in the United States. We know relatively little about sex, race, and age patterns, but these data suggest that demographic factors are important and that shifts in the population dynamics may impact estimates. Although IP% rates are higher among black individuals than among white individuals, actual counts are higher among white persons because of the higher incidence of the original tumor. Although IP% is higher at older ages for breast cancer, the actual counts are greatest among patients with breast cancer who are aged 50–59 years. This pattern may suggest a younger age distribution in the occurrence of those subtypes with a higher propensity to develop metastasis.35–37 Having estimates available by demographic subgroups would be helpful for clinics serving specialty populations.
By applying IP% from a selected clinical study to national population data, we are assuming that those rates apply across the entire population without considering diversity. As demographic characteristics, treatments, availability of specialties, types of hospitals, access to care, and insurance status of patients may all vary widely throughout regions of the country, this assumption may not hold. Moreover, how investigations and institutions determine brain metastasis are non-uniform and can be influenced by broad factors, including investigator experience and rigorousness, quality and access to imaging, travel mobility of patients, and accuracy of data collection. We are reliant on the quality of available data to provide IP%. In many tumor types, such as lung and breast, we have cited several recent investigations that have similar IP% to those used in this study; however, for many of the less common tumor types, it has been necessary to rely on large but single investigations. This increases the possibility of less accuracy. In addition, if standardized guidelines for treating brain metastasis are implemented and variation in the rate of brain metastasis stabilizes, the IP% from selected studies and institutions should be a better reflection of the population experience.6,38 In summary, the structure and quality of the many investigations used are certainly different and need to be taken into consideration; however, our results are in keeping with the general experience of the field; metastasis to the brain is evolving as an increasingly important site of disease involvement. The current estimates provide a baseline from which to begin to understand the pattern of brain tumor metastasis in the United States. Over time, repeated estimates using this method will reflect the changing patterns in the occurrence of primary cancers, the impact of specific diagnosis and associated treatments, site-specific information on duration from diagnosis to onset of metastatic disease, and the population access to those treatments.
Supplementary Material
Acknowledgments
Partial aspects of this work were presented as a poster at the Society of NeuroOncology meetings in November 2010, and these data were presented at the American Brain Tumor Association Annual Meeting July 2011.
Conflict of interest statement. None declared.
Funding
This work was supported by a grant from the American Brain Tumor Association to the Central Brain Tumor Registry of the United States.
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