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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2865-2872 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.149 Incidence Proportions of Brain Metastases in Patients Diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance SystemFrom the Department of Internal Medicine, Division of Hematology/Oncology, Department of Neurosurgery, Wayne State University School of Medicine; Population Studies and Prevention–Epidemiology Section, Barbara Ann Karmanos Cancer Institute, Detroit, MI; Division of Epidemiology and Biostatistics, University of Illinois at Chicago School of Public Health, Chicago, IL; Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Jill S. Barnholtz-Sloan, PhD, Karmanos Cancer Institute, Wayne State University School of Medicine, 110 E Warren, Detroit, MI 48201; e-mail: jbsloan{at}med.wayne.edu
PURPOSE: Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer. PATIENTS AND METHODS: Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs. RESULTS: Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites. CONCLUSION: Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.
Metastatic brain tumors are the most common intracranial neoplasms in adults and are a significant cause of morbidity and mortality. The incidence rate of primary brain tumors is 6.6 per 100,000,1 and estimates of the incidence rate of metastatic brain tumors has varied from 8.3 per 100,0002 to 11 per 100,000.3 The frequency of metastatic brain tumors is thought to be rising due to longer survival after primary cancer diagnosis, which is a direct result of earlier detection and more effective treatment. Individuals with primary lung, breast, melanoma, renal, and colorectal cancers account for the majority of people diagnosed with brain metastases.4-7 Although the highest numbers of brain metastases come from the lung, it has been documented that melanoma has the highest propensity of all malignant tumors to metastasize to the brain.7 Estimates of incidence proportions (IPs) of brain metastases vary widely (from 20% to 50%) depending on the data source. IPs of brain metastases have been studied in international registries, as well as in one United States population–based registry, but these studies were performed more than 20 years ago.2,3,8,9 More recent studies have used autopsy- and hospital-based populations.4-6,10-25 IPs vary by study and primary site of cancer, though lung primary cancers consistently show the highest IP of brain metastases (18% to 65% of all patients with primary lung cancer).7 The need for accurate, unbiased, and consistent estimates of IPs of brain metastases is high, since diagnosis and treatment of brain metastases has become an increasing burden on the health care system spanning across many medical subspecialties. Using population-based registries to estimate IPs is generally considered to be less biased and hence more accurate than using hospital-based registries. The objective of this study was to estimate IPs of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancers from the population-based Metropolitan Detroit Cancer Surveillance System (MDCSS) to characterize IPs of brain metastases in a large population.
Study Population Information was obtained from the population-based MDCSS on 16,210 subjects who had developed brain metastases after diagnosis with single primary lung, melanoma, breast, renal, or colorectal cancers that were diagnosed between 1973 and 2001. The MDCSS is population-based cancer surveillance system for the Metropolitan Detroit area, which encompasses three counties: Wayne, Oakland, and Macomb (population approximately 4.5 million people). Incident cancer cases have been collected through MDCSS since 1973 when it joined the national Surveillance, Epidemiology, and End Results (SEER) program.26 Information on newly diagnosed metastatic disease was collected in MDCSS from routine medical chart review. The MDCSS was used for this analysis because metastatic information was collected that was not available in the national SEER Public-Use Data. Variables of interest included race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer. Race was categorized as white, African American, other, and unknown. The "other" category consisted of a heterogeneous group of races/ethnicities—Japanese, Chinese, American Indian, Filipino, Hawaiian, Korean, Pakistani, Vietnamese, and various Pacific Islander groups in which there was not a large enough proportion of people in any one to analyze as a separate ethnic category. Patient age at diagnosis of primary cancer was grouped into five categories: 20 to 39 years, 40 to 49 years, 50 to 59 years, 60 to 69 years, and older than 70 years. SEER stage of primary cancer, classified as localized, regional, distant, or unstaged, was used instead of the more detailed American Joint Committee on Cancer (AJCC) tumor-node-metastasis system classification system, because AJCC staging information was only available for individuals diagnosed during 1995 or later. Localized disease was defined as an invasive neoplasm confined entirely to the organ; regional disease was defined as a neoplasm that had extended either beyond the organ or into regional lymph nodes; distant disease was defined as a neoplasm that had spread to parts of the body remote from the primary tumor; and unstaged disease was defined as a neoplasm that was not staged for a variety of reasons that were not always identified. Grade of tumor was not evaluated in this analysis because approximately 40% of all individual records were missing information for grade.
Statistical Analysis
 = .05). Absolute frequency of brain metastases and IP% of brain metastases by age at diagnosis of primary cancer and SEER stage of primary cancer were graphed in order to compare differences in trends in absolute frequency to trends in IP (Fig 1A and B, and Fig 2A and B).
The total numbers of individuals who developed brain metastases were 11,763, 566, 2635, 467, and 779, for patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer, respectively, in the Metropolitan Detroit area between 1973 and 2001. The total IP% for brain metastases from all five primary sites combined was 9.6% (95% CI, 9.4 to 9.7). The IP% of brain metastases was highest for lung cancer (19.9%; 95% CI, 19.6 to 20.2; Table 1) and lowest for colorectal cancer (1.8%; 95% CI, 1.7 to 1.9; Table 5). The IP% of brain metastases for African Americans was significantly higher compared with the IP% for white patients, for lung, melanoma, and breast cancers, and was significantly lower for renal cancer (similar IP% seen by race for colorectal cancer). Men had similar or higher IP% of brain metastases compared with women, except for those individuals with primary lung cancer, for which the IP% was significantly higher for women. IP% of brain metastases was highest for those diagnosed at age 40 to 49 years with primary lung cancer; age 50 to 59 years with primary melanoma, renal, or colorectal cancers; and age 20 to 39 with primary breast cancer. The trends by age showed that the absolute frequency of brain metastases increased to a certain age and then decreased, although the age at which the absolute frequency peak occurred did not directly correlate with the age at which the peak in IP% occurred (Fig 1A and B). Individuals diagnosed with primary lung cancer at age 60 to 69 years showed the highest absolute frequency of brain metastases, but the peak IP% of brain metastases was seen for those diagnosed at age 40 to 49 years with primary lung cancer. Individuals diagnosed with primary melanoma at age 50 to 59 years had the highest absolute frequency and highest IP% of brain metastases, as did individuals in the same age range diagnosed with primary renal cancer. Individuals diagnosed with primary colorectal cancer at age 60 years and older had the highest absolute frequency of brain metastases, but individuals diagnosed at age 50 to 59 years had the highest IP%. Most surprising were the results for primary breast cancer, which showed that early-onset breast cancer cases (individuals diagnosed at age 20 to 39 years) had the highest IP% of brain metastasis, though the absolute frequency of breast cancer resulting in brain metastases was low in this group compared with other groups. A statistically significant trend of increased IP% of brain metastases as SEER stage of primary cancer became more severe was seen for all primary sites (Fig 2A and B); in other words, for all primary sites, those individuals with distant-stage primary cancer had the highest IP% of brain metastases. Of all individuals with distant-stage primary disease, those individuals with primary melanoma showed the highest IP% for brain metastases, which corroborates with previously reported data about the propensity of this disease to migrate to the brain.7 Peak absolute frequency of brain metastases and peak IP% of brain metastases perfectly correlated for patients with primary lung or renal cancer and distant-stage disease. Individuals with primary colorectal cancer had the lowest IP% of brain metastases for all stages of disease compared with the other primary sites studied.
The five primary sites examined in this study represented 46.9% of all single cancers diagnosed during the last 28 years in the Metropolitan Detroit area, where the MDCSS categorizes all primary cancers into 56 primary site groups. Within the five primary sites, 9.6% of the total patients who had single cancer diagnoses were diagnosed with brain metastases. More specifically, 19.9% of lung cases, 6.9% of melanoma cases, 5.1% of breast cases, 6.5% of renal cases, and 1.8% of colorectal cases developed brain metastases. Our data also show a correlation between the IP% of brain metastases, and both age at diagnosis of primary cancer and SEER stage of primary cancer. For example, the highest IP% for brain metastases in individuals with primary breast cancer occurred in the youngest age category (IP%, 10%; 95% CI, 9.8 to 10.3; age at diagnosis, 20 to 39 years), and the highest IP% for brain metastases across all primary sites, stratified by SEER stage of primary cancer, occurred for individuals diagnosed with distant-stage primary melanoma (IP%, 36.8%; 95% CI, 35.8 to 37.8). The need for accurate estimates of numbers of individuals developing brain metastases is vital to our understanding of cancer and how to treat these patients. This study using MDCSS, a population-based cancer registry that collects all incident cases of cancer in the Metropolitan Detroit area, is the first population-based study of brain metastases performed in almost 20 years, making it distinct from most of the current studies. The total IP% found in this study (9.6%; 95% CI, 9.4 to 9.7), is much lower than any of the published population-based or hospital-based studies. However, the methodologies of the other recent studies varied as widely as the calculated IP%, making comparisons problematic and the data less useful. Previous studies include both hospital-based studies4,5,10-25 and population-based studies.2,3,8,9 Some included all intracranial lesions presumed to represent metastatic tumor on imaging studies, while others described only pathologically verified metastasis. Some studies also included autopsy data, which would be expected to overestimate IP% by detecting lesions that were not symptomatic or that developed in such a late stage of disease that clinical presentation was not indicated or masked by the diffuse morbidity associated with late-stage disease. In recent literature, only four population-based studies of brain metastases have been published. In a population-based study in Iceland (1954 to 1963),8 the IP% of brain metastasis was less than 20%. Brain metastases were found in 18% of all CNS neoplasms in a study performed in central Finland (1975 to 1982).9 A study from Rochester, Minnesota (1935 to 1968)3 demonstrated that 41% of the patients studied had brain metastases. However, this study included not only clinical data, but autopsy data as well (70% underwent autopsy). In a US national survey of CNS tumors (1973 to 1974),2 the IP% of brain metastases was 51%; however, only 20% of these cases were verified by tissue examination. All of the above studies surmised that under-reporting of metastatic brain tumors was present. Hospital-based studies have been performed using autopsy data (patients diagnosed in the 1970s),11,23 radiologic data (patients diagnosed in the 1970s and 1980s),4,12,22 surgical data (patients diagnosed from the 1970s to present),5,10,16-20,24,25 and medical record reviews of data (patients diagnosed from the 1970s to present).13-15,21 These have shown a wide variation in their estimates of the IP% of brain metastases ranging from 3% to 50%. These studies are limited by the selection bias inherent in all case studies from large tertiary referral centers, since such cases cannot be presumed to be representative of the population at large, unlike the study presented here, which encompasses all patients from an entire diverse metropolitan area. Indeed, some of the more recent hospital-based populations would be more comparable to the current study population compared with those of studies performed more than 20 years ago. Previous studies showed that the most common primary site to metastasize to the brain was lung, followed by breast, melanoma, and renal sites, with brain metastases from primary colorectal, prostate, and unknown primary cancers being uncommon.2,4,6,7,12 Our study also showed that lung was the most common primary tumor to metastasize to the brain by more than three-fold, followed by melanoma, renal, breast, and colorectal cancers. Melanoma and renal cancers have had increasing rates over time1 (which could account for our findings in terms of higher frequency of brain metastases being different than previous studies performed using patients diagnosed in less recent years), whereas the incidence of breast cancer has leveled off over time.1 The current study and previous studies have shown that the proportion of patients with brain metastases differed significantly by age at diagnosis of primary cancer. In the current study, for patients with melanoma, renal, and colorectal cancers, peak IP% was in the fifth to sixth decades of life, while for breast and for lung the peak IP% was in the second, third, and fourth decades of life, respectively. The IP% peak ages likely reflect the time interval between diagnosis of the primary cancer and metastatic brain tumor diagnosis, and the survival rate from the primary cancer. For most of the cancers studied here, patients are living longer after diagnosis with the primary cancer,1 which would give them more time than those diagnosed in earlier years (ie, those diagnosed in the 1970s) to develop brain metastases, which could lead to peak IP being present in earlier decades. This trend could also be indicative of an age-related tendency to develop brain metastases (ie, early-onset disease). Analyzing another population-based database with date of metastatic diagnosis would further our understanding of the relationship between peak IP and survival after primary cancer diagnosis. We also found differences by sex as well as by race. Differences by sex were most pronounced for individuals with lung cancer (significantly higher in women) and melanoma (significantly higher in men). These differences could follow from the fact that the incidence of primary lung cancer is rising in women,27 and the incidence of melanoma is much higher in males than in women and also rising more rapidly in men.1 Differences by race were also observed in these data, which had previously been reported to not be significant.6 Compared with any other racial group, African Americans had significantly higher IP% of brain metastases from melanoma and breast cancers from lung compared with white patients only, and from renal and colorectal cancers compared with the "other" category only. We studied IP% of brain metastases by SEER stage of primary cancer and found that IP% increased as the stage of disease became more advanced, as would have been expected. Also, we further confirmed the observation that melanoma has the highest propensity to migrate to the brain given that individuals with distant-stage melanoma had the highest IP% of brain metastases compared with all stages of any of the other primary sites.7 Various limitations of this study could have led to underestimating the absolute frequency and thus the IP of brain metastasis. This study includes only those patients with single primary lung, melanoma, breast, renal, or colorectal cancers (ie, an individual with multiple primary tumors who then developed brain metastases would not have been included in this analysis, leading us to underestimate the IP of brain metastases). However, the total number of single cancer cases in this study comprised 75.3% of all cancer cases (single and multiple) diagnosed in MDCSS between 1973 and 2001 for the five primary sites combined (ie, single and multiple primary lung, melanoma, breast, colorectal, and renal); thus, the majority of patients were represented. The data were compiled by review of medical records, including all available computed tomography (CT) and magnetic resonance imaging (MRI) reports, and if the CT or MRI reports were not present in the chart for review, under-reporting of brain metastases could result. Other sources of bias in the reporting of brain metastases in this study could be (1) that individuals with end-stage disease who developed neurologic symptoms may not have been imaged for diagnosis of brain metastases if their systemic disease was considered beyond treatment (ie, under-reporting of brain metastases), or (2) that not all intracranial lesions identified on CT or MRI in an individual with cancer represents a brain metastases (ie, over-reporting of brain metastases). The data in MDCSS are meticulously checked for accuracy, and because this is a large population-based cancer registry, these results should be reasonably generalizable to areas of the United States with similar demographics to Metropolitan Detroit.
The authors indicated no potential conflicts of interest.
This work was supported in part by National Institutes of Health contract No. N01-PC-65064 (Detroit Surveillance, Epidemiology, and End Results Registry) and support for J.S.B.-S. by National Cancer Institute grant No. K07 CA91849, and a grant from the American Brain Tumor Association. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Percy AK, Elveback LR, Okazaki H, et al: Neoplasms of the central nervous system. Epidemiologic considerations. Neurology 22:40-48, 1972 4. Posner JB: Brain metastases, 1995: A brief review. J Neurooncol 27:287-293, 1996[CrossRef][Medline] 5. Weinberg JS, Lang FF, Sawaya R: Surgical management of brain metastases. Curr Oncol Rep 3:476-483, 2001[CrossRef][Medline] 6. Johnson JD, Young B: Demographics of brain metastasis. Neurosurg Clin N Am 7:337-344, 1996[Medline] 7. Sawaya R, Bindal RK, Lang FF, et al: Metastatic brain tumors, in Kaye EL (ed): Brain Tumors 2nd Edition: An Encyclopedic Approach. London, UK, Churchill Livingstone, 2001, pp 999-1026 8. Guomundsson KR: A survey of tumors of the central nervous system in Iceland during the 10-year period 1954-1963. Acta Neurol Scand 46:538-552, 1970[CrossRef][Medline] 9. Fogelholm R, Uutela T, Murros K: Epidemiology of central nervous system neoplasms: A regional survey in Central Finland. Acta Neurol Scand 69:129-136, 1984[CrossRef][Medline] 10. Haar F, Patterson RH Jr: Surgical for metastatic intracranial neoplasm. Cancer 30:1241-1245, 1972[CrossRef][Medline] 11. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 19:579-592, 1978[Medline]
12. Delattre JY, Krol G, Thaler HT, et al: Distribution of brain metastases. Arch Neurol 45:741-744, 1988 13. Nussbaum ES, Djalilian HR, Cho KH, et al: Brain metastases: Histology, multiplicity, surgery, and survival. Cancer 78:1781-1788, 1996[CrossRef][Medline] 14. Cascino TL, Leavengood JM, Kemeny N, et al: Brain metastases from colon cancer. J Neurooncol 1:203-209, 1983[CrossRef][Medline] 15. Byrne TN, Cascino TL, Posner JB: Brain metastasis from melanoma. J Neurooncol 1:313-317, 1983[CrossRef][Medline] 16. Wronski M, Arbit E: Resection of brain metastases from colorectal carcinoma in 73 patients. Cancer 85:1677-1685, 1999[CrossRef][Medline] 17. Wronski M, Arbit E: Surgical treatment of brain metastases from melanoma: A retrospective study of 91 patients. J Neurosurg 93:9-18, 2000[Medline] 18. Wronski M, Arbit E, Burt M, et al: Survival after surgical treatment of brain metastases from lung cancer: A follow-up study of 231 patients treated between 1976 and 1991. J Neurosurg 83:605-616, 1995[Medline] 19. Wronski M, Arbit E, McCormick B: Surgical treatment of 70 patients with brain metastases from breast carcinoma. Cancer 80:1746-1754, 1997[CrossRef][Medline] 20. Wronski M, Arbit E, Russo P, et al: Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology 47:187-193, 1996[CrossRef][Medline] 21. Tremont-Lukats IW, Bobustuc G, Lagos GK, et al: Brain metastasis from prostate carcinoma: The M.D. Anderson Cancer Center experience. Cancer 98:363-368, 2003[CrossRef][Medline] 22. Bartelt S, Lutterbach J: Brain metastases in patients with cancer of unknown primary. J Neurooncol 64:249-253, 2003[CrossRef][Medline] 23. Takakura K, Teramoto A, Nakamura O, et al: Epidemiology of brain tumors [English translation]. No To Shinkei 34:465-472, 1982[Medline] 24. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494-500, 1990[Abstract] 25. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al: Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol 33:583-590, 1993[CrossRef][Medline] 26. Surveillance, Epidemiology and End Results (SEER) Program. http://seer.cancer.gov
27. Weir HK, Thun MJ, Hankey BF, et al: Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 95:1276-1299, 2003 Submitted December 19, 2003; accepted April 28, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
