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Keywords:

  • brain metastases;
  • incidence;
  • breast neoplasms;
  • colorectal neoplasms;
  • lung neoplasms;
  • kidney neoplasms;
  • skin melanoma;
  • the Netherlands

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The objective of this study was to report on the incidence of and factors related to the occurrence of central nervous system metastases in a cohort of patients who were diagnosed with colorectal, lung, breast, or kidney carcinoma or melanoma.

METHODS

Using the population-based Maastricht Cancer Registry (MCR), a cohort was created of patients with colorectal carcinoma (n = 720 patients), lung carcinoma (n = 938 patients), breast carcinoma (n = 802 patients), renal carcinoma (n = 114 patients), and melanoma (n = 150 patients). The patients had to live in the catchment area of the University Hospital Maastricht (UHM) and had to have been diagnosed at the UHM during the period 1986–1995. Patients with brain metastases were searched for by linking the MCR to the Neuro-Oncology Registry of the UHM. Radiology files were checked as well. Follow-up lasted until December 31, 1998.

RESULTS

Brain metastases were diagnosed in 232 patients (8.5%) in the cohort (n = 2724 patients). Of these patients, 84 patients were diagnosed with brain metastases within 1 month after their primary diagnosis, 82 patients were diagnosed with brain metastases within 1 year of their primary diagnosis, and 66 patients were diagnosed with brain metastases more than 1 year after their primary diagnosis. The cumulative incidence after 5 years was estimated at 16.3% in patients with lung carcinoma, 9.8% in patients with renal carcinoma, 7.4% in patients with melanoma, 5.0% in patients with breast carcinoma, and 1.2% in patients with colorectal carcinoma. The incidence was lower in patients age ≥ 70 years compared with younger patients (breast and lung carcinoma), lower in patients who were diagnosed before 1991 compared with patients who were diagnosed after 1991 (breast and lung carcinoma), and lower in patients who had nonsmall cell lung carcinoma compared with patients who had small cell lung carcinoma.

CONCLUSIONS

The frequency of brain metastases in this cohort was highest in patients with lung carcinoma, followed by patients with renal carcinoma. There was no evidence of an increasing incidence of brain metastasis in patients with carcinoma of the breast or lung. Cancer 2002;94:2698–705. © 2002 American Cancer Society.

DOI 10.1002/cncr.10541

Cancer is the second most important cause of death in the Western world. In the Netherlands, an annual number of > 54,000 patients develop cancer, and approximately 35,000 persons die each year of cancer. 1 Brain metastasis is the most common diagnosis in patients who are referred because of neurologic complications of systemic malignant disease. Morbidity and mortality rates are high in patients who develop brain metastasis.

In approximately 15% of all patients with cancer, the primary tumor metastasizes to the central nervous system (CNS). 2 However, incidence rates of brain metastases vary according to, for instance, primary tumor type and method of investigation. Colorectal carcinoma, for instance, rarely metastasizes to the brain, and an incidence rate of only 1% has been reported. 3 In contrast, an incidence rate of 54% has been reported for brain metastases in patients with adenocarcinoma of the lung. 4 With regard to the method of investigation, clinical studies generally have reported lower incidence rates than autopsy studies. The interpretation of these data also is difficult because of probable selection bias due to the referral of patients to specialized clinics.

There is some evidence that the frequency of CNS metastases is increasing, probably due to longer survival of patients because of more aggressive treatment of the primary tumor. 5 The use of better neuroimaging techniques also may have contributed to a higher detection rate (and, hence, a higher incidence) of CNS metastases. 5

We investigated the current incidence of brain metastases in a cohort of patients with breast, colon, renal, and lung carcinoma and melanoma. These tumors were chosen because some metastasize frequently and other metastasize infrequently to the brain. The influence of tumor site, histology, disease stage, patient age, and period of diagnosis was studied in relation to the incidence of brain metastases.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

The Maastricht Cancer Registry (MCR) 6 was used to select patients who were at risk of developing brain metastases. Patients were selected who were treated at the University Hospital Maastricht (UHM) and lived in the catchement area of the UHM (the municipalities of Eijsden, Maastricht, Margraten, and Meerssen). More than 95% of the patients with malignant disease from these municipalities are referred to the UHM for diagnosis and treatment (data from the MCR).

Patients were included if they had been diagnosed during the years 1986–1995 with one of the following types of malignant disease: breast carcinoma (International Classification of Diseases for Oncology-1 [ICD-O-1], T-174), colorectal carcinoma (ICD-O-1, T-153.0-154.1), lung carcinoma (ICD-O-1, T-162), renal carcinoma (ICD-O-1, T-189), or melanoma of the skin (ICD-O-1, T-173 and M-8720-8780). Patients with a previous invasive malignancy (excluding nonmelanoma skin carcinoma) were not eligible. Reports of all deaths were received from the municipal population registers. At the time of the study, death reports were available until December 31, 1998.

This cohort was linked to the Neuro-Oncology Registry (NOR) to detect patients with brain metastasis. The NOR is a registry of the Neuro-Oncology Department of the UHM, which records all patient contacts regarding primary CNS tumors and neurologic complications (including metastases to the CNS). 7

Records were linked for date of birth, gender, family name, and hospital administration number. The completeness of the brain metastasis records was evaluated by a manual check of the computerized radiologic files. The files of all patients with carcinoma of the breast, colorectal, and kidney and with skin melanoma were checked, and patients with missed brain metastasis in the cohort were added to the analysis files. Because a check of the patients diagnosed with lung carcinoma during the years 1988–1989 revealed only one additional incident of brain metastasis, the patients from the other years were not checked in the radiologic files.

Patients who were included in the cohort were considered at risk of developing brain metastases until their death or until another primary malignancy was diagnosed. Because the reports of death from the municipalities were received until the end of 1998, December 31, 1998, was defined as the end of follow-up. All patients for whom no notification of death was available were assumed to be alive at the end of follow-up.

Statistical Analysis

Statistical analysis was performed using SAS software (version 6.12; SAS Institute, Inc., Cary, NC). 8 Follow-up was censored at death, on the occurrence of a second primary malignancy, or on December 31, 1998. Because brain metastasis and death can be regarded as competing risks, survival curves were not estimated by using the Kaplan–Meier method. 9 To describe the differences between the various subgroups of patients, use was made of cumulative incidence curves, which allow direct probability interpretation. 10 The following variables were investigated in the analyses: age (in three categories: ages 0–49 years, 50–69 years, and ≥ 70 years), primary site, histology, year of diagnosis (1986–1990 vs. 1991–1995), and disease stage (according to the TNM classification system). 11

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Using the cancer registry files, 2724 patients were selected for the follow-up study (Table 1). Of these, 802 patients had a primary malignancy in the breast, 720 patients had a primary malignancy in the colon or rectum, 938 patients had a primary malignancy in the lung, and 114 patients had a primary malignancy in the kidney, whereas 150 patients had a skin melanoma. Record linkage with the NOR revealed 208 brain metastases. A thorough check of computerized radiologic files found 24 additional patients with brain metastases who complied with the eligibility criteria. This check included all patients with of breast, colorectal, and renal carcinoma and melanoma. Because the check on lung carcinoma patients who were diagnosed during 1987–1988 revealed only one additional eligible patient with brain metastasis, a further check was considered unnecessary.

Table 1. Number of Patients Selected for the Cohort and Number of Brain Metastases According to Site and Interval between Diagnosis of Primary Tumor and Brain Metastasis
SiteNo. of patients at riskBrain metastases (no. of patients)Interval between primary tumor and brain metastasis
Detected by record linkageDetected in radiologic filesTotal (n)< 1 Month< 1 yr< 2 yrs< 3 yrs< 4 yrs< 5 yrs> 5 yrs
  • a

    Completeness of the data on patients with lung carcinoma was checked only for those who were diagnosed in the years 1988–1989.

Breast8022913423589863
Colon/rectum72073102222101
Kidney11493122421111
Lung9381551a1567666101030
Melanoma15084121511301
Total2724208242328482231413106

Of the patients with brain metastasis, 166 patients were diagnosed within 1 year of the diagnosis of their primary malignancy, including 84 patients with brain metastases that were detected within 1 month (Table 2). Breast carcinoma was the exception: Only 8 of the 42 patients with breast carcinoma had brain metastases diagnosed within 1 year of the diagnosis of their primary tumor.

Table 2. Cumulative Incidence of Brain Metastasis and Event Free Survival in Patients with Breast Carcinoma, Colorectal Carcinoma, Lung Carcinoma, Melanoma, and Kidney Carcinoma
SiteNo. of patients at riskNo. with brain metastasis1 Month1 Yr5 Yrs
% Event free% CI of BM% Event free% CI of BM% Event free% CI of BM
  1. %CI of BM: cumulative incidence (%) of brain metastases.

Breast8024295.90.491.61.068.85.0
Colon/rectum7201095.80.171.80.650.31.2
Kidney1141291.21.764.05.248.69.8
Lung93815680.17.834.514.814.716.3
Melanoma1501298.70.791.34.078.77.4

The cumulative incidence of brain metastases at 1 year was estimated at 1.0% for patients with breast carcinoma, 0.6% for patients with colorectal carcinoma, 14.8% for patients with lung carcinoma, 4.0% for patients with melanoma, and 5.2% for patients with renal carcinoma (Fig. 1). At 5 years, the cumulative incidence was estimated at 5.0% for patients with breast carcinoma, 1.2% for patients with colorectal carcinoma, 16.3% for patients with lung carcinoma, 7.4% for patients with melanoma, and 9.8% for patients with renal carcinoma. Only for patients with breast and lung carcinoma was the number of brain metastases large enough for further analysis.

thumbnail image

Figure 1. Cumulative incidence (Cum. incid.) of brain metastases and event free survival in patients with carcinoma of the breast (A) and lung (B). CNS Metast.: central nervous system metastases.

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Lung Carcinoma

In patients with lung carcinoma, the cumulative incidence was greater for patients with small cell carcinoma (cumulative incidence at 5 years, 29.7%) compared with the incidence for patients with nonsmall cell carcinoma (12.6%) (Fig. 2). The occurrence of brain metastases was rarer in patients age ≥ 70 years for both small cell carcinoma and nonsmall cell lung carcinoma (Table 3). The incidence of brain metastases was 32.5% in patients with small cell lung carcinoma who were diagnosed during the period 1986–1990 and 26.0% for patients who were diagnosed during the period 1991–1995. Patients with nonsmall cell lung carcinoma also showed a lower cumulative incidence of brain metastases in the more recent diagnosis years. Eliminating all events in the first month allowed us to study the factor disease stage (Table 4). The cumulative incidence after 5 years was 8.4% for patients with Stage I–II nonsmall cell lung carcinoma; 4.3% for patients with Stage III nonsmall cell lung carcinoma, and 10.8% for patients with Stage IV nonsmall cell lung carcinoma.

thumbnail image

Figure 2. Cumulative incidence (Cum. incidence) of brain metastases and event free survival in patients with carcinoma of the lung according to histologic type.

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Table 3. Cumulative Incidence of Brain Metastases According to Histological Type and Age Group in Patients with Lung Carcinoma: All Events
Histologic typeAge group (yrs)No. of patients at riskNo. with brain metastasis1 Month1 Yr5 Yrs
% Event free% CI of BM% Event free% CI of BM% Event free% CI of BM
  1. %CI of BM: cumulative incidence (%) of brain metastases; NSCLC: nonsmall cell lung carcinoma; SCLC: small cell lung carcinoma.

NSCLC0–49 y541088.93.535.214.214.817.6
NSCLC50–69 y3786082.88.241.513.920.315.6
NSCLC70+ y3102678.45.831.67.713.88.1
SCLC0–49 y13576.913.030.833.523.133.5
SCLC50–69 y1084179.611.726.932.46.336.8
SCLC70+ y751468.010.022.717.51.317.5
NSCLCAll7429681.46.836.911.417.212.6
SCLCAll1966075.011.225.527.25.529.7
AllAll93815680.17.834.514.814.716.3
Table 4. Cumulative Incidence of Brain Metastases According to Histologic Type and Age Group in Patients with Lung Carcinoma: Only Events > 1 Month after Diagnosis
Histologic typeGroupNo. of patients at riskNo. with brain metastasis1 Yr5 Yrs
% Event free% CI of BM% Event free% CI of BM
  • %CI of BM. cumulative incidence (%) of brain metastases; NSCLC: non-small cell lung carcinoma; SCLC: small cell lung carcinoma; X: stage unknown.

  • a

    Stage was determined according to the International Union Against Cancer TNM classification system (1987 and 1992).

Age group (yrs)
 NSCLC0–4948839.612.016.715.9
 NSCLC50–693132850.27.024.59.0
 NSCLC70+244740.22.417.52.9
 SCLC0–4910340.026.630.026.6
 SCLC50–69862833.726.18.031.6
 SCLC70+51633.311.12.011.1
Stagea
 NSCLCI–II1801571.75.541.78.4
 NSCLCIII2331041.23.012.34.3
 NSCLCIV1461619.910.88.710.8
 NSCLCX46243.52.123.94.1
 NSCLCAll6054345.35.621.07.1
 SCLCAll1473734.021.47.324.6
 AllAll7528043.18.718.410.6

Breast Carcinoma

The cumulative incidence of brain metastases after 5 years was 7.5% years in patients age ≤ 49 years at the time of diagnosis, 5.3% in patients age 50–69 years, and 2.7% in patients age ≥ 70 years (Table 5). The incidence of brain metastases was lower in patients who were diagnosed after 1991 (3.9% and 6.5%, respectively, after 5 years). Eliminating all events that occurred within 1 month of the diagnosis of the primary tumor did not substantially change the point estimates for age and diagnosis year (Table 6). Disease stage clearly was related to the incidence of brain metastases; at 5 years, the incidence was 3.1% in patients with Stage I breast carcinoma, 3.6% in patients with Stage II breast carcinoma, 8.6% in patients with Stage III breast carcinoma, and 12.6% in patients with Stage IV breast carcinoma (including patients with unknown stage).

Table 5. Cumulative Incidence of Brain Metastases According to Age Group and Year of Diagnosis in Patients with Breast Carcinoma: All Events
GroupNo. of patients at riskNo. with brain metastasis1 Month1 Yr5 Yrs
% Event free% CI of BM% Event free% CI of BM% Event free% CI of BM
  1. %CI of BM: cumulative incidence (%) of brain metastases.

Age group (yrs)
 0–49 yrs1971699.50.097.50.581.07.5
 50–693461996.00.693.61.169.35.3
 70+259793.10.484.61.159.12.7
Yr of diagnosis
 1986–19903542696.30.392.11.166.46.5
 1991–19954481695.50.491.30.971.13.9
All8024295.90.491.61.068.85.0
Table 6. Cumulative Incidence of Brain Metastasis According to Age Group, Year of Diagnosis, and Stage in Patients with Breast Carcinoma: Only Events > 1 Month After Diagnosis
GroupNo. of patients at riskNo. with brain metastasis1 yr5 yrs
% Event free% CI of BM% Event free% CI of BM
  • %CI of BM: cumulative incidence (%) of brain metastases.

  • a

    Stage was determined according to the International Union Against Cancer TNM Classification System (1987 and 1992).

Age group (yrs)
 0–491961698.00.581.47.5
 50–693321797.60.672.25.0
 70+242690.50.863.22.5
Yr of diagnosis
 1986–19903422595.30.968.76.4
 1991–19954281495.60.574.43.6
Stagea
 I240798.80.085.23.1
 II3751696.80.372.73.6
 III94894.70.058.08.6
 IV/X61875.95.430.212.6
All7703995.50.671.74.8

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The current study examined the incidence of brain metastases in patients several types of solid tumors. What made the study unique was the use of a population-based cancer registry for the study base and a neuro-oncologic registry to determine the outcome. After 5 years of follow-up, the cumulative incidence of brain metastases was estimated at 5.0% for patients with breast carcinoma, 1.2% for patients with colorectal carcinoma, 16.3% for patients with lung carcinoma, 7.4% for patients with melanoma, and 9.8% for patients with renal carcinoma. In patients with lung carcinoma, the incidence was highest in patients with the small cell type and decreased with increasing age. In patients with breast carcinoma, the incidence increased with the disease stage and decreased with age.

The follow-up with respect to brain metastases was done by two methods. First, records for the cohort were linked to the NOR of the UHM, in which the Neurology Department records all contacts with patients with a malignant disease. 7 Second, the radiologic files were checked to detect any patients with additional brain metastasis who had not been referred to the Neurology Department or who erroneously were not recorded in the NOR. This second method identified several new patients with metastasis, especially in patients with longer follow-up. The UHM is the only hospital in the southwestern part of the Dutch province of Limburg. By limiting the initial cohort to patients living in the neighborhood of the hospital and patients that were referred to the UHM for initial treatment of their primary tumors, we tried to limit the proportion of patients who were referred to other hospitals for diagnosis and treatment of a possible brain metastasis. It is possible, however, that we missed a few patients with brain metastases. For example, brain metastases that remain asymptomatic during life probably will not be diagnosed. This is less likely for patients with small cell lung carcinoma, because the department was conducting a magnetic resonance imaging study of patients with asymptomatic brain metastases during the study period. 12

Incidence rates of brain metastases from lung carcinoma that have been reported in the literature range from as low as 9.7% to as high as 54%. 4, 13–19 The incidence rates vary with the type of study, the method used to select patients, the duration of follow-up, and the histologic type of lung carcinoma. The highest incidence (54%) was found in an autopsy study of patients with primary adenocarcinoma of the lung, 4 whereas the lowest incidence (9.7%) referred to the incidence of brain metastases among patients with nonsmall cell lung carcinoma at the time of the diagnosis of the primary tumor. 17 Among patients with breast carcinoma, incidence rates of 30%, 20 16%, 21 and 4% 22 have been reported: The first two rates were based on autopsy studies, and third rate summarized the results of 17 clinical studies. Our estimate is in agreement with the latter study. 22

The incidence rates of brain metastasis in patients with colorectal carcinoma generally are quite low, varying from 1% to 4%. The only study based on an autopsy series also found the highest estimate, i.e., 4%. 23 The other studies were done in clinical settings 3, 24, 25 and found estimates ranging from 1.0% to 1.8%. Our estimate is slightly lower than those figures.

Clinical studies relating to renal carcinoma have found incidence rates of 3.9–7.7% in clinically based studies 26–29 and rates of 9.7–10.0% in autopsy studies. 30, 31 Our estimate (9.8% at 5 years of follow-up) is higher than the estimates in the clinical studies and is in line with the findings of the two autopsy studies.

Only one study has been published that estimated the incidence of brain metastases from melanoma. 32 That clinically based study yielded an estimate of 10.1%, which is a little higher than our result (7.4%).

With respect to age, there was evidence of a lower incidence of brain metastases in the group of patients age ≥ 70 years for both breast carcinoma and lung carcinoma. This tendency also was observed in one other publication on patients with breast carcinoma 21 and in one publication on patients with lung carcinoma. 13 This may reflect diagnostic bias, because it is likely that the diagnostic work-up to detect brain metastasis probably will be less extensive in older patients. This is in agreement with the fact that the whole diagnostic work-up in older patients with malignant disease is less extensive compared with the work-up in younger patients. 33 It also is conceivable that these malignancies have a different, less aggressive biologic behavior in the elderly.

Some studies have suggested that the incidence of brain metastases is increasing. 5 The current study found no confirmation of this with respect to patients with carcinoma of the breast or lung. Over a period of 10 years, we did not observe any increase in incidence rates for brain metastases in these sites; rather, we found a statistically nonsignificant decrease. Also, the incidence rates we found were much lower compared with the rates found in other studies. With regard to breast carcinoma, the observed relation with disease stage may explain the decreasing incidence. The greater awareness of breast carcinoma among women since the 1970s and 1980s 34 and the implementation of the National Breast Cancer Screening Program since 1990 35 have changed the disease stage distribution in patients with breast carcinoma. Unlike what happened in the past, the majority of patients with breast carcinoma currently have their disease detected at a very early stage. With respect to lung carcinoma, a shift in the distribution by disease stage is unlikely, because there is no screening program in the Netherlands for this malignancy.

The current study was able to measure the incidence of brain metastases after 5 years and 10 years of follow-up. The incidence was lower than what has been reported in most autopsy studies but was comparable to the rates reported in clinical studies. In contrast to what has been claimed, we did not find any evidence of increasing incidence of brain metastases. Rates were not higher than the historic rates reported in the literature, and, over the period we studied, we observed a decrease rather than an increase. More research is needed with respect to the risk factors for brain metastasis and the opportunities to prevent this serious complication.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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