Affiliations of authors: J. M. Legler, L. A. Gloeckler Ries, J. L. Warren (Cancer Surveillance Research Program, Division of Cancer Control and Population Sciences), M. A. Smith, R. S. Kaplan (Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis), E. F. Heineman, M.S. Linet (Division of Cancer Etiology), National Cancer Institute, Bethesda, MD.
Correspondence to: Julie M. Legler, Sc.D., National Institutes of Health, Executive Plaza North, Suite 313, Bethesda, MD 20892-7344.
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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Brain cancer incidence data (for malignant tumors only, the SEER Program does not require reporting benign brain tumors) were derived from the SEER Program's nine long-standing population-based registries throughout the United States, which represent approximately 10% of the total U.S. population, including the states of Connecticut, Iowa, New Mexico, Utah, and Hawaii and the metropolitan areas of Atlanta (GA), Detroit (MI), San Francisco (CA), and Seattle (WA). The data begin in 1975, when all of these areas were reporting (15). U.S. mortality data were from the National Center for Health Statistics, Hyattsville, MD. Imaging and stereotactic biopsy procedure data for the elderly were obtained from Medicare claims from physicians and hospital outpatient departments for persons 65 years old or older who were eligible for Medicare and who resided in any of the SEER areas from 1986 through 1994. The Medicare data evaluated were restricted to fee-for-service coverage among participants eligible for part B. This dataset has been described in detail elsewhere (16).
Classification
Incident cancers diagnosed from 1973 through 1976 and reported in SEER Program registries were classified according to the Manual of Tumor Nomenclature and Coding (17). Those cancers diagnosed during the period from 1977 through 1991 were classified according to the International Classification of Diseases for Oncology (ICD-O) (18), and those diagnosed in 1992 or later were classified according to the International Classification of Diseases for Oncology, 2nd edition (ICD-O-2) (19). After publication of ICD-O-2, all incident cancer cases diagnosed and reported in the SEER Program before 1992 were recoded to ICD-O-2 criteria by use of a standardized computer algorithm. Because the level of histologic detail included in the Manual of Tumor Nomenclature and Coding codes was sometimes insufficient to recode to the more specific codes in ICD-O, our analyses by histologic category were restricted to the period from 1977 through 1995, which encompasses the years in which tumors were coded according to either the first or the second edition of ICD-O. Because of relatively small numbers of brain cancer cases in many histologic categories of gliomas, we combined subtypes into two major groups: high-grade gliomas (ICD-O-2 codes = 9380, 9381, 9401, 9422, 9423, 9430, 9440, 9441, 9442, 9443, and 9481) and low-grade gliomas (ICD-O-2 codes = 9383, 9384, 9400, 9410, 9411, 9420, 9421, and 9424) [see Prados et al. (20) for a comprehensive summary of issues related to classification].
Primary brain cancer incidence trends were also delineated with respect to anatomic site, including cerebrum (ICD-O-2 codes C71.0-C71.4), cerebellum (code C71.6), brain stem (code C71.7), and other anatomic sites (codes C70.0-C70.9, C71.5, C71.8, C71.9, and C72.0-C72.9). Excluded from our analyses were lymphomas arising in the brain, tumors of the pituitary and pineal glands, and any brain and other central nervous system tumors designated as benign. The ninth revision of the International Classification of Diseases, Injuries, and Causes of Death (21) (ICD-9 codes = 191.0-191.9, 192.0-192.3, and 192.8-192.9) was used to define brain and other central nervous system cancers as the underlying causes of death.
Role of Diagnostic Technologies
To evaluate how changing medical practice and technical improvements in the diagnosis and
treatment of elderly patients may have affected brain cancer incidence trends, we examined
imaging and stereotactic biopsy procedure trends in the elderly population at large, not just
among those with brain cancer. Age-specific rates for head and other central nervous system MRI
(CPT [Common Procedural Terminology] codes 70551-70553) and CT (CPT codes
70450, 70460, and 70470; American Medical Association's Physicians' Current
Procedural Terminology, 4th edition (22)
[CPT-4]), obtained from Medicare data, were computed separately for the elderly age
subgroups (65-74 years old, 75-84 years old, and 85 years old). Comparable data are not
available for those under 65 years old because persons of that age are not generally eligible for
Medicare. In addition, age-specific stereotactic biopsy rates were examined as a proxy for
physician willingness to pursue an aggressive line of treatment for the same subgroups and years.
A recent thorough description of diagnostic neuroimaging has been provided by Prados et al. (20).
Statistical Methods
Age-specific incidence rates of brain cancer were computed for the period from 1975 through
1995 by use of data from the SEER Program (23). Like all of the rates
reported herein, U.S. mortality rates were calculated per 100 000 person-years, where a
person-year represents one person surviving an entire year. Both the incidence and mortality rates
were age adjusted to the 1970 U.S. standard million population. We examined age-specific
incidence at diagnosis during the earliest (1975 through 1979) and the most recently available
(1991 through 1995) 5-year periods. Lower and upper 95% confidence intervals for
individual rates are reported for selected age groups. The age at diagnosis is particularly
important in characterizing brain cancer; therefore, throughout this article, we analyzed trends by
using four broad age groups (ages 0-14 years, 15-44 years, 45-64 years, and 65 years). To
describe trends in incidence and mortality over time, we fit segment-wise linear models to the
logarithms of the rates by using several permutation tests to identify the number of changes in the
trend and those years (referred to as "join points") when the linear trends in the
logarithm of the rates changed. Each P value was found by use of Monte Carlo methods,
and a Bonferroni correction is used to maintain the overall asymptotic significance level
[for more detail on this method, see Kim et al. (24)];
all P values are two-sided. The model that we considered requires that there are no
abrupt jumps or discontinuities in the trend. For time periods between join points, we computed
the estimated annual percent changes by using the estimated slopes of the segments. The
estimated annual percent changes in the last time interval were then tested to determine whether
there was evidence of a trend upward or downward in the most recent years. In those cases where
no change in the trend was identified throughout the 21-year study period, we also calculated the
estimated annual percent changes for the last decade of the study (1986 through 1995) to provide
a sense of recent trend patterns. All of the estimated annual percent changes were tested for
equality to zero by use of the corresponding standard errors. Because of the higher incidence of
brain tumors in older patients, there were sufficient numbers of patients in older age groups to
allow a similar analysis of incidence trends for an even finer gradation of the elderly, i.e., those
65-74 years old, those 75-84 years old, and those 85 years old or older.
Join points and recent estimated annual percent changes were also computed for analyses of
trends by grade for the broader age groups (0-14 years old, 15-44 years old, 45-64 years old, and
65 years old) as described above. In addition, we evaluated trends in the proportion of brain
cancers microscopically confirmed and in incidence by anatomic site for 3-year intervals from
1975 through 1995 for these same age groups because small numbers of patients precluded the
use of annual rates for these breakdowns. We also calculated 5-year relative survival rates (25), i.e., the ratio of the observed survival rate to the expected survival
rate, for a patient cohort diagnosed from 1975 through 1985 and from 1986 through 1995
according to age group. Cases where the only source of a brain cancer diagnosis was a death
certificate or autopsy report were excluded from the survival analysis.
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RESULTS |
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Incidence by Age
Fig. 1 compares the age-specific incidence for
the earliest 5-year period (1975 through 1979) with the most recently
available 5-year period (1991 through 1995). For persons under age 70
years, the age-specific rates were similar in both periods. Among
children 0-14 years old, rates were highest for children 0-4 years
old and declined throughout the remaining years of childhood.
Adolescents (15-19 years old) had the lowest rates of all age groups,
with approximately two cases per 100 000 individuals. Incidence
rates increased slowly, but steadily, with age from young adulthood.
After age 45 years, rates accelerated more rapidly. For both periods,
rates dropped from the group aged 70-74 years old to the group aged
75-79 years old and continued to decline for each successively older
age group thereafter.
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Incidence and Mortality Trends
Fig. 2 contrasts the incidence and mortality
trends over time for four broad age groups by use of a logarithmic
scale to facilitate comparisons of changes in rates over time. Only the
youngest and oldest age groups experience significant changes in the
incidence trend over the study period (1975 through 1995), with
statistically significant changes2 in the trend occurring at
1977, 1983, and 1986 for those under 15 years of age and at 1988 for
those 65 years old or older. Data for patients under 15 years of age
showed statistically significant changes in the trend in 1986 (from
increasing to stabilizing), and data for patients 65 years old or older
showed statistically significant changes in the trend in 1988 (from
increasing to stabilizing). During the last period (1986 through 1995
for those 0-14 year olds and 1988 through 1995 for those
65 years
old), neither age group exhibited substantial increases or decreases in
incidence. There were no statistically significant join points for the
young adults (15-44 years old) or middle-aged persons (45-64 years
old), and neither of these age groups exhibited a statistically
significant trend upward or downward over the entire 21-year study period.
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A closer examination of patterns among subgroups of the elderly revealed some distinctions
between three elderly age groups (65-74 years old, 75-84 years old, and 85 years old; Fig. 3
). Incidence trends for the older age groups appeared similar to, but
lagged behind, those in the younger elderly subgroups. For patients 65-74 years old, incidence
increased at approximately 1.5% per year from 1975 to 1987 (P<.001) and
then remained steady (estimated annual percent change from 1987 through 1995 is -0.8%
[not statistically significantly different from zero]). Mortality increased slowly, but
steadily, for this age group throughout the study period (estimated annual percent change from
1975 through 1995 is 0.9% [P<.001]). For those aged 75-84 years,
incidence rates began at a lower level, and the trend rose at a faster rate (3.9% per year
from 1975 through 1989 [P<.001]) and then slowed down 2 years after
the slowdown for the group 65-74 years old (trend change at 1989, estimated annual percent
change from 1989 through 1995 is -3.1% [not statistically significantly
different from zero]). Escalating mortality for this group slowed at 1978 and again at 1989,
after which mortality stabilized (estimated annual percent change from 1990 through 1995 is
-0.04% [not statistically significantly different from zero]). In contrast,
among those 85 years old or older, incidence rates started out considerably lower than for persons
65-74 years old, with sharper increases (estimated annual percent change is 5.5% [P<.001]) sustained throughout the study period (1975 through 1995, no
statistically significant change in trend). Mortality rate increases of 8.5% (P<.001) per year slowed at 1988, increasing at only 2.1% (P = .021) per
year from 1988 through 1995. By 1995, incidence rates in the youngest elderly age groups were
very similar (16.1 and 16.7 cases of cancer per 100 000 individuals aged 65-74 years
and 75-84 years, respectively), and rates among those 85 years old or older were considerably
closer to these two age groups than they were at the start of the study period (13.6 cases per
100 000 individuals in 1995).
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Our classification of high-grade and low-grade gliomas included close to 90% of incident brain cancers for persons 45 years old or older at diagnosis, whereas this group of gliomas represented 80%-85% of those patients 15-44 years old at diagnosis and less than 70% of those under 15 years of age at diagnosis. These percentages remained consistent over the time of this study. The proportion of cases identified as high-grade gliomas increased with age. For children, high-grade gliomas represented only 21% of brain cancers and low-grade gliomas represented approximately 44% of brain cancers (1991 through 1995 SEER data). For those 15-44 years old, 37% and 48% were high grade and low grade, respectively. In contrast, among those aged 45-64 years, high-grade gliomas represented 71% and low-grade gliomas represented 21% of cases of brain cancers, which was similar to the percentages observed for those 65 years old or older (73% and 15%, respectively).
Trends in the incidence of gliomas by grade for the different age groups are shown in Fig. 4 with a logarithmic scale. Although the estimated annual percent changes
computed for the 19 years of available data (1977 through 1995) suggest steady increases in
childhood glial tumors (estimated annual percent changes of 2.1% [P= .034] for high-grade gliomas and 1.5% [P =
.002] for low-grade gliomas), in the last decade of our study, there were no statistically
significant increases in the rates for high-grade or low-grade gliomas among children aged 0-14
years (estimated annual percent changes from 1986 through 1995 are -2.2% [not
statistically significantly different from zero] for high grade and 0.8% [not
statistically significantly different from zero] for low grade). For those 15-44 years old,
high-grade and low-grade glioma rates converged over the study period (1977 through 1995),
with rates for high-grade gliomas stabilizing in the last decade (estimated annual percent change
from 1986 through 1995 is 0.9% [not statistically significantly different from
zero]) and low-grade incidence declining statistically significantly (estimated annual
percent change from 1986 through 1995 is -2.9% [P<.001]).
In contrast to the fairly constant difference between low-grade and high-grade
tumors in the very young and the near convergence of the two among young adults, incidence
rates for high-grade and low-grade gliomas diverged over time for both of the older age groups
(45-64 years old and
65 years old). Low-grade glioma incidence trends began to decline
after 1981 for those 45-64 years old (estimated annual percent change from 1981 through 1995 is
-5.6% [P<.001]) and after 1986 for those 65 years old or
older (estimated annual percent change from 1986 through 1995 is -8.3% [P<.001]). High-grade glioma rates continued to rise throughout the study
period among those 45-64 years old (estimated annual percent change = 1.6%
[P<.001]), whereas increases subsided among those in the oldest age
group (
65 years old) by 1992 (estimated annual percent change from 1992 through 1995 is
-3.6% [not statistically significantly different from zero]).
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Anatomic Site
The proportion of tumors at various anatomic sites differed by age.
Among children younger than 15 years during the period from 1993
through 1995, tumors of the brain stem and cerebellum accounted for
43% of brain cancer, whereas malignancies at these sites accounted for
only 13% of neoplasms among young adults and only 5% of tumors among
persons 45 years old or older. In contrast, tumors of the cerebrum
accounted for only one third of the brain cancer among children but
represented more than 60% of total brain cancer for persons 15 years
old or older in this most recently available 3-year period. The
age-specific incidence trends by anatomic site are presented for 3-year
periods on a logarithmic scale in Fig. 5. Among
children, there was a marked increase in rates of brain stem cancer as
well as a smaller increase in the rate of tumors arising in the
cerebrum. The brain stem was the only site for which young and
middle-aged adults demonstrated any increase in rates during the study
period. Elderly adults also experienced increases in the rates of
tumors of the brain stem, as well as tumors of the cerebellum and
cerebrum. However, for all age groups beyond childhood, the incidence
of brain stem tumors was low, and only a small fraction of brain
cancers arose in this location. Brain not otherwise specified
constitutes approximately one third of the "other brain"
category for any one age group and represents from 6.5% (age group
15-44 years old) to 12.7% (age group
65 years old) of total
incidence. Because these "other brain" rate series are fairly flat
in each age group, it is unlikely that the patterns for the identified
sites changed as a result of increasingly precise specification, but
this situation cannot be categorically ruled out.
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The proportion of cases microscopically confirmed was considerably lower among the elderly than among the younger age groups. Throughout the study period (1975 through 1995), approximately 90% of tumors among people under age 65 years were microscopically confirmed, whereas the proportions were closer to 80% for those aged 65-74 years and dropped below 70% and 60% for those aged 75-84 years and 85 years or older, respectively. The proportion of microscopically confirmed cases increased over time for persons diagnosed at ages 65-84 years; however, for those 85 years old or older at diagnosis, the proportion of cases with microscopic confirmation actually declined from 53% in 1975 through 1977 to 35% in 1993 through 1995.
Relative Survival
Survival remained poor for the elderly compared with the survival
among younger brain cancer patients. Between the periods from 1975
through 1985 and from 1986 through 1995, the 5-year relative survival
increased modestly for children (0-14 years old) from 58% to nearly
63%, for young adults (ages 15-44 years) from 48% to 55%, and for
middle-aged adults (ages 45-64 years) from 12% to 16% (Fig.
6). There was little change in relative survival for
the elderly (
65 years old)from 4% to 5%.
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In Fig. 7, we turn from analyses of brain cancer
patients to an examination of imaging procedure data for all part
B-eligible Medicare participants in the SEER areas. From 1986 through
1994, no increases in head and/or central nervous system CT scan
procedure rates were evident for persons aged 65-74 years, whereas the
population-based rates for CT scans increased from 1986 through 1988
and were stable thereafter among persons aged 75-84 years. In
contrast, there was an increase in CT scan procedures throughout the
period (1986 through 1994) among persons 85 years old or older. The
rates for MRI were substantially lower than those for CT scans
throughout the period from 1986 through 1994 and showed steady
increases for each age group throughout the period, with similar rates
for the groups aged 65-74 years and 75-84 years and lower rates for
the group older than 85 years. The increased use of stereotactic biopsy
during the same period was notable for persons aged 65-74 years and
for those aged 75-84 years. The rates for persons 85 years old or
older were somewhat unstable as a result of the small number of
procedures performed in this age group. Nonetheless, the volume of
activity in the last half of the study period was larger than that
early in the study period.
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DISCUSSION |
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Although clearly affected by some common factors, the age-specific incidence patterns are distinctive, and our more thorough examination of the elderly revealed further distinctions. An abrupt rise in brain cancer incidence among children from 1984 through 1986 was followed by a decade of stable rates. Among the elderly, brain cancer incidence reached a plateau for the group 65-74 years old in 1987 and for the group 75-84 years old in 1989. Steadily increasing rates were observed for those 85 years old or older, with rates now approaching those observed for the age groups 65-74 years old and 75-84 years old. In contrast to the changing patterns of incidence for children and for the elderly, brain cancer incidence has been essentially constant for the population 15-64 years old during the years 1975 through 1995.
Smith et al. (11) have persuasively linked the rapid, although relatively small, rise in brain cancer incidence among children in this time period to the increased availability of MRI (30,31). MRI provides superior visualization of low-grade glial neoplasms compared with CT imaging (32-36). Other possible explanations for the sudden increase in incidence of childhood brain tumors include changes in histologic classification of brain tumors that occurred during the years from 1984 through 1985 (37). In addition, changes in neurosurgical practices (e.g., stereotactic biopsies) that occurred in the mid-1980s might have led to increased diagnosis and reporting of childhood brain tumors (38,39). The continuous, although modest, decline in mortality during the period from 1975 through 1995 supports the interpretation that the abrupt rise in incidence during the mid-1980s is due to diagnostic and reporting improvements rather than to other factors.
The relationship between the pattern of incidence increases among subsets of the elderly population and trends in central nervous system imaging is inherently different from that for children. In contrast to the low-grade glial tumors that predominate in children, the high-grade gliomas of adults are easily detected by CT scans, whereas MRI does not provide an appreciable gain in diagnostic sensitivity. Therefore, unlike Smith et al. (11) who used equipment diffusion data and Modan et al. (6) who looked at trends in all diagnostic head imaging procedures combined for patients 65 years old or older, we examined trends in the use of CT, MRI, and stereotactic biopsy procedures separately for the elderly subgroups in the population. In spite of the widespread availability of CT scanners since the late 1970s (30), we observed increasing use of CT for the older elderly subgroups from 1986 through 1994, with only the age group 65-74 years old having fairly stable use during this period. The increasing use of CT among older subgroups, despite its long availability, likely reflects more aggressive diagnostic testing by physicians for older elderly persons presenting with neurologic symptoms. The increasing use of stereotactic biopsy procedures for the elderly subgroups indicates that physicians are applying more aggressive procedures to older patients throughout this time period. The increase in the number of imaging studies requested by physicians cannot be explained by an increasing frequency of brain cancers because the incidence of brain cancers among the older elderly population makes up less than 1% of brain imaging for this population. Thus, increases in imaging and stereotactic biopsy procedures among the elderly are consistent with a more widespread tendency of physicians to aggressively pursue diagnoses in older patients. Notably, these trends in imaging and stereotactic biopsy procedure rates are similar to the pattern of brain cancer incidence among the elderly subgroups for the same period.
Trends in brain cancer histology during the period from 1977 through 1995 are notable for the declining incidence of low-grade gliomas for all adult age groups. The decline appeared to begin in the early 1980s for the group aged 45-64 years and in the mid-1980s for the group 65 years old or older. Given the absence of a statistically significant change in incidence for high- and low-grade gliomas combined from 1985 through 1995 for the population 15 years old or older, the changing incidence pattern for low- and high-grade gliomas seems most consistent with changes in diagnostic classification. A less likely explanation is that exogenous factors have simultaneously caused a decline in low-grade and an increase in high-grade glial malignancies. The poor reproducibility among neuropathologists for diagnosis of high- versus low-grade gliomas in children has been documented; while it may have increased the variability in these series, it is unlikely to have produced the sustained trends that were observed (40).
Throughout the study period, mortality declined among patients with brain cancer who were under 65 years of age. Improvements in various components of brain cancer treatment (e.g., neurosurgical technique and delivery of radiation therapy) likely contributed to this decline. For the group 65 years old or older, mortality paralleled incidence trends, with initial increasing rates during earlier years followed by subsequent stabilization of mortality rates. Improvements in survival rates were decidedly modest for all age groups, and survival remained especially poor among brain cancer patients 45 years old or older. These observed age-specific patterns in mortality and survival rates are consistent with our analysis of glial tumors by grade and age. Low-grade gliomas, which are associated with favorable outcome, predominate among children and young adults, whereas high-grade gliomas, which have a very poor prognosis, predominate among middle-aged and elderly adults. Although advances in brain cancer therapy over the last decade have been modest at best, several important treatment initiatives provide a reason to anticipate treatment advances in the near-to-intermediate term. These include improvements in neurosurgical and radiation therapy techniques (41-43), development of new treatment approaches to circumvent resistance to conventional chemotherapy agents (44,45), and evaluations of novel therapeutic strategies such as inhibition of angiogenesis (46) and inhibition of signal transduction pathways involved in cell survival and growth (47). Important new clinical research infrastructures are being established to implement new treatment initiatives and include adult and pediatric brain tumor clinical trial consortia.
The only known risk factors for brain tumors in humans are high doses of ionizing radiation and selected congenital and genetic disorders (48). These factors explain only a small proportion of primary brain cancers and have not changed over time in such a way as to account for the observed incidence trends described above. Little is known about the factors responsible for the majority of primary brain cancers, although some data (48,49) have suggested that occupational exposures to organic solvents or pesticides may be linked. Early studies (50,51) suggested an association between electromagnetic fields and brain cancers, but more recent studies (52-60) have suggested that the risk, if present at all, is small. Diet, tobacco smoking, and alcohol consumption have not been strongly associated with increased risks or protective effects for brain cancer in adults (48). Limited evidence (49,53,61,62) inconsistently suggests associations between maternal diet and brain tumors in children. Overall, recent changes in lifestyle factors that play a major role in other cancers do not appear to have strongly affected or to be consistently linked with observed trends in brain cancer incidence.
In summary, brain cancer incidence has stabilized over the past decade for all major age
groups with distinctive age-specific patterns. Auxiliary analyses are consistent with differential
effects of potential explanatory factors such as imaging and classification. The continuing
increase in incidence for the oldest subset of the elderly population (those 85 years old)
may be related to more aggressive diagnostic testing for this population, as evidenced by similar
patterns of increase in CT imaging rates and age-specific brain cancer incidence trends in the
elderly subgroups. Careful monitoring of brain cancer incidence for all age groups needs to
continue, and analytical studies to identify causes and risk factors for brain cancers should be
prioritized.
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NOTES |
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2 A series of hypotheses tests led to the selection of the
model with three join points for those diagnosed before their 15th birthday. Null
versus alternative models with zero versus three join points (P = .004), one
versus three join points (P = .002), and two versus three join points (P
= .003) led to the selection of the three-join-point model. For those patients 65 years old
or older at diagnosis, models with zero versus three join points (P = .002), one
versus three join points (P = .135), and one versus two join points (P
= .100) led to the choice of a model with a single join point at 1988.
We are grateful for Dr. Hyune-Ju Kim's assistance with the join point analysis.
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Bunin GR, Kuijten RR, Buckley JD, Rorke LB, Meadows AT.
Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young
children. N Engl J Med 1993. 329:536-41.
Manuscript received March 22, 1999; revised June 10, 1999; accepted June 18, 1999.
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