Trends in Leukemia Incidence and Survival in the United States ( )

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1 2229 Trends in Leukemia Incidence and Survival in the United States ( ) Yang Xie, M.D., M.P.H. 1,2 Stella M. Davies, M.D., Ph.D. 1,2 Ying Xiang, M.D. 1,2 Leslie L. Robison, Ph.D. 1,2 Julie A. Ross, Ph.D. 1,2 1 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. 2 University of Minnesota Cancer Center, Minneapolis, Minnesota. Supported by the University of Minnesota Children s Cancer Research Fund and by the National Cancer Institute (Grant R01 CA-79940). The authors thank Angela Smit and Ginny Oie for assistance in the preparation of this article. Dr. Davies s current address: Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio. Address for reprints: Julie A. Ross, Ph.D., University of Minnesota Cancer Center, MMC 422, 420 Delaware St. S.E., Minneapolis, MN 55455; Fax: (612) ; ross@epi.umn.edu Received November 1, 2002; revision received December 31, 2002; accepted January 7, BACKGROUND. It is estimated that each year, approximately 30,800 individuals will be diagnosed with leukemia in the United States and 21,700 individuals will die of the disease. Although the overall incidence of leukemia has been declining in the United States, recent reports suggest that incidence rates may be increasing for certain age and racial groups. METHODS. Leukemia incidence (including acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], chronic myeloid leukemia [CML], and chronic lymphoblastic leukemia [CLL]) and 5-year survival rates were obtained from the Surveillance, Epidemiology, and End Results (SEER) program. Specific rates for age (birth 19, 20 44, 45 64, and 65 years), gender, and race (black, white) were also examined. RESULTS. A total of 66,404 cases of leukemia were identified for the period in the nine reporting SEER sites. For children younger than 20 years old, the overall incidence rate of leukemia increased significantly (estimated annual percent change [EAPC] 0.5%, 95% confidence interval [CI] ), whereas the rate decreased significantly among the group 65 years and older (EAPC 0.3, 95% CI 0.5 to 0.1). Incidence rates for CLL and CML decreased significantly during this time period, whereas incidence rates for AML remained stable. Children younger than 20 years old experienced a 15% increase in the 5-year survival rates for both ALL and AML when comparing the two 10-year periods of and In contrast, there was little overall improvement in survival for adults 45 years and older. In particular, there was a notable decrease in the overall 5-year survival for blacks older than 65 years and for black males older than 44 years. CONCLUSIONS. Although the current study confirmed some of the results noted in other populations, the observed overall decline in leukemia survival for blacks is surprising and warrants further investigation. Cancer 2003;97: American Cancer Society. DOI /cncr KEYWORDS: leukemia, incidence, survival, trends, epidemiology. Each year, the American Cancer Society estimates that 30,800 individuals will be diagnosed with leukemia in the United States and that 21,700 individuals will die of the disease. 1 With the exception of a few established risk factors including benzene and alkylating agents, which account for a fraction of cases, little is known about the causes of leukemia. 2 Leukemias are a heterogeneous group of hematopoietic malignancies that include many diverse and biologically distinct subgroups. The four major subtypes of leukemia described by most cancer registries include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), and 2003 American Cancer Society

2 2230 CANCER May 1, 2003 / Volume 97 / Number 9 chronic myeloid leukemia (CML). Several reports have studied the trends in leukemia incidence and survival Many of these studies have either addressed leukemia overall or have focused on young patients. Ecologic data that explore trends in cancer incidence can provide important information regarding potential changes in risk factors and can reflect underlying changes in diagnostic classification. The purpose of this article is to describe age (birth 19, 20 44, 45 64, and 65 years), race (white, black), and gender patterns of leukemia incidence and survival in the United States during the period MATERIALS AND METHODS Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. 13 The SEER program collects demographic, medical, and follow-up data on all incident malignancies that occur in several geographic areas in the United States. Data for this analysis were derived from nine population-based SEER registries that cover approximately 10% of the total U.S. population and include the states of Connecticut, Hawaii, Iowa, New Mexico, and Utah and the metropolitan areas of Atlanta, Detroit, San-Francisco-Oakland, and Seattle. The SEER program is considered the standard for quality among cancer registries around the world. Case ascertainment is estimated at 98%. Leukemia diagnoses were defined using International Classification of Diseases for Oncology (ICD- O) 14 codes as follows: overall leukemia ( ); ALL (9821, 9826, 9827, 9828); CLL (9823); AML (9840, 9841, 9861, 9866, 9867, , 9891, 9910); and CML (9863). The annual age-adjusted incidence rates for leukemia for the period were calculated using the SEER public-use CD-ROM. 13 These data include information on all incident cases of malignancies and estimates of the population (based on U.S. Census data) in each of the SEER reporting areas. All nine SEER registries contributed data for the entire time period except for the Seattle registry, which began in 1974, and the Atlanta registry, which began in Age (birth 19, 20 44, 45 64, and 65 years), gender, race (black, white), and leukemia-specific trends were evaluated to determine if any observed trends might be accounted for by a subgroup of the population. Incidence and survival rates are expressed per million persons and were age adjusted using the world standard population. Survival rates are expressed as percentages and were adjusted for general population mortality. The estimated annual percent change (EAPC) for incidence rates and the corresponding 95% confidence intervals (CI) were calculated using the weighted least squares method. 15 Local regression methods (which take into account the incidence and survival rates immediately adjacent to each year s rates) were employed in the plots to assist in the visualization of trends. 16,17 RESULTS Incidence A total of 66,404 cases of leukemia were identified from 1973 to 1998 in the nine reporting areas of the SEER program. Overall leukemia incidence rates and trends among the four age groups are shown in Table 1. The age-specific incidence rate of leukemia was 15 times higher among the oldest group (545 per million persons) compared with the youngest group (36 per million persons). With the exception of the year-old age group, blacks had lower rates of leukemia compared with whites. Males had higher incidence rates than females for all age groups. Among children and adolescents, the overall incidence rate of leukemia increased significantly during the time period (EAPC 0.5%, 95% CI ), whereas the rate decreased significantly among the group 65 years and older (EAPC 0.3%, 95%CI 0.5 to 0.1). There were no significant trends for the young adult or middle-age group. When race and gender-specific incidence rates were evaluated, there was a statistically significant increase (EAPC 0.7%) among white females in the youngest age group. Among the oldest group, the incidence rate of leukemia in white males decreased significantly from 1973 to A similar decrease was observed for blacks, but it did not reach statistical significance. Although a model based on a constantly increasing incidence rate can be applied to overall leukemia incidence data to estimate the EAPC, a visual inspection of these data provided more revealing patterns over time (Fig. 1). For example, among white females in the youngest age group, the overall EAPC in incidence was 0.7 (95% CI ; Table 1). As shown in Figure 1, there was a slight but steady increase in the incidence of leukemia in females younger than 20 years of age during the period In contrast, for black males in the year age group, the overall EAPC was 0.7 (95% CI 1.9, 0.6). However, visual inspection revealed a nonlinear pattern in the incidence rate. The rate increased until about 1980, decreased from 1981 to 1985, plateaued during the period , and then increased again. Leukemia subtypes revealed different patterns (Table 2). With the exception of the oldest group, ALL incidence rates increased significantly. This increase was particularly notable in the two middle age groups.

3 Leukemia in the United States/Xie et al TABLE 1 Trends and Overall Leukemia Incidence (Rate per Million Persons), SEER Total Male Female No. Rate a Change (%) b 95% CI No. Rate a Change (%) b 95% CI No. Rate a Change (%) b 95% CI Birth c 0.1, , c 0.1, , , , , , , , , c 0.5, , c 0.7, , c 0.6, 0.1 Birth c 0, , c 0.1, , , , , , , , , c 0.5, 0 18, c 0.7, , , 0 Birth , , , , , d d c 2.4, , c 3.1, c 1.3, , , 0.3 SEER: Surveillance, Epidemiology, and End Results program; CI: confidence interval. a Incidence rates are per million persons and are age adjusted to the 1970 U.S. standard million population. b Estimated annual percent change (EAPC) was calculated using the weighted least squares method. c The EAPC is significantly different from zero (P 0.05). d Statistic could not be calculated due to small numbers. time among the different age groups, although there was a slight increase among the oldest group. Race and gender-specific incidence rates and trends also were evaluated among the various leukemia subgroups (data not shown). For ALL among the youngest group, incidence rates have been increasing slightly,which was particularly apparent among blacks. The EAPC for black males and females was 2.2% (95% CI ) and 1.8% (95% CI ) in the birth 19 group, respectively. There was little other evidence for race or gender differences among the different subtypes of leukemia. FIGURE 1. Leukemia incidence during the period by age and gender. Unbroken line: white males; dotted line: white females; dashed line: black males; dashed/dotted line: black females. Incidence rates increased by an average of 2.6% and 2.9% per year for the and the groups, respectively. In contrast, the incidence of both CLL and CML decreased significantly, with a decrease particularly remarkable among the oldest group with CML ( 2.2% per year, 95% CI 2.7 to 1.6). In general, incidence rates for AML have been stable over Survival Figure 2 shows the 5-year survival trends among the various age groups by race and gender for the period The youngest age group demonstrated the most marked improvement in 5-year survival, with rates increasing from about 30% in the mid-1970s to approximately 60% in the late 1990s. However, survival rates decreased over time for blacks in the older age groups. In particular, the 5-year survival rate for blacks in the year age group decreased from 1985 onward. We also compared the 5 and 10-year survival rates for the two 10-year periods ( and ; Table 3). Overall, there has been little

4 2232 CANCER May 1, 2003 / Volume 97 / Number 9 TABLE 2 Trends and Subtype Leukemia Incidence (Rate per Million Persons) SEER No. Rate a Change (%) b 95% CI ALL (yrs) c Birth d 0.6, d 1.7, d 1.7, , 2.0 AML (yrs) Birth , , , , d 0.0, 0.8 CLL (yrs) Birth e e , d 1.0, , d 1.1, 0.1 CML (yrs) Birth , , d 1.7, d 2.7, 1.6 SEER: Surveillance, Epidemiology, and End Results program; CI: confidence interval; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CLL: chronic lymphoblastic leukemia; CML: chronic myeloid leukemia. a Incidence rates are per million persons and are age adjusted to the 1970 U.S. standard million population. b Estimated annual percent change (EAPC) was calculated using the weighted least squares method. c Median age were 11, 66, 71, and 64 years for ALL, AML, CLL, and CML, respectively. d The EAPC is significantly different from zero (P 0.05). e Statistic could not be calculated due to small numbers. improvement in survival for individuals 45 years and older who were diagnosed with leukemia. Upon further inspection by race, the lack of improvement in survival was particularly evident for blacks in the older age groups. Table 4 shows 5-year survival rates by subtype of leukemia during the 10-year time periods of and There has been a 15% improvement in 5-year survival rates for ALL. Although survival rates almost doubled for AML in the youngest age group, outcomes in this category remain unsatisfactory. Adults with either ALL or AML have not fared well. In particular, there has been little improvement in survival for adults in the older age groups, with overall 5-year survival rates still less than 15%. In contrast, individuals with CLL who were younger than age 65 years continued to experience 5-year survival rates in excess of 70%. DISCUSSION In the current study, we describe incidence rates, survival rates, and trends for leukemia overall and for FIGURE 2. Five-year leukemia survival rates during the period by age and gender. Unbroken line: white males; dotted line: white females; dashed line: black males; dashed/dotted line: black females. subtypes within different age and race groups in the United States during the period Although leukemia is the most common malignancy among children and adolescents, the majority of cases of leukemia occur in older people. The highest incidence rates occur in the age group 65 years and older, followed by the year age group. For children, ALL accounts for 73% of all leukemias diagnosed, whereas for young adults (age years) AML is most common. For middle-age and elderly adults, CLL and CML are the most frequent. To our knowledge, the last comprehensive report on leukemia incidence and survival in the United States was published by Groves et al. 12 and covered the period In a comparison of overall leukemia incidence rates during the 6-year periods of and , they reported that rates generally decreased, particularly among individuals age 65 years. We also observed declines in leukemia incidence during the period , particularly among the groups of individuals age 45 years. We also noted a modest but statistically significant increase in incidence among children younger than 20 years of age. For subtypes, Groves et al. 12 reported declines in incidences of CML and CLL when comparing the period with the period They also noted that AML incidence decreased less rapidly and appeared to be increasing among black males. In contrast, ALL rates increased for all four race/gender groups. During the period , we observed increases among the four age groups for ALL, which were statistically significant for all but the oldest age group (65 years). This was accounted for primarily

5 Leukemia in the United States/Xie et al TABLE 3 5 and 10-Year Survival Rates of Overall Leukemia by Gender, Age, Race, and Time Period, SEER year survival rate (%) for year survival rate (%) for Total Male Female Total Male Female Rate 95% CI Rate 95% CI Rate 95% CI Rate 95% CI Rate 95% CI Rate 95% CI Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , 38.8 Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , year survival rate (%) for year survival rate (%) for Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , Birth , , , Birth , , , , , , , , , , , , , , , , , , , , , SEER: Surveillance, Epidemiology, and End Results Program; CI: confidence interval. by the youngest cases. In a recent evaluation of data from the Manchester Children s Tumour Registry, Mc- Nally et al. 8 also reported a statistically significant increase in childhood ALL during the time period (average annual percent increase 0.7%, P 0.005). Moreover, for the period , they reported that the increase was highest among females in the youngest age group (1 4 years). Groves et al. 12 reported that the overall survival rates for all leukemia patients improved only slightly when comparing the periods and , but were consistently higher in whites compared with blacks, with little gender difference. We analyzed survival rates in more detail and found that in comparing the period with , overall survival rates improved notably among all races/age groups, whites, and blacks younger than the age of 45 years. However, for blacks 45 years and older, there was little improvement in overall survival. In particular, for blacks older than 65 years, survival rates were decreasing, which was not observed in the earlier data by Groves et al. 12 The improvement in survival among the youngest age group is likely attributable to the success of the cooperative clinical trials groups including the former Children s Cancer Group (CCG) and the Pediatric Oncology Group. These clinical trials groups are estimated to treat nearly 90% of pediatric patients in the United States. 18 The performance of large-scale systematic clinical trials has allowed the optimization of

6 2234 CANCER May 1, 2003 / Volume 97 / Number 9 TABLE 4 Five-Year Survival Rate by Subtype of Leukemia, SEER year survival rate (%) for % confidence interval 5-year survival rate (%) for % confidence interval ALL (yrs) Birth , , , , , , , , 8.22 AML (yrs) Birth , , , , , , , , 8.22 CLL (yrs) Birth 19 a a , , , , , , CML (yrs) Birth , , , , , , , , SEER: Surveillance, Epidemiology, and End Results program; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CLL: chronic lymphoblastic leukemia; CML: chronic myeloid leukemia. a Statistic could not be calculated due to small numbers. chemotherapy studies and the performance of highquality epidemiologic and biologic studies. 19,20 The lack of overall improvement in survival for adults is disappointing. This finding may reflect biologic differences in the leukemia cells of older persons, which may render them less curable, and differences in tolerance for intensive therapy. 21 In addition, young adults may receive chemotherapy regimens designed with consideration for the limited drug tolerance of elderly patients, reducing their survival. Stock et al. 22 compared outcomes for 103 patients aged years enrolled on the adult trials of the Cancer and Leukemia Group B (CALGB) with the outcomes of 196 patients of the same age treated on CCG trials. Comparison of risk factors showed a higher incidence of adverse cytogenetics in the CALGB group, but similar frequencies of B- and T-cell lineage and a white cell count above 50,000 at presentation. The 6-year eventfree survival rate was 38% for patients treated on CALGB trials and 64% for those treated on CCG studies. These data underscore the importance of establishing large-scale clinical cancer trials for individuals older than the age of 21 years and using a doseintensive approach in younger adults who will tolerate this strategy. There are some limitations to our analyses. First, these rates reflect the SEER areas only. It is possible that there are geographic differences in leukemia incidence and survival rates in areas not covered by SEER. In an ad hoc analysis, we evaluated whether there were any notable differences in leukemia incidence or survival among the nine registries, as these registries represent different populations and perhaps different access to health care. Hawaii, which was the smallest registry (2179 cases), had both a lower overall leukemia incidence and survival compared with the other 8 registries. There were no notable differences in either leukemia incidence or survival among the remaining registries. Second, leukemia is a heterogeneous disease. Classification by the 4 major subgroups will not provide information regarding specific subpopulations within these subgroups (e.g., myelodysplastic syndrome, AML-M3, and chronic myelomonocytic leukemia [CMML]). In addition, changes in classification, such as the World Health Organization redefinition of AML, 23 could also influence the results presented in the current study. Perhaps as more registries are added to SEER, along with more detailed clinical information, more detailed analyses of incidence and survival can be performed. The strengths of this study include the use of a population-based program with complete case ascertainment from diverse geographic areas and populations and the relatively long period of time over which trends were evaluated. The SEER program is well suited to age, gender, and race-specific analyses because these populations are fairly well represented in the program. The incidence of leukemia in the United States generally has been declining, although the rates are modestly but significantly increasing for individuals younger than 20 years old. Although the 5-year survival rates have improved markedly for children with acute leukemia, there is a notable lack of improvement in survival for adult leukemias, particularly ALL, AML, and CLL. When comparing the period with , black males older than 44 years have experienced a decrease in 5-year survival rates. REFERENCES 1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics CA Cancer J Clin. 2002;52: Linet MS, Cartwright RA. The leukemias. In: Schottenfeld D, Fraumeni JF Jr. Cancer epidemiology and prevention, 2nd ed. New York: Oxford University Press, 1996: Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the United States. Cancer. 1996;78: Linet MS, Ries LAG, Smith MA, Taron ED, Devesa SS. Recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst. 1999;91:

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