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Increases in the incidence of childhood acute lymphoblastic leukemia (ALL) have been reported in some countries, while other reports from similar geographical regions have indicated stable rates. The reasons for the discrepancies have been debated in the literature, with the focus on whether the observed increases are “real” or an artifact resulting from improvements in diagnosis, case ascertainment and population coverage over time. We used population-based data from Western Australia to investigate trends in the incidence of childhood ALL between 1960 and 2006. Age-standardized incidence rates (ASRs) and rate ratios (indicating annual percent change) were estimated using Poisson regression. Between 1960 and 2006, the ASR was 3.7 per 100,000 person-years, with an annual percent increase of 0.40% (95% CI: −0.20, 1.00). Between 1982 and 2006, the ASR was 3.8, with an annual percent increase of 0.80% (95% CI = −0.70 to 2.30). This increased to 1.42% (95% CI: −0.30, 3.0) when a sensitivity analysis was undertaken to assess the effect of excluding the final 2 years of data. Annual increases of 3.7% (95% CI: −0.50, 8.00) among children aged 5–14 years, and of 3.10% (95% CI: 0.50, 5.70) in girls, were observed for this latter period. These results were supported by national Australian incidence data available for 1982–2003. There may have been a small increase in the incidence of ALL since 1982 among girls and older children, but an overall increase appears unlikely. No impact of folate supplementation or fortification is apparent. © 2007 Wiley-Liss, Inc.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, accounting for ∼25% of childhood cancer diagnoses each year worldwide.1 Despite extensive research over many years, little is known about the etiology of ALL, although a growing number of theories implicating genetic, in utero and environmental factors are emerging.
Research groups from the UK, Europe, the USA and New Zealand have reported increases in the incidence of childhood ALL over the last 3 to 4 decades, while other research groups from similar geographical regions have reported stable rates.2 There has been considerable debate in the literature as to whether such reported increases are “real,” and possibly due to changes in environmental or demographic risk factors; or whether they represent—at least in part—artifact resulting from improvements in diagnosis, case ascertainment and population coverage over time.2, 3 As cancer reporting is voluntary and national coverage not yet achieved in many of these countries,4, 5 distinguishing between these possibilities is problematic.
In Australia, cancer notification has been mandatory from 1982 and population coverage and case ascertainment of the childhood leukemias are considered to be virtually complete. Furthermore, in Western Australia (WA), we have population-based incidence data on hematological malignancies from 1960.
A study published in 2001 by our colleagues reported a 60% reduction in risk of common ALL among children of WA women who took folate supplements (with or without iron) during pregnancy.6 Periconceptional folate supplementation for the prevention of neural tube defects has been promoted in WA since 1992. In addition, voluntary fortification of some foods (mainly breakfast cereals) has been permitted since 1996. Mandatory fortification of bread making flour with folic acid was recently approved for Australia and New Zealand (June 2007).
The aim of this study was to use population-based Western Australian data to investigate whether the rate of childhood ALL has increased over the past 47 years. We also aimed to investigate whether the promotion of folate supplementation or voluntary fortification of foods may have influenced the incidence of ALL.
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There were 220 ALL diagnoses in Western Australia during the LADR period (1960–1981) and 341 notified to the WACR (1982–2006). The age at diagnosis was similar in the 2 periods, while the male-to-female ratio appeared to be higher in the WACR period (Table I). Consistent with the known epidemiology of childhood ALL, the rates were higher in males than females and higher in the 0–4 years age group than in the older children. Among males, the rate was somewhat higher in the WACR period than in the LADR period (Table I). Age-standardized rates of ALL in WA between 1960 and 2006 are shown graphically in Figure 1.
Figure 1. Age-standardized incidence rates of acute lymphoblastic leukemia in Western Australia (1960–2006) and Australia overall (1983–2003). Open circles = Western Australia; Solid squares = Australia.
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Table I. Acute Lymphoblastic Leukemia Incidence in Western Australia by Sex, Age Group at Diagnosis, and Specified Time Period
| ||Total N||Sex||Age-standardized rates||Age-specific rates|
|Males, N (%)||Females, N (%)||Male:female ratio||Total||Males||Females||0–4 years (N; %)||5–9 years (N; %)||10–14 years (N; %)|
|LADR:1960–1981||220||117 (53.2)||103 (46.8)||1.14||3.6||3.6||3.5||5.5 (117; 53.2)||2.9 (63; 28.6)||1.9 (40; 18.2)|
|WACR:1982–2006||341||193 (56.6)||148 (43.4)||1.30||3.8||4.2||3.4||5.9 (182; 53.4)||3.1 (99; 29.0)||1.8 (60; 17.6)|
|Whole period:1960–2006||561||310 (55.3)||251 (44.7)||1.24||3.7||4.0||3.5||5.7 (299; 53.3)||3.0 (162; 28.9)||1.8 (100; 17.8)|
The rate ratios—indicative of the percent annual change in incidence—overall, by sex and by age group for specific time periods, are shown in Table II. In both the LADR and WACR periods, the confidence intervals for the rate ratios all included unity. Nonetheless, the results for the WACR period (1982–2006) were suggestive of a 3% annual increase in the older 2 age groups. The annual percent increase for the entire period 1960–2006 was 0.40% (Table II).
Table II. Trends in the Diagnosis of Acute Lymphoblastic Leukemia in Western Australia for Specified Time Periods and by Sex and Age-Group
| ||LADR: 1960–1981||WACR: 1982–2006||1960–2006||WACR: 1982–20041|
|Cases N||RR||95% CI||Cases N||RR||95% CI||Cases N||RR||95% CI||Cases N||RR||95% CI|
|Year by sex|
|Year by age group|
| 0–4 years||117||1.014||0.985–1.045||182||0.989||0.970–1.010||299||1.002||0.994–1.011||172||0.996||0.973–1.018|
| 5–9 years||63||1.003||0.964–1.043||99||1.028||0.999–1.057||162||1.008||0.996–1.020||91||1.037||1.004–1.071|
| 10–14 years||40||0.965||0.919–1.014||60||1.031||0.994–1.068||100||1.002||0.987–1.017||54||1.037||0.995–1.080|
When data from the first 2 years (1960 and 1961) or the last 2 years (2005 and 2006) were excluded from the analysis of trend across the entire period, the results remained unchanged (data not shown). However, when data from 2005 and 2006 were excluded from the analysis of the WACR period, the overall annual increase was 1.42%, almost double that observed when those years were included (Table II). These results were also consistent with annual increases of 3.70% among children aged 5 years and older, and of 3.08% in females (Table II). The observed effect of excluding data from the most recent 2 years may be attributable to the lower than average number of cases diagnosed in 2006 (8 compared with a median of 12).
The incidence rate of childhood ALL in Australia between 1982 and 2003 was similar to that observed in WA for the same period (4.1 and 3.9 per 100,000 person-years, respectively). There was a similar pattern in the annual percent increase in the incidence of ALL in WA and Australia in the period 1982–2003, although the increase was greater in WA (1.60% vs. 0.70% in Australia) (Fig. 1; Table III). The annual percent increase in Australia was 1.30% in females and ∼1.46% in children aged 5–14 years old, compared with 3.44% and 3.51–4.05% in WA females and 5–14 year-olds, respectively (Table III).
Table III. Trends in the Diagnosis of Acute Lymphoblastic Leukemia in Western Australia and Australia by Sex and Age-Group, 1982–2003
| ||Western Australia||Australia|
|Cases N||RR||95% CI||Cases N||RR||95% CI|
|Year by sex|
|Year by age group|
| 0–4 years||166||0.998||0.974–1.022||1,793||1.001||0.993–1.008|
| 5–9 years||86||1.041||1.005–1.077||891||1.016||1.005–1.026|
| 10–14 years||50||1.035||0.990–1.082||541||1.014||1.001–1.027|
The introduction of promotion of periconceptional folic acid supplements in WA in late 1992 and voluntary fortification of food items with folate in 1996 nationally are shown as vertical lines on the age-group-specific trends in ALL between 1982 and 2006 in Figure 2. There was no apparent change in the age-specific rates in ALL in relation to the intake of folic acid.
Figure 2. Age-specific incidence of acute lymphoblastic leukemia in Western Australia (1982–2006). Open squares = 0–4 years; solid triangles = 5–9 years; open circles = 10–14 years. A = Promotion of periconceptional folate supplementation; B = Voluntary fortification of folate in some foods.
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The rate of childhood ALL in WA between 1960 and 2006 was 3.7 per 100,000 person years, similar to other western populations.9, 11, 12, 16, 17 During that period, there may have been a weak upward trend in incidence (0.40% per year), although our results are inconclusive.
As elsewhere, the quality and specificity of cancer diagnosis in Australia have improved over time; accordingly, the WACR data (1982–2006) are likely to be more accurate than the LADR data (1960–1981). The annual increase in the incidence of ALL during the WACR period was 0.80%, double that observed for the entire study period. In addition, the annual percent change in the WACR period almost doubled when the last 2 years of data were excluded, although all these trend estimates were still consistent with no increase. Conducting such a sensitivity analysis has been recommended for studies of rates conducted in relatively small populations,10 because of the potential influence that the rate estimates at the end of the time period can have on the observed trend, and because of the possibility that the end-of-period data are incomplete. The data for Australia were also consistent with a weak increase in the incidence of childhood ALL since 1982.
A number of studies from other countries have reported an increasing trend in the incidence of ALL during the past few decades, while others have reported no change. A significant increasing trend of 0.8% (p < 0.0001) between 1978 and 1997 was reported in Europe by a large collaboration of cancer registries.9 Upward trends have also been reported in Italy between 1977 and 2001 (+1.2%; 95% CI 0.2, 2.3%),16 USA between 1974 and 1991 (+1.6%; 95% CI 0.9, 2.3%),18 New Zealand (+2.2%) between 1968 and 1990,12 and Sweden between 1960 and 1998 (+5.8%; 95% CI 4.7, 6.9).19 Relatively stable rates of ALL have been reported by another Australian study for the period 1982–1991,17 in the UK between 1974 and 1997,10 in Nordic countries between 1982 and 2001,20 and in France between 1990 and 1999.11
A number of reasons have been postulated for the apparent discrepancies in reports from countries that are relatively close geographically, such as Italy and France, or Sweden and other Nordic countries. These include between-country differences in levels of improvement in diagnostic criteria and tools, extent of mandatory reporting and national coverage, completeness of ascertainment over time and time period under study.4, 19, 21 Another possibility is double-reporting of cases registered in more than 1 location as ascertainment improves.
Despite the weak evidence of an overall increase in incidence of ALL in our study, our findings are consistent with a 3–4% increase since 1982 in females and children aged 5–14 years. The national data showed a similar pattern in these groups, but the average yearly increase was lower at 1.3–1.6%. Magnani et al. reported a 3.4% increase in females only in Italy between 1975 and 1998, and a 2.6% increase in the youngest age group.22 Dalmasso et al.,16 Dockerty et al.,12 and Dreifaldt et al.19 all reported the greatest increase in the youngest age group, and Dreifaldt et al. also reported a greater increase among females in that age group.
Studying changes in rates of disease over extended periods of time can assist in elucidating the contributions of putative etiological factors. This is particularly so for childhood diseases where, given the relatively short latency period, changes in environmental causes are likely to influence the incidence of disease in the relative short term. The promotion of periconceptional folic acid supplementation and voluntary fortification of foods with folic acid is one of a few relevant environmental factors known to have changed over time in Australia. However, there did not appear to be an effect of folate on age-specific incidence in this study. It should be borne in mind that there would be a lag in any observed effect of folate intake and that we may not be seeing an impact on ALL rates because only 30% of women have been found to take 200 μg or more daily of folic acid for at least 1 month before pregnancy and the first 3 months of pregnancy.23 At present, it is not known what proportion of women continue to take folic acid beyond the first trimester and for how long. These issues will be investigated in our population-based, Australia-wide case–control study of causes of ALL in children (“AUS-ALL”), which concludes its data collection at the end of 2007.
Our study has some strengths and limitations. The main strength is that we have population-based data for a 47-year time period from high quality sources. The LADR was run by those who managed leukemia treatment in WA between 1960 and 1981; so, cases were unlikely to be missed and most cases underwent a review of their diagnosis by an expert panel. Case notification has been mandatory in Australia since 1982, and the individual state and territory registries have a process in place for checking that cases diagnosed in one state are not also reported in another state or territory. The age-standardized rate of ALL in WA between 1982 and 2003 was similar to that in Australia overall, although the magnitude of the increasing trends in females and children 5 years and older were greater in the WA data. The reasons for these observed differences between WA and Australia may be related to there being fewer cases in WA and therefore greater fluctuation in the annual rates.
The acknowledged uncertainty of diagnoses (as indicated by 20 cases of “acute leukemia NOS”) in the earlier LADR period is a potential limitation. However, we believe that the majority of these are likely to have been ALL cases, since the proportion of all leukemia notifications that were ALL when the NOS cases were added was similar to the proportion of ALL cases in the WACR period, and to that observed nationally in Australia and in other countries.9, 10, 11, 12, 17 Indeed, we believe that our ability to identify these NOS cases, and to determine whether or not they should be included as ALL cases, is a strength of our study. Previous studies that have been unable to ascertain the possible “NOS” status of non-ALL cases in the earlier years are likely to have excluded them, leading to the incorrect reporting of increasing incidence over time.
A potential limitation is the small number of cases diagnosed annually in the WA population, leading to considerable fluctuation of rates over time, and allowing rates from individual years to have a relatively large impact on the observed trends. This is illustrated by the fact that excluding the final 2 years of data (2005 and 2006) led to a doubling of the observed annual increase; this could be related to the preliminary nature of the 2006 data from the WACR.
In conclusion, the age-standardized rate of childhood ALL in WA over the last 47 years is similar to published data from other western countries, but we have not seen the significant increases over time that have been reported elsewhere. However, our findings are consistent with a 3–4% increase in incidence since 1982 in females and children aged 5–14 years. Folate supplementation and fortification have not been accompanied by a decline in incidence of ALL in Western Australia.