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Keywords:

  • leukemia;
  • mortality;
  • trends;
  • Europe;
  • projections

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

We considered trends in mortality from leukemia in Europe over the period 1970–2009 using data from the World Health Organization. We computed age-standardized (world population) mortality rates, at all ages and in selected age groups, in 11 selected European countries, the European Union (EU) and, for comparative purposes, in the USA and Japan. For the EU, we also provided projections of the mortality to 2012. Over the period considered, mortality from leukemia steadily declined in most European countries in children and young adults, as well as in western and southern Europe at middle-age (45–69 years); in central/eastern Europe, reductions at ages 45–69 started since the mid-late 1990s. In the EU, annual percent changes were −3.7% in males and −3.8% in females at age 0–14, −2% in both sexes at age 15–44, and −0.6% in males and −1% in females at middle-age and overall. No decline was observed at age 70 or more. Between 1997 and 2007, overall EU rates decreased from 5.4 to 4.8/100,000 males and from 3.4 to 2.9/100,000 females. Declines were from 6.2 to 5.5/100,000 males and from 3.7 to 3.2/100,000 females in the USA and from 3.9 to 3.5/100,000 males and from 2.5 to 2.0/100,000 females in Japan. Projected overall rates in the EU at 2012 are 4.3/100,000 males (−11% compared to 2007) and 2.6/100,000 females (−12%).

Mortality from leukemia has been declining in European countries—as in the USA1 and Japan2—since the 1960s, following continuous and progressive therapeutic advancements, particularly for acute lymphoblastic leukemia (ALL) in childhood and young age.3, 4 Between 1990–1994 and 2000–2004 in the European Union (EU) as a whole, the fall in age-standardized (world population) death rates was 8% in both sexes, to reach a rate of 5.3/100,000 man-years and 3.3/100,000 woman-years.5 The falls were larger at age 20 to 44 years (i.e., −15%), and the declines were over 30% in children.6 The reductions were appreciably smaller and later in central and eastern European countries, opening a substantial gap in mortality for these—at least in part—curable neoplasms.5

To analyze recent patterns in mortality from leukemia in Europe, we updated trends to 2009 in the EU as a whole, in major European countries and, for comparative purposes, in the USA and Japan. Projections of the mortality to 2012 were also provided for the EU.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

We extracted official death certification data for leukemia over the period 1970–2009 from the World Health Organization (WHO) database as available on electronic support.7 Death certificate data are provided to WHO by national civil registration systems, with underlying cause of death coded by the relevant national authority according to detailed coding rules. We considered the EU as a whole, 11 selected European countries, including the largest ones in central and eastern Europe (i.e., Bulgaria, Hungary, the Czech Republic, Romania, Poland and the Russian Federation) and in the rest of Europe (i.e., Spain, Italy, France, the United Kingdom, UK and Germany), plus the USA and Japan. The EU was defined as the 27 member states as in 2007, excluding Cyprus, whose data were available only for a few recent years. Data for Spain were available since 1971, for Germany since 1973, for the Russian Federation since 1980, and for the Czech Republic since 1986. Data for the USA were available up to 2005, for Germany and the Russian Federation up to 2006, for France and Italy up to 2007, and for Bulgaria, Poland and Spain up to 2008. In a few countries, data were missing for one or more calendar years. No extrapolation was made for missing years within a single country. Only for the calculation of EU rates, when in a country data were not available for one or more years, data for the nearest available years were replicated.

During the calendar period considered (1970–2009), three different revisions of the International Classification of Diseases (ICD) were used.8–10 Classification of cancer deaths was recoded, for all calendar periods and countries, according to the 10th Revision of the ICD (ICD-10 code: C91-C95).10

Estimates of the resident populations, based on official censuses, were obtained from the same WHO database.7 From the matrices of certified deaths and resident populations, we computed age-specific rates for each 5-year age group (from 0, 1–4, 5–9, …, 80–84 and ≥85 years) and calendar year. We also computed age-standardized rates per 100,000 person-years at all ages and for selected age groups (0–14, 15–44, 45–69 years, and, for the EU only, also 45–59, 60–69 and ≥70 years) using the direct method, on the basis of the world standard population.11

To identify significant changes in trends, we performed joinpoint regression analysis using the “Joinpoint” software from the Surveillance Research Program of the US National Cancer Institute.12 This allows to identify the years where a significant change in the linear slope of the trend (on a log-scale) is detected over the study period.13 The estimated annual percent change (APC) was then computed for each of the identified trends by fitting a regression line to the natural logarithm of the rates using calendar year as a regressor variable. To simplify the trend comparison between sexes and countries, we also calculated the average APC (AAPC) over the entire period 1970–2009 (when available), based on an underlying joinpoint model. This was estimated as the geometric weighted average of the APC, with the weights equal to the length of each time interval segment.14

We also provided an estimate of overall leukemia death rates in the EU for the year 2012. This was obtained by fitting a joinpoint model to each 5-year age group, and by applying a linear regression to the time period identified by the joinpoint model in each age group, to predict standardized death rates and prediction intervals in 2012.15 Population projection estimates for 2012 were abstracted from the EUROSTAT database.16

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Table 1 gives the age-standardized mortality rates from leukemia per 100,000 person-years in the EU as a whole, at all ages and for subsequent age groups, in 1997 and 2007, the corresponding percent change in rates and the predictions for the year 2012. Between 1997 and 2007, overall leukemia rates in the EU decreased from 5.4 to 4.8/100,000 man-years (−10%) and from 3.4 to 2.9/100,000 woman-years (−13%). Over the same period, declines in mortality were observed in all subsequent age groups, the reductions being larger in the younger population, i.e., over 35% under age 15 years versus about 10% at age 60 to 69. In the elderly (age 70 or more), mortality rates increased by 5.6% in males and by 1.7% in females. Projected overall rates at 2012 are 4.3/100,000 man-years (−11% when compared with 2007, Table 1 and Fig. 1) and 2.6/100,000 woman-years (−12%).

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Figure 1. Age-standardized (world population) death certification rates from leukemia for the European Union between 1970 and 2007, and predicted rates for 2012. Males, •; Females ○.

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Table 1. Age-adjusted (world population) mortality rates per 100,000 males and females from leukemia in the European Union, at all ages and for selected age groups in 1997 and 2007, and predictions for the year 2012
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Table 2 gives the age-standardized mortality rates from leukemia per 100,000 person-years at all ages and at ages 0–14 and 15–44, in 11 selected European countries, the USA and Japan in 1997 and 2007, and the corresponding percent changes in rates. In 1997, the overall highest males rates were in Hungary (7/100,000), the Czech Republic (6.6) and Italy (6.1), whereas the lowest ones were in Romania (4.5), the UK (4.6) and Bulgaria (4.7). In 2007, the highest male mortality rates were in Hungary (5.7/100,000) and Poland (5.6), and the lowest one in Bulgaria (3.7). From 1997 to 2007, declines in mortality from leukemia in males were observed in most European countries, the greater changes being in the Czech Republic (−23%), Bulgaria (−21%) and Hungary (−19%). Only in Poland, Romania and the Russian Federation, male rates remained stable over the period considered. Corresponding declines were from 6.2 to 5.5/100,000 man-years (−10%) in the USA, and from 3.9 to 3.5/100,000 man-years (−10%) in Japan. Similar patterns were observed in females. In 1997, the overall highest female leukemia mortality rates were in Hungary (4.2/100,000) and the Czech Republic (4.1). Mortality rates in females declined between 1997 and 2007 in most countries, with greater falls in the Czech Republic (−22%), the UK (−19%), Bulgaria and Spain (−16%). In 2007, the highest female rate was in Hungary (4.1/100,0000), and the lowest ones in the UK and Spain (around 2.5). Female rates declined from 3.7 in 1997 to 3.2/100,000 woman-years in 2007 in the USA and from 2.5 to 2.0/100,000 woman-years in Japan. Larger declines were observed in the two young age groups, 0–14 and 15–44 years, in all the countries considered. In 2007, childhood (0–14 years) mortality rates from leukemia were below 1/100,000 person-years in both males and females from most European countries, as well as in the USA and Japan. The major exceptions were the Russian Federation (1.6/100,000 man-years and 1.2/100,000 woman-years), Romania (1.5 in males and 1.4 in females), Bulgaria (1.2 in males and 1.0 in females), and Hungary for females only (1.3). In young adults (15–44 years), male rates in 2007 were between 1 and 2/100,000 man-years, with the highest rate in Bulgaria (2.0/100,000) and the lowest one in the Czech Republic (0.9/100,000). In females, rates were between 0.8 and 1.4/100,000 woman-years, with the highest rates in Hungary and Russia (1.4), and the lowest ones in Germany and Spain (0.8).

Table 2. Age-adjusted (world population) mortality rates from leukemia per 100 000 males and females at all ages and at ages 0–14 and 15–44 in selected European countries, the USA and Japan, in 1997 and 2007 (unless otherwise indicated), and corresponding percent changes in rates
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Figures 2, 3, 4, 5, 2–5 (and the Supporting Information Table) show the joinpoint analysis for mortality from leukemia in 11 major European countries, the USA and Japan, over the period 1970–2009, for the age groups 0–14, 15–44 and 45–69 years, and overall. Mortality significantly declined in most European countries over the whole period both at age 0–14 years—AAPC in the EU −3.7% in males and −3.8% in females (Fig. 2) —and at age 15–44 years—AAPC around −2% in both sexes (Fig. 3). Similar reductions were observed in the USA and Japan, with AAPCs around −4% at age 0–14 and −2% at age 15–44 years. At age 45–69 years (Fig. 4) and at all ages (Fig. 5), mortality from leukemia declined over most of the period considered in countries from western and southern Europe, whereas reductions were later (i.e., since the mid-late 1990s) in countries of central and eastern Europe, such as the Czech Republic, Hungary, and Russia. In the EU as a whole, the AAPCs were −0.6% in males and around −1% in females both at age 45–69 and at all ages, with declines appreciably large since the late 1990s and early 2000s. In the USA, the AAPCs were −0.7% in males and −0.8% in females at age 45−69, and −0.8% in males and −1.2% in females at all ages, with stronger declines since the early/mid 1990s. Corresponding values in Japan were +0.2% (not significant) in males and −0.5% in females at age 45–69, and −0.5% in males and −1.2% in females at all ages, the declines starting in the late 1980s.

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Figure 2. Joinpoint analysis for age-standardized 0–14 years (world population) death certification rates from leukemia in selected European countries, the USA and Japan, 1970–2009. Males, •; Females ○.

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Figure 3. Joinpoint analysis for age-standardized 15–44 years (world population) death certification rates from leukemia in selected European countries, the USA and Japan, 1970–2009. Males, •; Females ○.

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Figure 4. Joinpoint analysis for age-standardized 45–69 years (world population) death certification rates from leukemia in selected European countries, the USA and Japan, 1970–2009. Males, •; Females ○.

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Figure 5. Joinpoint analysis for age-standardized (world population) death certification rates from leukemia in selected European countries, the USA and Japan, 1970–2009. Males, •; Females ○.

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Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

The present updated analysis of trends in mortality from leukemia in Europe showed declines in both sexes over the last decades, particularly in children and the young. We also projected a persistent decline by an additional 12% to 2012. The declines, however, happened later (since the mid-late 1990s) and were smaller in central and eastern European countries, when compared with western ones, particularly in middle-age adults. No decline was observed over age 70. This may reflect unfavorable incidence trends in the elderly, as well as increased search and diagnostic attention for leukemia, or problems of management and therapy, which may be less effective—but also less widely utilized—in the elderly.17–19 Furthermore, elderly patients more frequently have unfavorable cytogenetic abnormalities and multidrug resistance, and may develop secondary acute myelogenous leukemia (AML).17

The favorable trends observed in mortality from leukemia in childhood, young and middle-age adults are mainly due to therapeutic advancements, including the adoption of effective multidrug chemotherapy protocols (together with the introduction of various supportive measures to overcome toxicity), the availability of more refined radiotherapy treatments and improved diagnostic techniques.4, 6, 20 The variable turning points identified across European countries through joinpoint analyses are likely due to different timing in the adoption of such treatments. Thus, the later declines and the persistently higher mortality in some countries of central and eastern Europe are largely or totally attributable to the delays in the utilization of modern therapeutic protocols.

The different trends in mortality from leukemia in the subsequent age groups are also attributable to the different histotype composition of leukemia at different ages: ALL is the most common type in children and young adults, whereas chronic lymphocytic leukemia (CLL) is predominant in adulthood.21 Most acute leukemia are potentially curable, and 5-year survival from ALL has been increasing in childhood up to most recent years.21 Prognosis from ALL is less favorable in adolescents and adults, but appreciable improvements have been observed in these age groups as well, through better control of relapse using allogeneic hematopoietic stem cell transplantation, as well as monitoring of minimal residual diseases and improved management of complications of treatment.22–25 Newer chemotherapy schemes and hematopoietic cell transplant have lead to improved survival in AML as well.26 Chronic leukemia are not curable, but long-term survival has been achieved for chronic myeloid leukemia since the introduction of imatinib and other tyrosine kinase inhibitors in the late 1990s.27–30 Also for CLL, survival has improved in the last decades, particularly at young age, although there may be differences across various countries.31–33 Alemtuzumab, rituximab and autologous as well as allogeneic stem cell transplant are promising second-line treatments for CLL.34

Leukemia include an heterogenous group of diseases with different incidence, prognosis and classification systems.35 This limits comparison of leukemia rates across countries and over time. Data used in the present analyses were based on national death certifications, which do not allow to distinguish the various types of leukemia, apart from most recent calendar years. Moreover, also over most recent years, in most major European countries (except the UK) 15 to 30% of deaths are registered as “leukemia, undefined” thus making any trend analysis by subtype uncertain. In any case, although some change in composition of the disease is possible, it is unlikely to have appreciably modified mortality trends. Similarly, changes in the diagnosis and certification of mortality from all leukemia are unlikely to have substantially influenced the observed trends in most (major) countries, also indicated by the consistence of patterns in mortality from leukemia in several European countries, as well as in the USA and Japan.1, 2, 36

These data thus confirm the favorable patterns in mortality from leukemia in most European countries over the last decades, particularly in childhood and young adults. Declines were also observed over more recent calendar years in countries of central and eastern Europe, though in some of these countries mortality rates over the last few years remain higher than in western ones and comparable to those observed in western Europe in the mid 1990s. This translates in about one in six excess deaths in 2007 in countries like Poland, Hungary and the Czech Republic, i.e., an excess of ∼500 to 600 overall deaths per year. In proportional terms, the difference did not decrease over recent years. This highlights the importance and urgency for a more widespread and better adoption of modern and efficacious treatment of leukemia in central and eastern Europe, which may lead to the avoidance of a substantial number of deaths, particularly in the young.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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IJC_27624_sm_SuppAppendix.doc266KSupporting Information

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