Trends in mortality from leukemia in subsequent age groups

(2000) 14, 1980 1985 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Trends in mortality from leukemia in subsequent age groups F Levi 1, F Lucchini 1, E Negri 2, T Barbui 3 and C La Vecchia 2,4 1 Registre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive, Centre Hospitalier Universitaire Vaudois, and Unité d Épidémiologie du Cancer, Lausanne, Switzerland; 2 Istituto di Ricerche Farmacologiche Mario Negri, Milano; 3 Divisione di Ematologia, Ospedali Riuniti di Bergamo, Bergamo; and 4 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milano, Italy Trends in age-standardized death certification rates from leukemias in subsequent age groups were analyzed on the basis of the World Health Organization database over the period 1960 1997 in the European Union (EU) and other developed areas of the world. In the EU, the peak rate at age 0 14 was observed in 1960 1964, and the fall in mortality was over 70%, to reach 1.2/100 000 males and 0.9/100 000 females in 1995 1997. In the age group 15 44, the fall was about 40% for males and 45% for females. In the age group 45 59, the fall was around 25%. At age 60 69, the peak rate was observed in the late 1970s, and the subsequent fall was only 6% for females. At age 70, leukemia mortality rose up to the late 1980s, and levelled off thereafter. Overall, the falls in leukemia mortality over the 35-year calendar period corresponded to the avoidance of about 7000 deaths per year. In eastern Europe, the falls in children and young adults started later in the late 1970s and were less than 40% for children and 30% for young adults (15 44 years). Overall age-standardized mortality from leukemia did not appreciably change over the 35-year period considered. mortality rates in the USA and Japan started from different values, but were similar to those of the EU in the late 1990s, indicating that the impact of therapeutic advancements has been comparable in developed areas of the world. In eastern Europe, however, the declines in leukemia mortality were later and appreciably smaller. (2000) 14, 1980 1985. Keywords: leukemias; trends; mortality rates; descriptive epidemiology; Europe Introduction s account for over 3% of total cancer mortality in Europe and North America, and include a number of different diseases, whose response to treatment varies substantially. Efficacious chemotherapy for acute lymphoblastic leukemias 1 has been available since the late 1950s or early 1960s, and its impact on national mortality rates particularly for childhood leukemias 2 has been observed since the late 1960s or early 1970s. Advancements in treatment and survival have been observed for acute myeloid leukemia in patients under 60 years, but less clearly in elderly ones. 3 5 Some advantage of newer chemotherapy regimens and bone marrow transplantations has been reported for chronic myeloid leukemias, 6 and perhaps chronic lymphocytic leukemia too, 7 but their impact on mortality rates on a population level remains undefined. 8 National mortality data do not allow to reliably distinguish between various histological types of leukemias. They allow, however, to analyze trends in age-specific mortality, which is a relevant correlate of treatment and prognosis. We have, therefore, systematically considered trends in age-specific leukemia mortality over the period 1960 1997 in Europe and, for comparative purposes, in other developed areas of the Correspondence: F Levi, Registre Vaudois des Tumeurs, CHUV- Falaises 1, 1011 Lausanne, Switzerland; Fax: 41 21 323 03 03 Received 21 April 2000; accepted 5 July 2000 world, on the basis of the World Health Organization mortality database. Materials and methods Numbers of death certifications from leukemias over the period 1960 1997 were abstracted from the World Health Organization (WHO) database for the 15 European countries members of the European Union (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, The Netherlands, Portugal, Spain, Sweden, and United Kingdom), four eastern countries (Bulgaria, Hungary, Poland, Romania), Switzerland, USA and Japan. All classifications used were re-coded according to the Ninth Revision of the International Classification of Diseases (ICD-9 code 204 208). 9 Estimates of the resident populations, based on official censuses, were obtained from the same WHO database. Average annual populations in the European countries considered are given elsewhere. 10 12 In 1995 the population was 128 313 800 males and 134 441 500 females for the USA, 60 919 200 males and 63 379 800 females for Japan. From the matrices of certified deaths and resident populations, overall age-standardized rates and age-standardized rates for age groups 0 14, 15 44, 45 59, 60 69 and 70 years, and for the 5-year calendar periods from 1960 1964 to 1990 1994, plus 1995 1997, were computed. Age-standardized rates were based on the world standard population. Trends in age-standardized rates at ages 0 59 were also plotted for the European Union, selected eastern European countries, USA and Japan. Results Table 1 gives trends in age-standardized death certification rates for leukemias in the European Union for subsequent age groups. At age 0 14, the peak rate (4.1/100 000 males; 3.4/100 000 females) was observed in 1960 1964, and the fall in mortality was over 70%, to reach 1.2/100 000 males and 0.9 females in 1995 1997. In the age group 15 44, the peak rate was also reached in 1960 1964 for both sexes (2.9/100 000 males, 2.3 females), and the fall was about 40% for males and 45% for females, to reach 1.7 and 1.2/100 000 in 1995 1997. In the subsequent age group 45 59, the peak rate was again reached in the 1960s for both sexes, and the fall in 1995 1997 was only around 25%. At age 60 69, the peak rate was observed in the late 1970s, and the subsequent fall was only 6% for females. At age 70, leukemia mortality rates rose up to the late 1980s, and levelled off thereafter. Overall, the fall in all age-standardized leukemia mortality between the late 1960s or early 1970s and the late 1990s was about 15% for males and 20% for females in the European Union, corresponding to the avoidance of about 7000 deaths

mortality trends Table 1 Trends in death certification age-standardized (world) rates/100 000 population from leukaemias in the European Union, from 1960 1964 to 1995 1997, for selected groups and at all ages 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 0 14 4.1 3.9 3.5 3.0 2.4 1.8 1.5 1.2 70.7 3.4 3.2 2.8 2.2 1.8 1.4 1.1 0.9 73.5 15 44 2.9 2.8 2.6 2.5 2.4 2.2 1.9 1.7 41.4 2.3 2.2 2.0 1.9 1.8 1.6 1.3 1.2 47.8 45 59 7.0 7.1 6.9 6.8 6.5 6.2 5.7 5.3 24.3 5.4 5.4 5.1 5.0 4.8 4.6 4.1 4.0 25.9 60 69 17.5 18.8 18.8 19.7 18.9 18.9 18.3 18.7 +6.9 11.2 11.9 11.6 11.7 11.6 10.9 10.9 10.9 2.7 70 29.1 36.1 41.2 47.8 51.8 55.6 54.6 53.1 +82.5 17.1 20.7 22.8 26.6 29.0 29.9 29.8 29.4 +71.9 All ages 6.0 6.2 6.2 6.3 6.2 6.0 5.6 5.3 11.7 4.3 4.4 4.2 4.2 4.0 3.7 3.5 3.4 20.9 Table 2 Trends in death certification age-standardized (world) rates/100 000 population from leukaemias in Eastern Europe a, from 1960 1964 to 1995 1997, for selected groups and at all ages 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 0 14 3.4 3.5 3.4 3.1 2.8 2.5 2.1 2.0 41.2 2.6 3.0 2.7 2.4 2.2 1.8 1.6 1.7 34.6 15 44 2.5 2.7 2.5 2.5 2.3 2.4 2.1 1.8 28.0 2.1 2.2 2.1 2.0 1.8 1.8 1.6 1.4 33.3 45 59 6.4 6.7 6.9 7.0 7.0 6.8 6.6 7.3 +14.1 4.8 5.0 5.2 5.1 5.1 4.8 4.6 4.5 6.3 60 69 13.6 15.8 17.3 18.0 19.0 19.2 19.5 19.3 +41.9 8.6 9.2 10.2 11.2 11.5 11.0 11.0 11.4 +32.6 70 14.6 19.6 23.3 27.1 29.5 34.1 36.1 37.8 +158.9 8.1 10.7 13.8 15.3 17.3 18.8 20.4 21.3 +163.0 All ages 4.6 5.1 5.3 5.4 5.4 5.5 5.4 5.4 +17.4 3.4 3.7 3.8 3.8 3.7 3.6 3.5 3.5 +2.9 a Bulgaria, Hungary, Poland, Romania. 1981

mortality trends 1982 Table 3 Trends in death certification age-standardized (world) rates/100 000 population from leukaemias in the United States, from 1960 1964 to 1995 1997, for selected groups and at all ages 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 0 14 4.0 3.5 2.9 2.2 1.8 1.4 1.2 1.1 72.5 3.3 2.8 2.3 1.7 1.3 1.1 0.9 0.8 75.8 15 44 2.8 2.8 2.5 2.3 2.2 2.1 1.9 1.7 39.3 2.0 1.9 1.8 1.7 1.6 1.4 1.4 1.2 40.0 45 59 8.3 8.2 7.6 7.5 7.3 6.9 6.9 6.5 21.7 5.8 5.5 5.2 5.0 5.1 4.9 4.8 4.4 24.1 60 69 24.4 23.9 22.5 22.0 22.6 21.8 23.2 23.1 5.3 14.1 13.8 12.4 11.8 12.6 12.5 12.7 12.6 10.6 70 53.4 59.0 60.5 62.1 62.1 60.9 63.2 65.8 +23.2 30.0 33.3 32.8 32.2 33.0 32.9 34.2 34.9 +16.3 All ages 7.6 7.5 7.1 6.8 6.7 6.3 6.4 6.3 17.1 4.9 4.8 4.4 4.1 4.1 3.9 3.8 3.7 24.5 Table 4 Trends in death certification age-standardized (world) rates/100 000 population from leukaemias in Japan, from 1960 1964 to 1995 1997, for selected groups and at all ages 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 0 14 3.6 3.6 3.4 3.1 2.5 1.9 1.5 1.2 66.7 2.8 2.9 2.9 2.5 1.8 1.5 1.2 0.9 67.9 15 44 2.8 2.9 3.0 3.0 2.7 2.6 2.2 2.0 28.6 2.3 2.4 2.2 2.2 2.0 1.8 1.7 1.3 43.5 45 59 4.3 4.8 5.2 5.7 6.0 6.4 5.7 5.4 25.6 3.6 3.8 4.0 4.1 4.2 4.2 5.1 3.7 +2.8 60 69 5.6 7.4 8.5 10.3 11.6 13.2 12.8 12.9 +130.4 3.9 4.9 5.8 6.4 6.9 7.3 9.0 7.0 +79.5 70 4.1 6.2 9.3 14.3 19.5 24.3 24.4 27.2 +563.4 2.1 3.2 4.9 7.7 10.2 12.5 16.2 14.3 +581.0 All ages 3.5 3.8 4.1 4.4 4.4 4.5 4.2 4.0 +14.3 2.7 3.0 3.1 3.1 3.0 2.9 3.2 2.5 7.4

mortality trends Table 5 Trends in death certification age-standardized (world) rates/100 000 population aged 0 59 years, in European Union (France, Germany, Italy, Spain, Switzerland and UK), from 1960 1964 to 1995 1997, for selected groups and at all ages Country Males Females 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % 1960 64 1965 69 1970 74 1975 79 1980 84 1985 89 1990 94 % European Union 4.0 3.9 3.6 3.4 3.1 2.7 2.4 2.1 47.5 3.2 3.1 2.8 2.6 2.3 2.0 1.7 1.6 50.0 France 4.3 4.0 3.7 3.6 3.3 2.9 2.4 44.2 3.4 3.1 2.8 2.6 2.5 2.0 1.7 50.0 Germany 3.8 3.7 3.4 3.1 2.7 2.5 2.4 2.0 47.4 3.1 3.0 2.7 2.4 2.1 1.9 1.7 1.5 51.6 Italy 4.6 4.6 4.2 4.0 3.6 3.1 2.9 37.0 3.7 3.5 3.3 3.0 2.6 2.3 2.1 43.2 Spain 3.1 3.3 3.2 3.2 3.1 2.8 2.6 2.4 22.6 2.6 2.7 2.6 2.5 2.2 2.1 1.9 1.6 38.5 Switzerland 3.8 3.6 3.8 3.0 2.5 2.3 2.4 36.8 3.5 2.7 2.9 2.2 1.9 1.8 1.6 52.3 UK 3.6 3.3 3.2 3.1 2.9 2.5 2.2 2.1 41.7 2.8 2.7 2.4 2.2 2.0 1.9 1.6 1.5 46.4 1983

1984 mortality trends per year, based on proportional difference in age-specific rates. Corresponding values for the four eastern European countries providing data are given in Table 2. The falls in children and young adults (15 44 years) started later (in the 1970s), and were only less than 40% for children and 30% for young adults. No major change was observed in middle age, and rates were appreciably upwards in the elderly. Consequently, overall age-standardized mortality from leukemia did not appreciably change over the 35-year calendar period considered in eastern Europe. Data for the USA and Japan are given, for comparative purposes, in Tables 3 and 4. In the USA, the pattern of trends was similar to that of the European Union up to age 59. In the elderly, the rises were smaller, but the absolute rates were higher, possibly reflecting different standards of diagnostic accuracy, particularly in the past. Overall, mortality from leukemias in the USA declined by 17% in males and 24% in females (Table 3). In Japan, consistent declines were observed in children and young adults (15 44 years) only, while trends were inconsistent from middle age onwards (Table 4). Absolute values, however, were so low in the past to leave open the issue of diagnostic and certification accuracy. Figure 1 gives trends in age-standardized death certification rates from all leukemias at age 0 59 years in the EU, eastern Europe, the USA and Japan, over the period 1960 1997. Although starting from different absolute values, in the late 1990s the EU, the USA and Japan had similar rates (around 2/100 000 males, 1.5/100 000 females). Mortality rates for eastern Europe were, however, considerably higher (around 3/100 000 males, 2/100 000 females). Table 5 gives trends in age-standardized leukemia deaths certification rates at age 0 59 in the five major EU countries, and Switzerland. The fall was somewhat smaller in Spain, while no systematic pattern was observed across other countries considered. Discussion The present systematic revision of trends in mortality from leukemias in Europe and other developed countries of the world indicates and further quantifies that: (1) mortality from leuke- mias has been declining since the 1960s onwards; (2) the falls have been larger in childhood and have been observed, although to a systematically and progressively lesser extent, in the middle age population, up to at least 60 years; and (3) some falls were observed in eastern Europe, too, although these were later and substantially smaller than in the European Union. At age 60 69, mortality from leukemias increased up to the late 1970s, but a modest decline (around 5%) has been observed over the last 15 years. These trends may reflect some recent, although limited, advancement in the treatment of acute, as well as chronic, leukemia in the elderly. In the elderly, some rise in leukemia death certification rates was observed up to the 1980s. This may, however, be due, partly or largely, to improved diagnosis and certification in the elderly, although these trends are inconsistent with any major favourable impact of newer therapies on leukemia mortality above age 70. The data analyzed were based on large numbers of national death certifications, which however do not allow to reliably distinguish between various histological types of leukemias. 13 The different trends in leukemia mortality in subsequent age groups are, in fact, at least in part attributable to the different histotype composition of leukemias in different age groups, acute lymphoblastic leukemias being by far the most common type in children and young adults, and chronic leukemias becoming progressively more frequent with advancing age. Even within each single histotype, however, the prognosis tends to be systematically more favorable at younger age. 4 Thus, for acute lymphoblastic leukemia, the 5-year event-free survival in the 1990s was around 80% for children, but only 40% for adults. 1 Whether this reflects more aggressive and optimized multidrug regimens and other therapeutic approaches in the young, or inherent biological characteristics of tumor, remains open to discussion and further quantification. No major or systematic difference was observed in leukemia mortality trends between major western European countries, but the falls in mortality were smaller, started later, and were restricted to children and young adults in the few eastern European countries providing data. This again underlines the importance and urgency of the application of available knowledge on treatment of leukemia in eastern Europe, which may well lead to the avoidance of about 1000 deaths per year. Figure 1 Trends in age-standardized (world population) death certification rates from all leukemias at age 0 59 years in the European Union (EU), four eastern European countries (EAST; Bulgaria, Hungary, Poland and Romania), the USA and Japan, over the period 1960 1997.

Acknowledgements This work was supported by the Swiss League against Cancer and the Italian Association for Cancer Research. References 1 Pui CH, Evans WE. Acute lymphoblastic leukemia. New Engl J Med 1998; 339: 605 615. 2 Levi F, La Vecchia C, Lucchini F, Negri E, Boyle P. Patterns of childhood cancer incidence and mortality in Europe. Eur J Cancer 1992; 28: 2028 2049. 3 Mitus AJ, Miller KB, Schenkein DP, Ryan HF, Parsons SK, Wheeler C, Antin JH. Improved survival for patients with acute myelogenous leukemia. J Clin Oncol 1995; 13: 560 569. 4 Burnett AK, Eden OB. The treatment of acute leukaemia. Lancet 1997; 349: 270 275. 5 Bloomfield CD, Herzig GP, Peterson BA, Wolff SN. Long-term survival of patients with acute myeloid leukaemia. Updated results from two trials evaluating postinduction chemotherapy. Cancer 1997; 80: 2186 2190. mortality trends 6 Silberman G, Crosse MG, Peterson EA, Weston RC, Horowitz MM, Appelbaum FR, Cheson BD. Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukaemia in 10 countries. New Engl J Med 1994; 331: 1063 1067. 7 Rozman C, Montserrat E. Chronic lymphocytic leukemia. New Engl J Med 1995; 333: 1052 1057. 8 Bailar JC, Gornik HL. Cancer undefeated. New Engl J Med 1997; 336: 1569 1574. 9 World Health Organisation. International Classification of Disease, 9th revision. World Health Organisation: Geneva, 1977. 10 Levi F, Maisonneuve P, Filiberti R, La Vecchia C, Boyle P. Cancer incidence and mortality in Europe. Soz Praeventivmed 1989; 34 (Suppl. 2): S1 S83. 11 Levi F, La Vecchia C, Lucchini F, Boyle P. Cancer incidence and mortality in Europe, 1983 87. Soz Praeventivmed 1993; 38 (Suppl. 3): S155 S229. 12 Levi F, Lucchini F, Boyle P, Negri E, La Vecchia C. Cancer incidence and mortality in Europe, 1988 92. J Epidemiol Biostat 1998; 3: 295 373. 13 Rushton L, Romaniuk H. Comparison of the diagnosis of leukemia from death certificates, cancer registration and histological reports implications for occupational case-control studies. Br J Cancer 1997; 75: 1694 1698. 1985