Changes in period and cohort effects on haematological cancer mortality in Spain, 1952-2006
© Pastor-Barriuso and López-Abente; licensee BioMed Central Ltd. 2014
Received: 29 November 2013
Accepted: 31 March 2014
Published: 10 April 2014
In contrast to other haematological cancers, mortality from non-Hodgkin’s lymphoma and multiple myeloma increased dramatically during the second half of the 20th century in most developed countries. This widespread upward trend remains controversial, as it may be attributable either to progressive improvements in diagnosis and certification or to increasing exposures to little-known but relevant risk factors.
To assess the relative contribution of these factors, we analysed the independent effects of age, death period, and birth cohort on haematological cancer mortality rates in Spain across the period 1952-2006. Weighted joinpoint regression analyses were performed to detect and estimate changes in period and cohort curvatures.
Although mortality rates were consistently higher among men, trends across periods and cohorts were virtually identical in both sexes. There was an early period trend reversal in the 1960s for Hodgkin’s disease and leukaemia, which was delayed to the 1980s for multiple myeloma and the 1990s for non-Hodgkin’s lymphoma. Birth cohort patterns showed a first downturn for generations born in the 1900s and 1910s for all haematological cancers, and a second trend reversal for more recent cohorts born in the 1950s and 1960s for non-Hodgkin’s lymphoma and leukaemia.
The sustained decline in Hodgkin’s disease mortality and the levelling off in leukaemia seem to be driven by an early period effect linked to improvements in disease treatment, whereas the steep upward trends in non-Hodgkin’s lymphoma and multiple myeloma mortality in Spain are more likely explained by a cohort effect linked to better diagnosis and death certification in the elderly. The consistent male excess mortality across all calendar periods and age groups points to the importance of possible sex-related genetic markers of susceptibility in haematological cancers.
KeywordsHaematological cancer mortality Period and cohort effects Change-points Diagnosis and certification improvements
Haematological malignancies constituted 6.9% of all incident cancer cases and 7.2% of all cancer deaths in Spain in 2012 . Morbidity and mortality from haematological cancers in Spain are fairly similar to the European average , with age-adjusted incidence and mortality rates of 2.4 cases and 0.3 deaths per 100,000 person-years for Hodgkin’s disease, 10.0 cases and 3.3 deaths for non-Hodgkin’s lymphoma (NHL), 3.5 cases and 2.2 deaths for multiple myeloma, and 8.3 cases and 4.4 deaths for leukaemia.
Since the mid-1970s, mortality from Hodgkin’s disease and leukaemia declined steadily in most Western European countries [3, 4], a downward trend that was mainly attributable to substantial improvements in disease treatment. In contrast, in the second half of the 20th century, there was a dramatic increase in incidence and mortality from NHL and multiple myeloma in many European countries [3, 5–7] and North America [8, 9], which has only begun to level off in recent years [10–13]. The reasons for this widespread upward trend in developed countries are not fully understood, since it may be largely artefactual due to the progressive implementation of modern diagnostic imaging techniques over recent decades, or it may partly reflect a real increase in underlying incidence linked to changes in environmental exposures to lymphomagenic agents and other unknown risk factors. In addition, lymphoid tumours have shown several problems of case ascertainment and death certification from the beginning of cancer registry activities, which further complicated the interpretation of time trends in these haematological cancers .
Age-period-cohort models allow to disentangle the independent effects of age, death period, and birth cohort on long-term time trends in cancer mortality, after controlling for the potential confounding effects of the remaining factors . In particular, the identification of significant trend changes in period and cohort effects may help explain some features of the observed time trends in haematological cancer mortality and assess the relative contribution of both long-term exposure to risk factors and recent improvements in diagnosis and treatment. To this end, the present study sought to analyse changes in period and cohort effects on haematological cancer mortality in Spain across the period 1952-2006.
The number of deaths from Hodgkin’s disease, NHL, multiple myeloma, and leukaemia in Spain, broken down by single calendar year, sex, and 5-year age group (0-4, 5-9, …, 80-84, and ≥ 85 years), was obtained from the Spanish National Institute of Statistics for the period 1952-2006 . The study period was restricted to 1962-2006 for multiple myeloma, due to the reduced number of deaths from this cause registered in Spain before 1962. Deaths from these haematological cancers corresponded to different codes from successive revisions of the International Classification of Diseases (ICD) over the study period (Additional file 1: Table S1). Haematological cancer death certification in Spain has been shown to be accurate during the 1980s and 1990s, with detection and confirmation rates of 86% and 80% for lymphomas, 96% and 94% for multiple myeloma, and 93% and 93% for leukaemia, as compared with clinical and pathological reports . Mid-year population estimates for Spain were also obtained from the Spanish National Institute of Statistics from 1952 to 2006 .
Age-adjusted mortality rates of haematological cancers were calculated for each sex and 5-year calendar period (1952-1956 to 2002-2006) using the direct method with the European standard population. For each haematological cancer, age-adjusted male-to-female mortality rate ratios and their 95% confidence intervals (CIs) were computed for each 5-year period by assuming a Poisson distribution for the observed number of deaths.
since due to the linear dependence among the three factors. All parameters of this model are identifiable and hence have unique maximum likelihood estimates . This paper focused on the cross-sectional age effect for an average period , which was obtained from the linear function , the net drift or sum of period and cohort linear slopes β l + γ l , and the period and cohort curvatures and .
where the intercept . The parameters β l + β 1 and β l + β 1 + β 2 represented the period slopes below and above the change-point τ, respectively, which were not estimable since the overall period slope β l cannot be uniquely determined . However, the change in period slopes at the change-point can be estimated directly as the coefficient β 2 from joinpoint regression analysis of period curvatures. Similar arguments can be applied to cohort effects, as well as to the presence of multiple change-points.
Age-adjusted mortality rates of haematological cancers in Spain (per 100,000 European standard population) by sex and 5-year calendar period
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
No. of deaths
Male-to-female ratio1 (95% CI)
Male-to-female ratio1 (95% CI)
Male-to-female ratio1 (95% CI)
Male-to-female ratio1 (95% CI)
Effect of age, death period, and birth cohort
Changes in period and cohort effects on haematological cancer mortality rates by sex, Spain 1952-2006
Change in period effect2
Change in cohort effect3
Year of death
APC (95% CI)
APC (95% CI)
APC (95% CI)
-2.3 (-2.6 to -2.1)
-6.3 (-7.5 to -5.0)
-2.3 (-2.9 to -1.7)
-1.8 (-2.0 to -1.5)
-5.2 (-6.0 to -4.4)
-3.5 (-4.8 to -2.2)
1.5 (0.2 to 2.9)
2.3 (2.0 to 2.5)
-3.3 (-5.1 to -1.5)
-3.6 (-4.1 to -3.1)
-4.9 (-6.2 to -3.6)
3.0 (2.7 to 3.3)
-3.5 (-6.0 to -1.0)
-4.3 (-4.6 to -3.9)
-2.3 (-2.9 to -1.6)
3.6 (3.4 to 3.9)
-4.3 (-6.0 to -2.6)
-6.1 (-6.9 to -5.2)
-1.8 (-2.3 to -1.3)
3.6 (3.2 to 3.9)
-3.9 (-5.7 to -2.0)
-6.1 (-7.8 to -4.5)
-2.9 (-3.5 to -2.3)
-0.1 (-0.2 to 0.1)
-3.6 (-5.8 to -1.3)
-4.3 (-4.9 to -3.7)
-2.5 (-3.3 to -1.7)
-0.3 (-0.5 to -0.2)
-4.4 (-5.7 to -3.0)
-5.1 (-5.8 to -4.4)
-2.8 (-3.6 to -2.0)
Our results show that, although mortality rates from haematological malignancies were consistently higher among men than among women throughout the extensive period studied, death period and birth cohort patterns were virtually identical in both sexes. In the case of period effects, the change-point at which mortality attenuated was located in different calendar years, depending on the cause of death. Hodgkin’s disease and leukaemia were the first tumours displaying this attenuation in the 1960s, followed by multiple myeloma in the 1980s and NHL in the 1990s. The early period trend reversal for Hodgkin’s disease and leukaemia was essentially attributable to substantial improvements in the treatment of these haematological tumours, as has already been documented in other European countries [3, 4].
With respect to cohort effects, two findings should be highlighted, namely, the homogeneous upward trends for generations born before the 1920s for all four haematological tumours and both sexes, and the similar inverted U-shaped trends for NHL and leukaemia across all birth cohorts. The widespread rises in earlier cohorts suggest a phenomenon of progressive improvement and subsequent saturation in the diagnosis and certification of haematological tumours, particularly in the elderly. It is also noteworthy that the decline in NHL mortality for more recent generations occurred a decade later in men than in women, since men born around 1960 were most affected by the human immunodeficiency virus epidemic derived from injection drug use.
Joinpoint analyses of period and cohort curvatures
Joinpoint analyses of age-adjusted rates are commonly used to identify significant trend changes over a given period. However, with this approach, we are unable to disentangle whether the observed trend changes across periods are due to a unique period effect or to an indirect effect induced by birth cohorts . We therefore conducted weighted joinpoint analyses of the estimated period and cohort curvatures from the three-factor model, rather than relying directly on age-adjusted rates. Although curvatures are hard to interpret in isolation from the overall linear slopes , the locations of change-points and the associated changes in period and cohort slopes remain estimable from curvature components.
Non-Hodgkin’s lymphoma and multiple myeloma mortality trends
The steady rise in mortality from haematological cancers until the generations born in the 1920s and the subsequent levelling off would suggest that diagnosis and, by extension, certification of these diseases increase as health care improves and develops. While there may feasibly be a strong chance of diagnostic enhancements [12, 13, 23] and universal access to health care in Spain being incorporated into the dramatic increases in NHL and multiple myeloma rates, it has been argued that diagnostic improvements cannot fully explain the widespread rise in NHL incidence until the end of the 1990s in other countries, with the most likely explanation being an increase in exposure to risk factors . If the uniform escalation in NHL incidence and mortality occurred due to greater exposure to risk factors of different nature, then such factors should not only be strongly associated with NHL risk, but should also be widely distributed across all adult age groups, both sexes, and most developed countries. Severe immunosuppression and certain infectious agents are the only well-established, strong risk factors for NHL , but these conditions are too infrequent in the general population to account for a substantial part of the widespread rise in NHL rates. Weaker and less consistent associations with NHL risk have been reported for occupational and environmental exposures to chemicals, pesticides, and persistent organic pollutants, as well as for several dietary and lifestyle factors, including high intake of fats and meat, overweight, and smoking for specific NHL subtypes . While exposure to chemicals and pesticides has mainly been occupational and hence unevenly distributed between sexes and age groups, the whole population in developed countries was uniformly and increasingly exposed to persistent organic pollutants and unhealthy lifestyle habits during the second half of the 20th century. The slight but sustained upward period effects on NHL mortality observed in Spanish men and women up to the middle 1990s could be attributable to increased exposure to these potential risk factors, as has been suggested for NHL incidence in other European countries . Nevertheless, our results show a more prominent role of birth cohort, rather than death period, in defining the dramatic upward trends in NHL and multiple myeloma mortality in Spain. The sharp rises for earlier generations of both sexes suggest that progressive improvements in case ascertainment and certification in the elderly have probably played a major role in the dramatic increase in mortality from haematological tumours. In line with these countrywide mortality findings, previous studies on NHL incidence trends in several Spanish regions have also reported a recent attenuation of the long-term epidemic increase in NHL [6, 13], which was mainly attributable to the progressive introduction and subsequent full implementation of modern diagnostic procedures.
Hodgkin’s disease and leukaemia mortality trends
As in most Western European countries [3, 12, 27], mortality from Hodgkin’s disease has declined markedly in Spain during the last decades, since this neoplasm is highly amenable to treatment . The continued downward period effects after the middle 1960s, together with the relatively flat cohort effects, indicate that advancements in the integrated treatment of Hodgkin’s disease had a favourable impact in all age groups. With regard to leukaemia, our results are consistent with previous studies in showing that there has been considerable progress in its treatment among children and young adults [4, 29], as indicated by the downward trends across periods and recent generations born after the middle 1960s. However, the favourable effect of leukaemia treatment in young patients was partially offset by the increase in mortality linked to better diagnosis and certification in earlier cohorts born before the 1920s , thus resulting in an overall levelling off in leukaemia mortality rates from 1990 onwards.
Male excess mortality from haematological cancers
It is very striking that, despite the markedly different time trends in mortality from each haematological cancer, male-to-female mortality rate ratios remained fairly constant throughout the entire study period for all haematological tumours. The male excess mortality persisted not only across successive calendar periods, but also across all age groups, including children younger than 15 years (see age- and period-specific mortality rates of NHL and leukaemia in Additional file 2: Video S1 and Additional file 3: Video S2). The same consistent predominance among men has been reported for NHL incidence in Spain , as well as for the incidence of all four haematological tumours in different countries around the world . Lifestyle and environmental factors known to be unevenly distributed between sexes, such as smoking, alcohol drinking, and occupational carcinogens, can hardly account for these enigmatic sex disparities in haematological cancer incidence and mortality , giving way to endogenous sex-specific biological or genetic factors as a more plausible explanation. The existence of X-chromosome-linked suppressor factors of haematological tumours has recently been suggested, something that would help explain the systematic lower mortality observed in women. In particular, the loss of the PHF6 tumour suppressor gene, linked to the X chromosome, has been identified as possibly being involved in the genesis of T-cell acute lymphoblastic leukaemia  and adult acute myeloid leukaemia , though neither paper reports the frequency of this disorder in the general population. While it is uncertain whether these findings on very specific types of lymphomas and leukaemia could be generalised to other lymphoid neoplasms and leukaemias, they have already been observed for some solid tumours .
Limitations of the study
Several limitations of the study must be mentioned. First, we were unable to analyse long-term countrywide time trends in haematological cancer incidence because most population-based cancer registries in Spain began collecting incidence data from 1980 to 1995 and covered only 26% of the total Spanish population . Nevertheless, mortality is a complex indicator that allows assessing both the effect of risk factors on cancer incidence and the impact of diagnostic and therapeutic advances on cancer survival. Second, deaths from haematological cancers were coded according to successive ICD revisions, which are not supported by the new classification of lymphoproliferative syndromes established in 1995, known as the Revised European-American Classification of Lymphoid Neoplasms . Although ICD rubrics for lymphomas, multiple myeloma, and leukaemia have an overlap in several cell lines, haematological cancer death certification in Spain has been shown to be accurate from 1980 onwards . However, there is no information on the quality of death certification in Spain before 1980 and we cannot rule out some degree of under-certification of haematological cancer deaths in earlier periods. To evaluate the potential impact of under-certification on the observed time trends, sensitivity analyses were performed excluding deaths during the initial quinquennia 1952-1956 and 1957-1961 and results remained virtually unchanged (data not shown).
The dramatic increases in NHL and multiple myeloma mortality observed in Spain during the second half of the 20th century are best explained by a cohort effect linked to progressive improvements in the diagnosis and certification of these haematological tumours, particularly in the elderly. After full implementation of modern diagnostic procedures, the recent stabilisations or slight declines in NHL and multiple myeloma mortality rates are expected to continue in the near future. In contrast, the sustained decline in Hodgkin’s disease mortality and the levelling off in leukaemia during the last decades are mainly attributable to a period effect linked to advancements in disease treatment. Also, the consistent male excess mortality across all calendar periods and age groups points to the importance of possible sex-related genetic markers of susceptibility in haematological cancers.
Annual percent change
International classification of diseases
The study was supported in part by a research grant from the Spanish Health Research Fund (FIS PI11/00871). The study sponsor had no role in the study design; the collection, analysis, and interpretation of data; the writing of the manuscript; and the decision to submit the manuscript for publication.
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