IJC International Journal of Cancer
Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: A population-based cohort study of 32,308 one-year survivors Thorgerdur Gudmundsdottir1, Jeanette F. Winther1, Sofie de Fine Licht1, Trine G. Bonnesen2, Peter H. Asdahl2, Laufey Tryggvadottir3,4, Harald Anderson5, Finn Wesenberg6,7,8, Nea Malila9, Henrik Hasle2, and Jørgen H. Olsen1; on behalf of the ALiCCS study group 1
Danish Cancer Society Research Center, Copenhagen, Denmark Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark 3 The Icelandic Cancer Registry, Reykjavik, Iceland 4 Faculty of Medicine, Laeknagardur, University of Iceland, Reykjavik, Iceland 5 Department of Cancer Epidemiology, Lund University, Lund, Sweden 6 Department of Pediatrics, Oslo University Hospital, Nydalen, Oslo, Norway 7 Faculty of Medicine, University of Oslo, Blindern, Oslo, Norway 8 The Norwegian Cancer Registry, Majorstuen, Oslo, Norway 9 Finnish Cancer Registry, Helsinki, Finland
Epidemiology
2
The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population-based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one-year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0–2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person-years. At the end of follow-up 12% of the survivors were 50 years of age and 4.5% 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ~500–600 per 100,000 person-years at age 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5–5.9), valvular dysfunction (4.6; 3.8–5.5) and cerebrovascular diseases (3.7; 3.4– 4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow-up for this rapidly growing population.
Continued advances in childhood cancer treatment have led to impressive improvements in survival, with an overall five-year survival now reaching 80%.1 However, increased survival comes at a price, as long-term sequelae such as second cancers, increased mortality and diverse, not yet fully described chronic morbidities
seem to emerge as the survivors become older.2–6 Thus, in the North American Childhood Cancer Survivor Study (CCSS), an eightfold increased risk for a severe or life-threatening condition was found when compared with a sibling comparison group.7,8 Research on cause-specific late mortality indicates that cardiac
Key words: childhood cancer, late complications, cardiovascular disease, hospitalizations, clinical epidemiology Abbreviations: AER: absolute excess risk; ALiCCS: adult life after childhood cancer in Scandinavia; CCSS: childhood cancer survivor study; CI: confidence interval; CNS: central nervous system; CVD: cardiovascular disease; HD: Hodgkin disease; ICCC: international classification of childhood cancer; ICD: international classification of diseases; NHL: non-Hodgkin lymphoma; RR: standardized hospitalization rate ratio; STS: soft-tissue sarcoma Additional Supporting Information may be found in the online version of this article. Grant sponsor: The Danish Council for Strategic Research; Grant number: 09-066899 DOI: 10.1002/ijc.29468 History: Received 30 June 2014; Accepted 19 Jan 2015; Online 3 Feb 2015 Correspondence to: Thorgerdur Gudmundsdottir, MD, PhD fellow, Danish Cancer Society Research Center, Survivorship Unit, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Tel.: [4535257648], Fax: 1[45-3527-1811], E-mail: [email protected]
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disease is among the leading non-malignant causes of death in long-term survivors of childhood cancer.9–11 Large studies presenting a thorough description of the pattern of chronic disease, in all phases of life, are needed to alert awareness of this growing challenge, not least for primary care physicians and medical specialists working outside the late effect area. Large, population-based, longitudinal studies are required to provide a full overview of lifelong complications, supplemented by accurate estimates of absolute and relative risks by comparison with a population-based cohort. We therefore studied the risk of cardiovascular disorders by long-term follow-up of childhood cancer survivors in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) through nationwide cancer registries dating back to the 1940s and 1950s, with complete follow-up of the survivors in population registers and information about all types of cardiovascular outcomes from national hospital registers.
Material and Methods This study is “Adult Life (ALiCCS), an for childhood
part of an ongoing inter-Nordic cohort study after Childhood Cancer in Scandinavia” investigation of late complications of treatment cancer (www.aliccs.org).12
Patient and comparison cohorts
Through the five national cancer registries, we identified individuals in whom cancer was diagnosed before they were 20 years of age between the start of the cancer registries in the 1940s and 1950s and December 31, 2008. To be included in the study, patients had to be alive on or after the date on which centralized registration of residents of each country was operational with all the required variables (Iceland, 1955; Norway, 1960; Sweden, 1968; Denmark, 1968; and Finland, 1971), leaving a total of 43,909 patients for further follow-up (Supporting Information Appendix Table I). All five cancer registries are nationwide with close to 100% coverage.2,13 From the registries, we obtained information on type of cancer and date of diagnosis and assigned individuals to one of 12 main diagnostic groups of the International Classification Scheme for Childhood Cancer, with lymphomas stratified into Hodgkin and non-Hodgkin lymphoma.14 Since the start of centralized civil registration in the Nordic countries, all residents (25 million in 2008) have been assigned a unique personal identification number that allows accurate linkage C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
among registers and follow-up for vital status and migration.15 To measure rates of cardiovascular morbidity in the background population, we randomly selected 219,131 comparison subjects from the population registries of the five countries (Supporting Information Appendix Table I). For each childhood cancer patient, five comparison subjects were randomly selected, who were alive on the date of cancer diagnosis of the corresponding patient, of the same sex, age, country (Denmark and Iceland) or county of residence (Finland, Norway and Sweden) and without a cancer diagnosis in the age-range 0–19 years. Fewer than five comparisons were available for 317 patients. Before linkage of study subjects to the respective national hospital register (see below), we excluded those in whom more than one primary cancer was diagnosed in childhood as they could not be classified unambiguously (n 5 305); those who died or emigrated before the start of the national hospital register (Sweden, stepwise inclusion of counties in 1968–1987 and nationwide since 1987; Denmark, 1977; Iceland, 1999; Norway, 2008; Finland, 1982; 7,251 patients and 5,146 comparison subjects); and those who died, emigrated or were censored during the year after the date of childhood cancer diagnosis or an equivalent time lag for comparison subjects (3,193 patients and 1,093 comparison subjects). This resulted in a total of 33,160 one-year survivors of childhood cancer and 212,892 population comparison subjects (Supporting Information Appendix Figure I). Hospital admissions for cardiovascular disease
The national hospital registers contain information on virtually all non-psychiatric hospital admissions in the five Nordic countries.16–18 Registration is mandatory and recorded by the treating physician. Each admission initiates a record, which includes the personal identification number of the patient, dates of admission and discharge, a primary discharge diagnosis and a varying number of supplementary diagnoses coded according to the International Classification of Diseases, 7th to 10th revisions (ICD-7 to ICD-10). We identified all hospital admissions for a primary or supplementary discharge diagnosis of the relevant cardiovascular sections of the ICD (ICD-7 codes 330–334 and 420–468; ICD8 codes 400–445, 447–457; ICD-9 codes 401–445, 447–457; ICD-10 codes I10–I89 and G45) for all study subjects. Diagnostic categories of ICD-7, ICD-8 and ICD-9 were adapted to
Epidemiology
What’s new? The long-term effects of cancer treatment in childhood cancer survivors can be serious, and more research is needed to fully investigate the relationship between treatment and chronic disease in aging survivors. This retrospective population-based cohort study focused on cardiovascular late effects among childhood cancer survivors in the five Nordic countries. Survivors were found to be at significantly increased risk for cardiovascular disease throughout their lives. Relative risk was highest for heart failure, valvular dysfunction, and cerebrovascular diseases. Overall, survivors had a twofold increased lifetime risk for hospitalization for cardiovascular disease.
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Table 1. Observed and expected number of first hospital admission for cardiovascular disease of any type among 32,308 one-year survivors of childhood cancer in the Nordic countries by sex and attained age
Person-years at risk1 Both sexes
No. of first hospital admissions Observed
Expected
Hospitalization rate2 RR
95% CI
Observed
Expected
AER2
95% CI
428,302
2,632
1,243.7
2.1
2.0–2.2
614.5
290.4
324
300–348
Male
223,407
1,417
661.4
2.1
2.0–2.3
634.3
296.1
338
304–373
Female
204,895
1,215
582.3
2.1
2.0–2.2
593.0
284.2
309
274–343
Attained age (years) 1–9
43,687
185
9.9
18.7
14.2–24.7
423.5
22.6
401
340–462
10–19
105,408
382
75.4
5.1
4.5–5.8
362.4
71.5
291
254–328
20–29
126,514
491
190.1
2.6
2.3–2.9
388.1
150.3
238
203–273
30–39
81,068
509
272.0
1.9
1.7–2.1
627.9
335.5
292
236–349
40–49
44,513
524
299.9
1.8
1.6–1.9
1,177.2
673.7
503
399–608
50–59
20,352
354
249.5
1.4
1.3–1.6
1,739.4
1,225.7
514
324–704
60
6,761
187
147.0
1.3
1.1–1.5
2,765.7
2,174.1
592
169–1014
Epidemiology
Abbreviations: AER: absolute excess risk; CI: confidence interval; RR: standardized hospitalization rate ratio. 1 Survivors only. 2 Per 100,000 person-years.
the ICD-10 to the extent possible. Outpatient and emergency visits were not included in this study. Linkage to the hospital registers revealed that 373 survivors and 429 comparison subjects had been admitted for a cardiovascular disease before the date of diagnosis of childhood cancer or the corresponding date for the comparisons; consequently, these individuals were excluded from the study. Furthermore, we excluded people in whom a congenital malformation of the circulatory system had been diagnosed (ICD-10 codes Q20–Q28) (282 survivors and 768 comparison subjects) and those with a congenital chromosomal abnormality (ICD-10 codes Q90–Q99) (197 survivors and 206 comparison subjects), as we considered that these diagnoses might confound any causal association between cancer treatment and cardiovascular late effects.19 Thus, 32,308 one-year survivors and 211,489 population comparison subjects remained for the analyses (Supporting Information Appendix Table I and Appendix Fig. I). Of the 32,308 one-year survivors, 26,016 (80.5%) were under continuous follow-up within the national hospital registries for five years or more after their cancer diagnosis. Statistical analysis
Follow-up for cardiovascular disease in the national hospital registers started one year after the date of diagnosis of childhood cancer and the corresponding date for the equivalent comparisons or the start of the hospital registries, whichever occurred latest. Follow-up ended on the date of death, emigration or the closing date of the study, whichever occurred first. Follow-up also ended if a second primary cancer was diagnosed in a survivor or first primary cancer in a population comparison subject. If study subjects had more than one hospital admission for a cardiovascular disease, only the first record was retained, as it was presumed to correspond to the
date of diagnosis. Risk analyses were carried out for any cardiovascular disease, on a yes/no level for each study subject, for each of the 10 main diagnostic categories and for each of the 30 subcategories or diagnoses within the main categories (see Table 2). The observed numbers of first hospital admission for a given cardiovascular disease among childhood cancer survivors were compared with expected numbers derived from the appropriate country-, sex-, age- and calendar period-specific cardiovascular morbidity rates of the population comparison cohort. We did not adjust for variables such as hyperlipidaemia, diabetes, smoking or other aspects of survivors’ diseases or lifestyle since we view these factors as mediators, rather than confounders of the association between childhood cancer and cardiovascular disease. The significance and 95% confidence intervals (CIs) for the standardized hospitalization rate ratio (RR, the observed-toexpected hospital admissions for each defined disease entity) were estimated using Fieller’s theorem and assuming that the observed number of first hospital admissions followed a Poisson distribution. The absolute excess risk (AER), i.e., the additional risk for hospitalization for a cardiovascular disease, was derived as the difference between the observed and expected first hospitalization rates for cardiovascular disease per 100,000 person-years of follow-up, with corresponding 95% CIs. We used SAS version 9.2 for all analysis.
Results Cancer survivors (see Supporting Information Appendix Table II for descriptive characteristics) were followed in the national hospital registers for 428,302 person-years (median, 10 years; range, 0–42 years); 2,632 survivors (8.1%) had at least one hospital admission for a cardiovascular disease, while 1,244 would have been expected, yielding a significantly C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
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Table 2. Observed and expected numbers of first hospital admissions for cardiovascular disease among 32,308 one-year survivors of childhood cancer in the Nordic countries by 10 main diagnostic categories and 30 subcategories or diagnoses No. of first hospital admissions
Hypertension
ICD-101
Observed2
Expected2
RR
95% CI
AER3
95% CI
Distribution of AER (%)4 16.3% (77/471)
I10–I15
658
326.9
2.0
1.9–2.2
77
65–89
Essential hypertension
I10
566
313.5
1.8
1.7–2.0
59
48–70
Hypertension with complications
I11–I13
46
17.0
2.7
1.9–3.8
7
4–10
Ischemic heart disease Acute myocardial infarction Pulmonary heart disease Pulmonary embolism Peri-, myo- and endocardial disease Pericarditis
I20–I25
360
217.1
1.7
1.5–1.9
33
24–42
I21
149
107.1
1.4
1.2–1.7
10
4–16
I26–I28
138
39.1
3.5
2.9–4.3
23
18–29
I26
110
34.0
3.2
2.6–4.0
18
13–23
I30–I33, I38–I41, I51.4
156
54.8
2.9
2.4–3.4
24
18–29
I30–I32
107
28.5
3.8
3.0–4.7
18
14–23
Acute pericarditis
I30
68
24.0
2.8
2.2–3.8
10
6–14
Other and chronic pericardial disease
I31–I32
47
6.6
7.1
4.8–10.6
9
6–13
Myocarditis
I40–I41, I51.4
33
21.7
1.5
1.1–2.2
3
20.1–5
Endocarditis
I33, I38–I39
23
7.3
3.1
1.9–5.1
4
1.4–6
Valvular disease (nonrheumatic)
I34–I37
178
38.6
4.6
3.8–5.5
33
26–39
Aortic valve disorders
I35
128
25.3
5.1
4.1–6.3
24
19–29
Mitral valve disorders
I34
65
14.0
4.6
3.4–6.3
12
8–16
I42–I43, I50, I51.5, I51.7
357
68.8
5.2
4.5–5.9
67
59–76
Congestive heart failure
I50
247
55.5
4.5
3.8–5.2
45
37–52
Cardiomyopathy
I42–I43
197
20.0
9.9
8.0–12.1
41
35–48
Conduction disorder
Heart failure
I44–I49
386
234.8
1.6
1.5–1.8
35
26–45
Atrial fibrillation/flutter
I48
149
97.2
1.5
1.3–1.8
12
6–18
Supraventricular tachycardia (SVT)
I47.1
66
41.6
1.6
1.2–2.1
6
2–10
Cardiac arrest and/or ventricular fibrillation/flutter
I46, I49.0
45
17.5
2.6
1.8–3.6
6
3–10
Sick sinus or AV block
I49.5, I44.0–3
43
15.1
2.9
2.0–4.0
7
3–10
Ventricular tachycardia (VT)
I47.2
18
10.7
1.7
1.0–2.8
2
20.3–4
I60–I69, G45
586
158.8
3.7
3.4–4.1
100
88–111
Cerebrovascular disease Cerebral infarction
I63
216
61.6
3.5
3.0–4.1
36
29–43
Cerebral hemorrhage
I61–I62
181
22.0
8.2
6.7–10.1
37
31–43
Stroke, unspecified
I64
54
19.4
2.8
2.0–3.8
8
5–12
Transient ischaemic attack (TIA)
I66, G45
56
29.8
1.9
1.4–2.5
6
3–10
Subarachnoid hemorrhage (SAH)
I60
54
21.2
2.6
1.9–3.5
8
4–11
Occlusion or stenosis of a.carotis
I65.2
13
5.6
2.3
1.3–4.3
2
0.0–3
Occlusion or stenosis of other preor cerebral arteries
I65.0–1, I65.3–9, I66
13
2.9
4.6
2.3–9.0
2
0.7–4
I70–I79
176
66.0
2.7
2.3–3.2
27
19–32
Arterial disease Atherosclerosis
I70
69
27.3
2.5
1.9–3.3
10
6–14
Arterial embolisms and thrombosis
I74
34
7.7
4.4
2.9–6.8
6
3–9
Aneurysms (aortic and other)
I71–I72
23
15.8
1.5
1.0–2.3
2
20.6–4
Venous- and lymphatic disease
I80–I89
655
431.6
1.5
1.4–1.7
52
40–64
Varicose veins
I83–I86
336
328.0
1.0
0.9–1.2
2
27–11
Venous embolism, thrombosis or thrombophlebitis
I80–I82
267
84.8
3.2
2.7–3.6
43
35–50
7.0% (33/471)
4.9% (23/471)
5.1% (24/471)
7.0% (33/471)
14.2% (67/471)
7.4% (35/471)
21.2% (100/471)
Epidemiology
Cardiovascular disorders
5.7% (27/471)
11.0% (52/471)
Abbreviations: AER: absolute excess risk; AV: atrioventricular; CI: confidence interval; RR: standardized hospitalization rate ratio. 1 International classification of diseases, 10th version. 2 Hospital admissions across the main diagnostic categories for cardiovascular disease sum up to more than the total number of survivors with cardiovascular disease since 25% of survivors received diagnosis from more than one category of cardiovascular disease over time. 3 per 100,000 person-years. 4 per 10 main diagnostic categories.
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increased RR of 2.1 (Table 1). Overall, 77% of cardiovascular diagnoses in survivors and 86% in comparisons were notified as the primary discharge diagnosis, i.e., the main reason for the admission to hospital. Survivors were on average seven years younger than comparisons at the date of first hospital admission, with a median age of 35 years (range, 1–83 years) and 60% of hospitalizations occurred before the age of 40 years. On the basis of observed and expected overall hospitalization rates for cardiovascular disease of 615 and 291 per 100,000 person-years, respectively, the AER was 324 per 100,000 person-years. This implies that, for each additional year of follow-up, a new excess cardiovascular disease was diagnosed at a hospital in 3 of 1,000 childhood cancer survivors (Table 1). Although the RR was significantly increased in all groups of attained age, the increase diminished considerably with age, from an RR of 18.7 in the first decade of life to 1.3 among survivors aged 60 years (Table 1). The AER did not vary similarly with age and ranged between 200 and 600 new excess hospital admissions for cardiovascular disease per 100,000 person-years of observation, with the lowest value in survivors aged 20–29 years and the highest at age 60 years. We stratified the survivor cohort into those with cancer diagnosed in 1943–1959, 1960–1974, 1975–1989 and 1990– 2008 and calculated the cumulative risk for hospitalization for any cardiovascular disease by attained age (data not shown). The cumulative risk by the age of 40 years was 9.6% in the 1943–1959 subcohort (prechemotherapy era), 12.9% in the 1960–1974 subcohort (first-generation chemotherapy era), 16.2% in the 1975–1989 subcohort (early combination chemotherapy era) and 18.3% in the 1990–2008 subcohort (late combination chemotherapy era). For survivors with cancer diagnosed in 1975–1989, for whom we were able to establish a hospitalization history covering the survivors’ subsequent life, 26.9% had ever been admitted to hospital for cardiovascular disease at the age of 50 years. Stratified analyses to compare sub-cohorts according to age at diagnosis of childhood cancer (0–4, 5–9, 10–14 and 15–19 years) revealed no significant variation in cumulative risk for overall cardiovascular disease by attained age. Childhood cancer survivors were at significantly increased risk of hospital admission for cardiovascular diseases of all the 10 main diagnostic categories (Table 2). The highest relative risks were seen for heart failure (RR, 5.2; males 3.9 [95% CI, 3.2–4.6]; females 8.3 [6.7–10.3]), valvular disease (4.6; 4.4 [3.5–5.6]; 5.0 [3.7–6.7]), cerebrovascular disease (3.7; 3.9 [3.4–4.4]; 3.4 [2.9–4.0]) and pulmonary heart disease (3.5; 4.0 [3.0–5.4]; 3.2 [2.4–4.2]). The significant difference in RR for heart failure between male and female survivors was due partly to lower background hospitalization rates among females. The AER for female survivors was not significantly higher than that for males (61 [49–73]; females 74 [62–87]; not shown in table). In the subset of 30 cardiovascular diagnoses, the highest relative risks were seen for cardiomyopathy (RR, 9.9), cerebrovascular hemorrhage (8.2), other and
CVD in Nordic childhood cancer survivors
chronic pericardial diseases (7.1), aortic- and mitral valve dysfunction (5.1 and 4.6, respectively) and congestive heart failure (4.5). Table 2 also shows that cerebrovascular disease had the highest AER of 100 per 100,000 person-years, followed by hypertension (77), heart failure (67) and venous and lymphatic disease (52). These four outcomes together constituted almost two thirds of all excess cardiovascular diseases. Figure 1 shows the observed and expected rates of hospitalization for selected cardiovascular diagnoses by survivors’ attained age. While there was an excess risk of cerebral hemorrhage in all age groups, cerebral infarction and transient ischemic attack were observed in more excess after the age of 30. Although the RR and the AER for heart failure were strongly increased in the age range 1–29 years, this disease is also a prominent complication of cancer treatment that appears later in life. In contrast, the majority of hospital admissions for valvular disease occurred before the age of 50 years, with no further increase in risk thereafter. Survivors of all main diagnostic groups of childhood cancer and the two subgroups of lymphoma had increased RRs for a hospital discharge diagnosis of cardiovascular disease, all significantly elevated except for survivors of retinoblastoma (Table 3 and Supporting Information Appendix Figure II). In analyses of the relative risks for a selected set of combinations of childhood cancer and cardiovascular disease for which the lower 95% confidence limit of the RR was 2, particularly high relative risks were seen for heart failure after hepatic tumors (RR, 58.0), leukemia (20.8), renal tumors (15.1), sympathetic nervous system neoplasms (16.2), Hodgkin and nonHodgkin lymphoma (12.1 and 9.1, respectively) and bone tumors (7.1). Very high risks were also seen for valvular disease after Hodgkin lymphoma (34.3) and for cerebral hemorrhage after central nervous system neoplasms (17.7).
Discussion In this population-based follow-up study of 32,308 one-year survivors of childhood cancer in the five Nordic countries, survivors had an overall twofold increased lifetime risk for hospital admission for cardiovascular disease. The RR varied considerably by age, from 19 in early life to 1.3 for survivors 60 years. This reduction in relative risk by age was mainly a consequence of an age-dependent increase in cardiovascular disease in the general population rather than a modification of the damaging effects associated with childhood cancer treatment. Thus the AER, attributable to status as a childhood cancer survivor, remained at 3–6 excess cardiovascular diseases per 1,000 person-years throughout life. For survivors diagnosed with cancer in 1975–1989, the cumulative risk for a hospitalization for cardiovascular disease was 26.9% at the age of 50 years. One-year survivors of leukemia, Hodgkin lymphoma, sympathetic nervous system neoplasms, and hepatic tumors had the highest overall risks. Particularly, high risks were seen in survivors of leukemia and lymphoma for heart failure, in survivors of Hodgkin lymphoma for C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
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Figure 1. Age-specific observed and expected hospitalization rates for a selected set of cardiovascular diseases among 32,308 one-year survivors of childhood cancer in the Nordic countries, to illustrate the different disease-pattern by age (note that three different scales are used).
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Table 3. Standardized hospitalization rate ratios (RR) for any and for selected1 diagnostic categories of cardiovascular disease by main diagnostic group of childhood cancer ICCC group
Childhood cancer2/Cardiovascular disease3
I
Leukemia (n 5 6,796) Any cardiovascular disease
IIa
328
3.5
3.1–3.9
20.8
15.5–28.1
Cerebrovascular disease
72
8.6
6.7–11.1
Hypertension
66
4.4
3.4–5.6
Pulmonary heart disease
14
4.4
2.5–7.6
Peri-, myo- and endocardial disease
26
3.6
2.4–5.4
Valvular disease
8
2.7
1.3–5.4
Hodgkin lymphoma (n 5 2,388) 333
3.2
2.9–3.6
Valvular disease
104
34.3
27.5–42.8
Heart failure
65
12.1
9.4–15.7
Peri-, myo- and endocardial disease
42
8.4
6.1–11.5
Ischemic heart disease
104
5.9
4.9–7.2
Pulmonary heart disease
17
5.5
3.4–8.9
Conduction disorders
72
3.7
3.0–4.7
Cerebrovascular disease
39
3.2
2.3–4.4
Venous and lymphatic disease
78
2.2
1.7–2.7
Non-Hodgkin lymphoma (n 5 1,750) 146
2.0
1.7–2.4
41
9.1
6.6–12.5
672
2.2
2.0–2.4
Cerebrovascular disease
282
7.0
6.2–8.0
Hemorrhage
99
17.7
13.9–22.7
Infarction
110
7.0
5.7–8.6
Heart failure Central nervous system neoplasm (n 5 7,723)
Epidemiology
Any cardiovascular disease
IV
Sympathetic nervous system neoplasm (n 5 1,281) Any cardiovascular disease
80
3.4
2.7–4.2
Heart failure
14
16.2
9.4–27.9
Pulmonary heart disease
9
11.8
6.0–23.1
Cerebrovascular disease
19
8.1
5.1–12.7
Hypertension
20
4.1
2.6–6.4
46
1.2
0.9–1.7
V
Retinoblastoma (n 5 819)
VI
Renal tumor (n 5 1,376)
Any cardiovascular disease
Any cardiovascular disease
VII
95% CI
62
Any cardiovascular disease
III
RR
Heart failure
Any cardiovascular disease
IIb
No. of first hospital admissions
108
2.8
2.3–3.4
Heart failure
24
15.1
9.9–22.9
Arterial disease
10
5.9
3.1–11.0
Hypertension
37
4.6
3.3–6.3
13
5.1
2.9–8.7
Hepatic tumor (n 5 231) Any cardiovascular disease Heart failure
4
58.0
21.4–157
Arterial disease
2
17.7
4.4–71.4
Venous and lymphatic disease
7
7.1
3.4–15.0
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Table 3. Standardized hospitalization rate ratios (RR) for any and for selected1 diagnostic categories of cardiovascular disease by main diagnostic group of childhood cancer (Continued) ICCC group
Childhood cancer2/Cardiovascular disease3
VIII
Malignant bone tumor (n 5 1,519) Any cardiovascular disease Heart failure
IX
No. of first hospital admissions
RR
95% CI
154
2.1
1.8–2.4
33
7.1
5.0–10.0
173
1.6
1.4–1.9
26
3.5
2.4–5.2
178
1.8
1.5–2.0
344
1.3
1.2–1.5
45
2.2
1.6–2.9
Soft-tissue sarcoma (n 5 1,972) Any cardiovascular disease Heart failure
X
Germ-cell and gonadal neoplasm (n 5 2,100)
XI
Malignant epithelial neoplasm (n 5 3,648)
XII
Other and unspecified neoplasm (n 5 461)
Any cardiovascular disease
Any cardiovascular disease
Any cardiovascular disease
valvular disease and in survivors of central nervous system neoplasms for cerebral hemorrhage. Cardiac disease associated with radiation was described as early as 1924.20 Subsequent clinical studies of patients with a variety of early onset cancers showed long-term adverse cardiovascular effects, including left ventricular dysfunction (resulting in congestive heart failure), ischemic heart disease and valvular and pericardial disease, mainly ascribed to the cardiotoxic effects of chemotherapeutic agents (especially anthracyclines) and radiotherapy.21,22 In general, these reports were based on relatively small, uncontrolled series of survivors, which obviated accurate calculation of risk estimates.23 More recently, the risks for a selected set of cardiovascular diseases and for hospitalization for cardiovascular disease of any type were investigated in the CCSS cohort of about 14,000 five-year survivors treated at 26 institutions in the USA and Canada during 1970–1986 and 4,000 sibling comparisons.4 Despite major methodological differences between our study (use of outcome data from hospital discharge records and of a population-based comparison cohort) and the CCSS (use of outcome data from patient questionnaires and of a comparison sibling cohort), where some 30% of survivors were lost to follow-up or did not respond to the first questionnaire in the CCSS,8 the increases in many of the outcomes were of the same order of magnitude. Table 4 shows the risk estimates for equivalent diagnoses or groups of diagnoses for the two cohorts. In the analyses of CCSS data by Oeffinger et al., Bowers et al. and Kurt et al.,8,24–26 the risk estimates for cardiovascular disease were in general compatible with ours (Table 4). Notable differences were seen, however, when we compared our results with the estimates obtained by Mulrooney et al. in their analysis of CCSS C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
data, not least with regard to heart failure (14.1 in ALiCCS and 5.9 in CCSS) and valvular dysfunction (11.6 in ALiCCS and 4.8 in CCSS).27 In a population-based study from British Columbia, Canada, with 1,374 five-year survivors diagnosed in 1981–1995 or a somewhat younger cohort than ours, the authors reported a RR of 4.9 (2.9–8.4) for hospital-related diseases of the circulatory system,28 which is comparable with our overall estimate of 2.9 (2.7–3.0) for survivors under follow-up in the age-range 1–39 years. In a study from the Netherlands of 1,362 five-year survivors of childhood cancer, who were followed for symptomatic cardiac events (congestive heart failure, cardiac ischemia, valvular disease, arrhythmia and/or pericarditis), the authors reported a cumulative risk of 7.2% 40 years from cancer diagnosis.29 This estimate is to be compared with a cumulative risk of 10.4% at age 50 for the same outcomes seen in our Nordic study. In a recently published record linkage study from the UK of 1,367 five-year survivors of childhood cancer, the authors reported a 7.5% cumulative risk of cardiovascular late effects at 20 years from diagnosis.30 This estimate is to be compared with a cumulative risk of 11.1% in our study. Recently, two smaller studies of five-year survivors of childhood cancer from Finland (n 5 4,459) and Denmark (n 5 2,243), respectively, reported risk estimates for common cardiac diseases similar in magnitude to ours; however, in either study the patient material was to a large extent a subset of that included in this study.31,32 Moreover, Armstrong et al. have reported a potentiation of the effect of modifiable cardiovascular risk factors on the risk of major cardiac events among survivors and therefore further emphasize the need for studies on cardiovascular late-effects among childhood cancer survivors.33
Epidemiology
Abbreviations: ICCC: international classification of childhood cancer; RR: standardized hospitalization rate ratio; CI: confidence Interval. 1 Distinguished by a lower 95% confidence limit of 2. 2 According to the International Classification of Childhood Cancer (ICCC).14 3 According to International classification of diseases (ICD).
1.7 (1.1–2.7) 1.4 (0.8–2.2)
Bone tumor
STS
2.0 (0.6–6.3)
8.6 (6.6–11.2) 11.0 (6.7–18.2) 4.4 (2.2–9.0) 15.2 (11.1–20.8)
All cancers
Leukemia
HD
CNS tumors
49.2 (27.7–87.5)
HD
3.0 (1.2–7.3) 11.6 (6.6–20.2)
CNS tumors
All cancers
16.2 (8.7–30.4)
HD
4.5 (2.7–7.3)
CNS tumors
All cancers
9.8 (5.1–18.6)
HD
STS 3.5 (2.0–6.2)
12.3 (5.0–30.5)
Renal tumors
All cancers
29.0 (11.2–74.8)
Neuroblastoma
1.8 (1.3–2.6)
2.7 (2.0–3.5)
1.4 (0.9–2.0)
1.3 (0.7–2.0)
2.7 (2.1–3.4)
2.5 (1.8–3.4)
6.6 (5.6–7.6)
1.5 (1.3–1.8)
–
RR2 (95% CI)
29.0 (13.8–60.7)
4.3 (2.0–9.3)
6.4 (3.0–13.8)
9.3 (4.1–21.2)
10.4 (4.1–25.9)
15.1 (4.8–47.9)
HR3 (95% CI)
10.5 (6.1–17.9)
4.8 (3.0–7.6)
2.9 (1.2–6.8)
10.4 (5.4–19.9)
6.3 (2.2–11.9)
6.1 (2.3–16.2)
12.2 (5.2–28.2)
5.0 (2.3–10.4)
4.6 (2.4–8.8)
4.9 (2.4–10.0)
4.1 (1.7–9.7)
5.1 (2.6–10.0)
6.8 (3.9–11.7)
4.2 (2.3–7.4)
5.9 (3.4–9.6)
HR4 (95% CI)
CCSS Author
Bowers et al. 2006
Bowers et al. 2005
Bowers et al. 2006
Oeffinger et al. 2006
Mulrooney et al. 2009
Mulrooney et al. 2009
Mulrooney et al. 2009
Oeffinger et al. 20063/ Mulrooney et al. 20094
Mulrooney et al. 2009
Oeffinger et al. 20063/ Mulrooney et al. 20094
Kurt et al. 2012
Kurt et al. 2012
Abbreviations: CCSS: childhood cancer survivor study; CI: confidence interval; CNS: central nervous system; HD: Hodgkin disease; HR: hazard ratio; NHL: non-Hodgkin lymphoma; RR: standardized hospitalization rate ratio; STS: soft-tissue sarcoma. 1 The ALiCCS cohort restricted to the same inclusion criteria as in the CCSS: 5-year survivors diagnosed with cancer in 1970–1986 and followed throughout year 2002. All cancers, as those cancer types included in the CCSS: leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, neuroblastoma, soft-tissue sarcoma and bone cancer. 2 Using annual U.S. population hospitalization rates and adjusted for calendar year only.26 3 HR, adjusting for age, sex and race. Accounting for within-family correlations with the use of sandwich standard-error estimates.8,24,25 4 HR, with adjustments for gender, race, household income, education and tobacco use. Potential within family correlation accounted for by the use of sandwich variance estimates. Multiple imputation methodology used for event-time relations when age at cardiac event was not reported.27
Cerebrovascular disease
Valvular dysfunction
Pericardial disease
Myocardial infarction
22.9 (11.5–45.8) 54.2 (20.7–141.8)
NHL
18.8 (10.5–33.7)
3.0 (1.9–4.8)
Renal tumors
28.4 (15.6–51.4)
5.9 (3.8–9.1)
Neuroblastoma
HD
2.8 (2.3–3.3)
CNS tumors
Leukemia
2.0 (1.3–3.2)
NHL
14.1 (9.7–20.4)
4.1 (3.3–5.0)
HD
All cancers
3.0 (2.3–3.9)
Leukemia
Heart failure
2.8 (2.5–3.2)
All cancers
Hospitalization for any cardiovascular disease
RR (95% CI)
Cancer
Outcome
ALiCCS1
Table 4. Relative risk estimates for compatible cardiovascular outcomes observed in this Nordic study (ALiCCS) in a restricted 5-year survivor cohort1 and in the North American CCSS
Epidemiology
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medical records of cancer survivors need to be organized. Such studies, designed to quantify the damaging effects of the various components of the childhood cancer treatment in regard to a selected set of cardiovascular outcomes, are ongoing within the Nordic childhood cancer cohort. This long-term follow-up study of one-year survivors of childhood cancer from northern Europe underscores the importance of following childhood cancer survivors regularly throughout life as it reveals a persistent excess risk for a broad range of cardiovascular diseases requiring hospital admission, the composition of which, however, changes with increasing age. An aggregated risk of nearly 30% for being admitted to a hospital for a cardiovascular disease before the age of 50 demonstrates that this group of diseases adds substantially to the total burden of chronic diseases among childhood cancer survivors. The combination of cardiovascular diseases as a persistent and lifelong health problem and a rapidly growing population of childhood cancer survivors represent a distinct challenge for the general health care system. This calls for the development of a risk-based, targeted follow-up care that can promote early detection of adverse late effects and deliver appropriate interventions. In particular, modifiable cardiovascular risk factors need to be identified during follow-up to prevent further increase in risk of major cardiac events.
Acknowledgements The authors thank Andrea Bautz for valuable contribution to data management, Klaus Kaae Andersen for statistical advice, Dr Lasse Wegener Lund for discussions, Dr Hj€ ortur Oddsson, cardiologist at the University Hospital in Iceland, for his input on conduction disorders, and members of the ALiCCS board (Catherine Rechnitzer, Kirsi Jahnukainen and Lars Hjorth) for their valuable guidance and discussions.
Contributors ThG is the principal investigator and has significantly contributed to study design, collection and assembly of data, data analysis and interpretation. She has written all manuscript drafts, tables and figures and the final version of the manuscript. JHO, JFW, HH and HA contributed to the conception and design. JHO, JFW, LT, HA and FW contributed to collection and assembly of data. JHO, JFW, SDFL, TGB, PHA, FW, NM and HH contributed to data analysis and interpretation. All authors have contributed to the manuscript writing and approval of the final version. The corresponding author (ThG) is the study guarantor and had full access to all the data and final responsibility to submit for publication.
Competing Interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Epidemiology
Previous studies of cardiovascular late effects after childhood cancer have either been limited to specific types of cardiovascular disease and/or hampered by a small sample size. To our knowledge, this is the largest population-based study conducted so far, which gives a full picture of cardiovascular late effects in childhood cancer survivors. We used hospital-based diagnoses by physicians as markers of disease outcome. While this increased the validity of the diagnostic information,18 less severe cases of cardiovascular complications treated in the primary health care system were missed. As this limitation also applies to the comparison cohort, however, the validity of the risk estimates is acceptable, although they are restricted to complications that require hospital admission. To obtain the most appropriate date of diagnosis for cardiovascular disease, we began follow-up of childhood cancer survivors one year after the date of cancer diagnosis. However, cardiovascular outcomes that occurred 1–4 years after cancer diagnosis might to some extent have been attributable to reversible side-effects of prolonged treatment for cancer or relapse, and this difference should be taken into account in comparisons of our results with those of the CCSS and others.22 The virtual completeness of nationwide cancer registration in all the Nordic countries and the prospective nature of our study, with registration of malignant disease before and independent of registration of cardiovascular outcomes, reduce the risk for bias due to selection of study subjects or differential reporting of cardiovascular outcomes. The unique personal identifiers ensured both random selection of population comparison subjects and virtually complete long-term follow-up. Nevertheless, we cannot exclude the possibility that our results were influenced by closer medical surveillance of survivors than of population comparison subjects. Surveillance bias would preferentially affect less well-defined, less severe conditions, such as hypertension without complications or venous and lymphatic disease and might—in addition to changes in treatment over time—have contributed to the increasing agespecific cumulative risk observed during the study period. The various types of cardiovascular diagnoses are in their essence not uniformly defined and since we covered all types of cardiovascular diagnoses in this study, we included estimates not only for overall cardiovascular disease, but also for each main diagnostic category and for each specific subcategory/diagnosis. This implies that diagnostic criteria differ, also because they follow general clinical practice in hospitals in the Nordic countries exercised over a time window of more than 30 years. However, most of these cardiovascular diagnoses signify serious illness and validation studies conducted in some of the national hospital registries have shown high positive predictive value for the majority of diagnoses and a good sensitivity.17,18 The usefulness of the Nordic cancer registry files in research of late effects in childhood cancer survivors are limited by lacking information on treatment variables in the individual patient. To compensate for this problem, casecohort studies with collection of treatment data from the
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Ethical Approval Human subjects research approval was obtained in each country from the respective national bioethics committee, data protection agency or national institute for health and
welfare (Denmark: 2010-41-4334, Finland: THL/183/5.05.00/ 2012, Iceland: VSN 10-041; Norway: REC 2011/884 and € 10-2010, 2011/19). Sweden: O
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Gatta G, Zigon G, Capocaccia R, et al. Group Survival of european children and young adults with cancer diagnosed 1995-2002. Eur J Cancer 2009;45:992–1005. 2. Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009;101:806–13. 3. Sklar CA. Overview of the effects of cancer therapies: the nature, scale and breadth of the problem. Acta Paediatr Suppl 1999;88:1–4. 4. Robison LL, Armstrong GT, Boice JD, et al. The childhood cancer survivor study: a national cancer Institute-supported resource for outcome and intervention research. J Clin Oncol 2009;27:2308–18. 5. Moller TR, Garwicz S, Barlow L, et al. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol 2001; 19:3173–3181. 6. Garwicz S, Anderson H, Olsen JH, et al. Association of the nordic cancer R, nordic society for pediatric hematology O. Late and very late mortality in 5-year survivors of childhood cancer: changing pattern over four decades–experience from the nordic countries. Int J Cancer 2012;131: 1659–66. 7. Diller L, Chow EJ, Gurney JG, et al. Chronic disease in the childhood cancer survivor study cohort: a review of published findings. J Clin Oncol 2009;27:2339–55. 8. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355:1572–82. 9. Tukenova M, Guibout C, Oberlin O, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 2010;28:1308–15. 10. Reulen RC, Winter DL, Frobisher C, et al. British childhood cancer survivor study steering G. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 2010;304:172–9. 11. Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the childhood cancer survivor study. J Clin Oncol 2001;19:3163–72.
12. de Fine Licht S, Winther JF, Gudmundsdottir T, Holmqvist AS, Bonnesen TG, Asdahl PH, Tryggvadottir L, Anderson H, Wesenberg F, Malila N, Holm K, Hasle H, et al. Hospital contacts for endocrine disorders in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): a population-based cohort study. Lancet 2014;383: 1981–99. 13. Tulinius H, Storm HH, Pukkala E, et al. Cancer in the nordic countries, 1981-86. A joint publication of the five nordic cancer registries. APMIS Suppl 1992;31:1–194. 14. Steliarova-Foucher E, Stiller C, Lacour B, et al. International classification of childhood cancer, third edition. Cancer 2005;103:1457–67. 15. Sankila R, Olsen JH, Anderson H, et al. Risk of cancer among offspring of childhood-cancer survivors. Association of the Nordic cancer registries and the Nordic society of paediatric haematology and oncology. N Engl J Med 1998;338:1339–44. 16. Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health 2011;39:30–3. 17. Sund R. Quality of the finnish hospital discharge register: a systematic review. Scand J Public Health 2012;40:505–15. 18. Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the swedish national inpatient register. BMC Public Health 2011;11:450 19. Altmann AE, Halliday JL, Giles GG. Associations between congenital malformations and childhood cancer. A register-based case-control study. Br J Cancer 1998;78:1244–9. 20. Schweizer E. Ueber spezifische roentgenschaedigungen des herzmuskels. Strahlentherapie 1924; 18:812–28. 21. Chen MH, Colan SD, Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res 2011;108:619–28. 22. Dillenburg RF, Nathan P, Mertens L. Educational paper: decreasing the burden of cardiovascular disease in childhood cancer survivors: an update for the pediatrician. Eur J Pediatr 2013;172:1149–60. 23. de Ville de Goyet M, Moniotte S, Brichard B. Cardiotoxicity of childhood cancer treatment:
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update and current knowledge on long-term follow-up. Pediatr Hematol Oncol 2012;29: 395–414. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin’s disease: a report from the childhood cancer survivor study. J Clin Oncol 2005;23:6508–15. Bowers DC, Liu Y, Leisenring W, et al. Lateoccurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the childhood cancer survivor study. J Clin Oncol 2006;24:5277–82. Kurt BA, Nolan VG, Ness KK, et al. Hospitalization rates among survivors of childhood cancer in the childhood cancer survivor study cohort. Pediatr Blood Cancer 2012;59:126–32. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the childhood cancer survivor study cohort. BMJ 2009;339:b4606 Lorenzi MF, Xie L, Rogers PC, et al. Hospitalrelated morbidity among childhood cancer survivors in british columbia, Canada: report of the childhood, adolescent, young adult cancer survivors (CAYACS) program. Int J Cancer 2011;128: 1624–31. van der Pal HJ, van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 2012;30: 1429–37. van Laar M, Feltbower RG, Gale CP, et al. Cardiovascular sequelae in long-term survivors of young peoples’ cancer: a linked cohort study. Br J Cancer 2014;110:1338–41. Kero AE, Jarvela LS, Arola M, et al. Cardiovascular morbidity in long-term survivors of early onset cancer: a population-based study. Int J Cancer 2014;134:664–73. Olsen M, Schmidt M, Lash TL, et al. Cardiovascular disease risk in childhood cancer survivors. Am J Epidemiol 2014;180:120–3. Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013;31:3673–80.
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Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: A population-based cohort study of 32,308 one-year survivors Thorgerdur Gudmundsdottir1, Jeanette F. Winther1, Sofie de Fine Licht1, Trine G. Bonnesen2, Peter H. Asdahl2, Laufey Tryggvadottir3,4, Harald Anderson5, Finn Wesenberg6,7,8, Nea Malila9, Henrik Hasle2, and Jørgen H. Olsen1; on behalf of the ALiCCS study group 1
Danish Cancer Society Research Center, Copenhagen, Denmark Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark 3 The Icelandic Cancer Registry, Reykjavik, Iceland 4 Faculty of Medicine, Laeknagardur, University of Iceland, Reykjavik, Iceland 5 Department of Cancer Epidemiology, Lund University, Lund, Sweden 6 Department of Pediatrics, Oslo University Hospital, Nydalen, Oslo, Norway 7 Faculty of Medicine, University of Oslo, Blindern, Oslo, Norway 8 The Norwegian Cancer Registry, Majorstuen, Oslo, Norway 9 Finnish Cancer Registry, Helsinki, Finland
Epidemiology
2
The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population-based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one-year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0–2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person-years. At the end of follow-up 12% of the survivors were 50 years of age and 4.5% 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ~500–600 per 100,000 person-years at age 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5–5.9), valvular dysfunction (4.6; 3.8–5.5) and cerebrovascular diseases (3.7; 3.4– 4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow-up for this rapidly growing population.
Continued advances in childhood cancer treatment have led to impressive improvements in survival, with an overall five-year survival now reaching 80%.1 However, increased survival comes at a price, as long-term sequelae such as second cancers, increased mortality and diverse, not yet fully described chronic morbidities
seem to emerge as the survivors become older.2–6 Thus, in the North American Childhood Cancer Survivor Study (CCSS), an eightfold increased risk for a severe or life-threatening condition was found when compared with a sibling comparison group.7,8 Research on cause-specific late mortality indicates that cardiac
Key words: childhood cancer, late complications, cardiovascular disease, hospitalizations, clinical epidemiology Abbreviations: AER: absolute excess risk; ALiCCS: adult life after childhood cancer in Scandinavia; CCSS: childhood cancer survivor study; CI: confidence interval; CNS: central nervous system; CVD: cardiovascular disease; HD: Hodgkin disease; ICCC: international classification of childhood cancer; ICD: international classification of diseases; NHL: non-Hodgkin lymphoma; RR: standardized hospitalization rate ratio; STS: soft-tissue sarcoma Additional Supporting Information may be found in the online version of this article. Grant sponsor: The Danish Council for Strategic Research; Grant number: 09-066899 DOI: 10.1002/ijc.29468 History: Received 30 June 2014; Accepted 19 Jan 2015; Online 3 Feb 2015 Correspondence to: Thorgerdur Gudmundsdottir, MD, PhD fellow, Danish Cancer Society Research Center, Survivorship Unit, Strandboulevarden 49, DK-2100, Copenhagen, Denmark, Tel.: [4535257648], Fax: 1[45-3527-1811], E-mail: [email protected]
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disease is among the leading non-malignant causes of death in long-term survivors of childhood cancer.9–11 Large studies presenting a thorough description of the pattern of chronic disease, in all phases of life, are needed to alert awareness of this growing challenge, not least for primary care physicians and medical specialists working outside the late effect area. Large, population-based, longitudinal studies are required to provide a full overview of lifelong complications, supplemented by accurate estimates of absolute and relative risks by comparison with a population-based cohort. We therefore studied the risk of cardiovascular disorders by long-term follow-up of childhood cancer survivors in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) through nationwide cancer registries dating back to the 1940s and 1950s, with complete follow-up of the survivors in population registers and information about all types of cardiovascular outcomes from national hospital registers.
Material and Methods This study is “Adult Life (ALiCCS), an for childhood
part of an ongoing inter-Nordic cohort study after Childhood Cancer in Scandinavia” investigation of late complications of treatment cancer (www.aliccs.org).12
Patient and comparison cohorts
Through the five national cancer registries, we identified individuals in whom cancer was diagnosed before they were 20 years of age between the start of the cancer registries in the 1940s and 1950s and December 31, 2008. To be included in the study, patients had to be alive on or after the date on which centralized registration of residents of each country was operational with all the required variables (Iceland, 1955; Norway, 1960; Sweden, 1968; Denmark, 1968; and Finland, 1971), leaving a total of 43,909 patients for further follow-up (Supporting Information Appendix Table I). All five cancer registries are nationwide with close to 100% coverage.2,13 From the registries, we obtained information on type of cancer and date of diagnosis and assigned individuals to one of 12 main diagnostic groups of the International Classification Scheme for Childhood Cancer, with lymphomas stratified into Hodgkin and non-Hodgkin lymphoma.14 Since the start of centralized civil registration in the Nordic countries, all residents (25 million in 2008) have been assigned a unique personal identification number that allows accurate linkage C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
among registers and follow-up for vital status and migration.15 To measure rates of cardiovascular morbidity in the background population, we randomly selected 219,131 comparison subjects from the population registries of the five countries (Supporting Information Appendix Table I). For each childhood cancer patient, five comparison subjects were randomly selected, who were alive on the date of cancer diagnosis of the corresponding patient, of the same sex, age, country (Denmark and Iceland) or county of residence (Finland, Norway and Sweden) and without a cancer diagnosis in the age-range 0–19 years. Fewer than five comparisons were available for 317 patients. Before linkage of study subjects to the respective national hospital register (see below), we excluded those in whom more than one primary cancer was diagnosed in childhood as they could not be classified unambiguously (n 5 305); those who died or emigrated before the start of the national hospital register (Sweden, stepwise inclusion of counties in 1968–1987 and nationwide since 1987; Denmark, 1977; Iceland, 1999; Norway, 2008; Finland, 1982; 7,251 patients and 5,146 comparison subjects); and those who died, emigrated or were censored during the year after the date of childhood cancer diagnosis or an equivalent time lag for comparison subjects (3,193 patients and 1,093 comparison subjects). This resulted in a total of 33,160 one-year survivors of childhood cancer and 212,892 population comparison subjects (Supporting Information Appendix Figure I). Hospital admissions for cardiovascular disease
The national hospital registers contain information on virtually all non-psychiatric hospital admissions in the five Nordic countries.16–18 Registration is mandatory and recorded by the treating physician. Each admission initiates a record, which includes the personal identification number of the patient, dates of admission and discharge, a primary discharge diagnosis and a varying number of supplementary diagnoses coded according to the International Classification of Diseases, 7th to 10th revisions (ICD-7 to ICD-10). We identified all hospital admissions for a primary or supplementary discharge diagnosis of the relevant cardiovascular sections of the ICD (ICD-7 codes 330–334 and 420–468; ICD8 codes 400–445, 447–457; ICD-9 codes 401–445, 447–457; ICD-10 codes I10–I89 and G45) for all study subjects. Diagnostic categories of ICD-7, ICD-8 and ICD-9 were adapted to
Epidemiology
What’s new? The long-term effects of cancer treatment in childhood cancer survivors can be serious, and more research is needed to fully investigate the relationship between treatment and chronic disease in aging survivors. This retrospective population-based cohort study focused on cardiovascular late effects among childhood cancer survivors in the five Nordic countries. Survivors were found to be at significantly increased risk for cardiovascular disease throughout their lives. Relative risk was highest for heart failure, valvular dysfunction, and cerebrovascular diseases. Overall, survivors had a twofold increased lifetime risk for hospitalization for cardiovascular disease.
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Table 1. Observed and expected number of first hospital admission for cardiovascular disease of any type among 32,308 one-year survivors of childhood cancer in the Nordic countries by sex and attained age
Person-years at risk1 Both sexes
No. of first hospital admissions Observed
Expected
Hospitalization rate2 RR
95% CI
Observed
Expected
AER2
95% CI
428,302
2,632
1,243.7
2.1
2.0–2.2
614.5
290.4
324
300–348
Male
223,407
1,417
661.4
2.1
2.0–2.3
634.3
296.1
338
304–373
Female
204,895
1,215
582.3
2.1
2.0–2.2
593.0
284.2
309
274–343
Attained age (years) 1–9
43,687
185
9.9
18.7
14.2–24.7
423.5
22.6
401
340–462
10–19
105,408
382
75.4
5.1
4.5–5.8
362.4
71.5
291
254–328
20–29
126,514
491
190.1
2.6
2.3–2.9
388.1
150.3
238
203–273
30–39
81,068
509
272.0
1.9
1.7–2.1
627.9
335.5
292
236–349
40–49
44,513
524
299.9
1.8
1.6–1.9
1,177.2
673.7
503
399–608
50–59
20,352
354
249.5
1.4
1.3–1.6
1,739.4
1,225.7
514
324–704
60
6,761
187
147.0
1.3
1.1–1.5
2,765.7
2,174.1
592
169–1014
Epidemiology
Abbreviations: AER: absolute excess risk; CI: confidence interval; RR: standardized hospitalization rate ratio. 1 Survivors only. 2 Per 100,000 person-years.
the ICD-10 to the extent possible. Outpatient and emergency visits were not included in this study. Linkage to the hospital registers revealed that 373 survivors and 429 comparison subjects had been admitted for a cardiovascular disease before the date of diagnosis of childhood cancer or the corresponding date for the comparisons; consequently, these individuals were excluded from the study. Furthermore, we excluded people in whom a congenital malformation of the circulatory system had been diagnosed (ICD-10 codes Q20–Q28) (282 survivors and 768 comparison subjects) and those with a congenital chromosomal abnormality (ICD-10 codes Q90–Q99) (197 survivors and 206 comparison subjects), as we considered that these diagnoses might confound any causal association between cancer treatment and cardiovascular late effects.19 Thus, 32,308 one-year survivors and 211,489 population comparison subjects remained for the analyses (Supporting Information Appendix Table I and Appendix Fig. I). Of the 32,308 one-year survivors, 26,016 (80.5%) were under continuous follow-up within the national hospital registries for five years or more after their cancer diagnosis. Statistical analysis
Follow-up for cardiovascular disease in the national hospital registers started one year after the date of diagnosis of childhood cancer and the corresponding date for the equivalent comparisons or the start of the hospital registries, whichever occurred latest. Follow-up ended on the date of death, emigration or the closing date of the study, whichever occurred first. Follow-up also ended if a second primary cancer was diagnosed in a survivor or first primary cancer in a population comparison subject. If study subjects had more than one hospital admission for a cardiovascular disease, only the first record was retained, as it was presumed to correspond to the
date of diagnosis. Risk analyses were carried out for any cardiovascular disease, on a yes/no level for each study subject, for each of the 10 main diagnostic categories and for each of the 30 subcategories or diagnoses within the main categories (see Table 2). The observed numbers of first hospital admission for a given cardiovascular disease among childhood cancer survivors were compared with expected numbers derived from the appropriate country-, sex-, age- and calendar period-specific cardiovascular morbidity rates of the population comparison cohort. We did not adjust for variables such as hyperlipidaemia, diabetes, smoking or other aspects of survivors’ diseases or lifestyle since we view these factors as mediators, rather than confounders of the association between childhood cancer and cardiovascular disease. The significance and 95% confidence intervals (CIs) for the standardized hospitalization rate ratio (RR, the observed-toexpected hospital admissions for each defined disease entity) were estimated using Fieller’s theorem and assuming that the observed number of first hospital admissions followed a Poisson distribution. The absolute excess risk (AER), i.e., the additional risk for hospitalization for a cardiovascular disease, was derived as the difference between the observed and expected first hospitalization rates for cardiovascular disease per 100,000 person-years of follow-up, with corresponding 95% CIs. We used SAS version 9.2 for all analysis.
Results Cancer survivors (see Supporting Information Appendix Table II for descriptive characteristics) were followed in the national hospital registers for 428,302 person-years (median, 10 years; range, 0–42 years); 2,632 survivors (8.1%) had at least one hospital admission for a cardiovascular disease, while 1,244 would have been expected, yielding a significantly C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
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Table 2. Observed and expected numbers of first hospital admissions for cardiovascular disease among 32,308 one-year survivors of childhood cancer in the Nordic countries by 10 main diagnostic categories and 30 subcategories or diagnoses No. of first hospital admissions
Hypertension
ICD-101
Observed2
Expected2
RR
95% CI
AER3
95% CI
Distribution of AER (%)4 16.3% (77/471)
I10–I15
658
326.9
2.0
1.9–2.2
77
65–89
Essential hypertension
I10
566
313.5
1.8
1.7–2.0
59
48–70
Hypertension with complications
I11–I13
46
17.0
2.7
1.9–3.8
7
4–10
Ischemic heart disease Acute myocardial infarction Pulmonary heart disease Pulmonary embolism Peri-, myo- and endocardial disease Pericarditis
I20–I25
360
217.1
1.7
1.5–1.9
33
24–42
I21
149
107.1
1.4
1.2–1.7
10
4–16
I26–I28
138
39.1
3.5
2.9–4.3
23
18–29
I26
110
34.0
3.2
2.6–4.0
18
13–23
I30–I33, I38–I41, I51.4
156
54.8
2.9
2.4–3.4
24
18–29
I30–I32
107
28.5
3.8
3.0–4.7
18
14–23
Acute pericarditis
I30
68
24.0
2.8
2.2–3.8
10
6–14
Other and chronic pericardial disease
I31–I32
47
6.6
7.1
4.8–10.6
9
6–13
Myocarditis
I40–I41, I51.4
33
21.7
1.5
1.1–2.2
3
20.1–5
Endocarditis
I33, I38–I39
23
7.3
3.1
1.9–5.1
4
1.4–6
Valvular disease (nonrheumatic)
I34–I37
178
38.6
4.6
3.8–5.5
33
26–39
Aortic valve disorders
I35
128
25.3
5.1
4.1–6.3
24
19–29
Mitral valve disorders
I34
65
14.0
4.6
3.4–6.3
12
8–16
I42–I43, I50, I51.5, I51.7
357
68.8
5.2
4.5–5.9
67
59–76
Congestive heart failure
I50
247
55.5
4.5
3.8–5.2
45
37–52
Cardiomyopathy
I42–I43
197
20.0
9.9
8.0–12.1
41
35–48
Conduction disorder
Heart failure
I44–I49
386
234.8
1.6
1.5–1.8
35
26–45
Atrial fibrillation/flutter
I48
149
97.2
1.5
1.3–1.8
12
6–18
Supraventricular tachycardia (SVT)
I47.1
66
41.6
1.6
1.2–2.1
6
2–10
Cardiac arrest and/or ventricular fibrillation/flutter
I46, I49.0
45
17.5
2.6
1.8–3.6
6
3–10
Sick sinus or AV block
I49.5, I44.0–3
43
15.1
2.9
2.0–4.0
7
3–10
Ventricular tachycardia (VT)
I47.2
18
10.7
1.7
1.0–2.8
2
20.3–4
I60–I69, G45
586
158.8
3.7
3.4–4.1
100
88–111
Cerebrovascular disease Cerebral infarction
I63
216
61.6
3.5
3.0–4.1
36
29–43
Cerebral hemorrhage
I61–I62
181
22.0
8.2
6.7–10.1
37
31–43
Stroke, unspecified
I64
54
19.4
2.8
2.0–3.8
8
5–12
Transient ischaemic attack (TIA)
I66, G45
56
29.8
1.9
1.4–2.5
6
3–10
Subarachnoid hemorrhage (SAH)
I60
54
21.2
2.6
1.9–3.5
8
4–11
Occlusion or stenosis of a.carotis
I65.2
13
5.6
2.3
1.3–4.3
2
0.0–3
Occlusion or stenosis of other preor cerebral arteries
I65.0–1, I65.3–9, I66
13
2.9
4.6
2.3–9.0
2
0.7–4
I70–I79
176
66.0
2.7
2.3–3.2
27
19–32
Arterial disease Atherosclerosis
I70
69
27.3
2.5
1.9–3.3
10
6–14
Arterial embolisms and thrombosis
I74
34
7.7
4.4
2.9–6.8
6
3–9
Aneurysms (aortic and other)
I71–I72
23
15.8
1.5
1.0–2.3
2
20.6–4
Venous- and lymphatic disease
I80–I89
655
431.6
1.5
1.4–1.7
52
40–64
Varicose veins
I83–I86
336
328.0
1.0
0.9–1.2
2
27–11
Venous embolism, thrombosis or thrombophlebitis
I80–I82
267
84.8
3.2
2.7–3.6
43
35–50
7.0% (33/471)
4.9% (23/471)
5.1% (24/471)
7.0% (33/471)
14.2% (67/471)
7.4% (35/471)
21.2% (100/471)
Epidemiology
Cardiovascular disorders
5.7% (27/471)
11.0% (52/471)
Abbreviations: AER: absolute excess risk; AV: atrioventricular; CI: confidence interval; RR: standardized hospitalization rate ratio. 1 International classification of diseases, 10th version. 2 Hospital admissions across the main diagnostic categories for cardiovascular disease sum up to more than the total number of survivors with cardiovascular disease since 25% of survivors received diagnosis from more than one category of cardiovascular disease over time. 3 per 100,000 person-years. 4 per 10 main diagnostic categories.
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increased RR of 2.1 (Table 1). Overall, 77% of cardiovascular diagnoses in survivors and 86% in comparisons were notified as the primary discharge diagnosis, i.e., the main reason for the admission to hospital. Survivors were on average seven years younger than comparisons at the date of first hospital admission, with a median age of 35 years (range, 1–83 years) and 60% of hospitalizations occurred before the age of 40 years. On the basis of observed and expected overall hospitalization rates for cardiovascular disease of 615 and 291 per 100,000 person-years, respectively, the AER was 324 per 100,000 person-years. This implies that, for each additional year of follow-up, a new excess cardiovascular disease was diagnosed at a hospital in 3 of 1,000 childhood cancer survivors (Table 1). Although the RR was significantly increased in all groups of attained age, the increase diminished considerably with age, from an RR of 18.7 in the first decade of life to 1.3 among survivors aged 60 years (Table 1). The AER did not vary similarly with age and ranged between 200 and 600 new excess hospital admissions for cardiovascular disease per 100,000 person-years of observation, with the lowest value in survivors aged 20–29 years and the highest at age 60 years. We stratified the survivor cohort into those with cancer diagnosed in 1943–1959, 1960–1974, 1975–1989 and 1990– 2008 and calculated the cumulative risk for hospitalization for any cardiovascular disease by attained age (data not shown). The cumulative risk by the age of 40 years was 9.6% in the 1943–1959 subcohort (prechemotherapy era), 12.9% in the 1960–1974 subcohort (first-generation chemotherapy era), 16.2% in the 1975–1989 subcohort (early combination chemotherapy era) and 18.3% in the 1990–2008 subcohort (late combination chemotherapy era). For survivors with cancer diagnosed in 1975–1989, for whom we were able to establish a hospitalization history covering the survivors’ subsequent life, 26.9% had ever been admitted to hospital for cardiovascular disease at the age of 50 years. Stratified analyses to compare sub-cohorts according to age at diagnosis of childhood cancer (0–4, 5–9, 10–14 and 15–19 years) revealed no significant variation in cumulative risk for overall cardiovascular disease by attained age. Childhood cancer survivors were at significantly increased risk of hospital admission for cardiovascular diseases of all the 10 main diagnostic categories (Table 2). The highest relative risks were seen for heart failure (RR, 5.2; males 3.9 [95% CI, 3.2–4.6]; females 8.3 [6.7–10.3]), valvular disease (4.6; 4.4 [3.5–5.6]; 5.0 [3.7–6.7]), cerebrovascular disease (3.7; 3.9 [3.4–4.4]; 3.4 [2.9–4.0]) and pulmonary heart disease (3.5; 4.0 [3.0–5.4]; 3.2 [2.4–4.2]). The significant difference in RR for heart failure between male and female survivors was due partly to lower background hospitalization rates among females. The AER for female survivors was not significantly higher than that for males (61 [49–73]; females 74 [62–87]; not shown in table). In the subset of 30 cardiovascular diagnoses, the highest relative risks were seen for cardiomyopathy (RR, 9.9), cerebrovascular hemorrhage (8.2), other and
CVD in Nordic childhood cancer survivors
chronic pericardial diseases (7.1), aortic- and mitral valve dysfunction (5.1 and 4.6, respectively) and congestive heart failure (4.5). Table 2 also shows that cerebrovascular disease had the highest AER of 100 per 100,000 person-years, followed by hypertension (77), heart failure (67) and venous and lymphatic disease (52). These four outcomes together constituted almost two thirds of all excess cardiovascular diseases. Figure 1 shows the observed and expected rates of hospitalization for selected cardiovascular diagnoses by survivors’ attained age. While there was an excess risk of cerebral hemorrhage in all age groups, cerebral infarction and transient ischemic attack were observed in more excess after the age of 30. Although the RR and the AER for heart failure were strongly increased in the age range 1–29 years, this disease is also a prominent complication of cancer treatment that appears later in life. In contrast, the majority of hospital admissions for valvular disease occurred before the age of 50 years, with no further increase in risk thereafter. Survivors of all main diagnostic groups of childhood cancer and the two subgroups of lymphoma had increased RRs for a hospital discharge diagnosis of cardiovascular disease, all significantly elevated except for survivors of retinoblastoma (Table 3 and Supporting Information Appendix Figure II). In analyses of the relative risks for a selected set of combinations of childhood cancer and cardiovascular disease for which the lower 95% confidence limit of the RR was 2, particularly high relative risks were seen for heart failure after hepatic tumors (RR, 58.0), leukemia (20.8), renal tumors (15.1), sympathetic nervous system neoplasms (16.2), Hodgkin and nonHodgkin lymphoma (12.1 and 9.1, respectively) and bone tumors (7.1). Very high risks were also seen for valvular disease after Hodgkin lymphoma (34.3) and for cerebral hemorrhage after central nervous system neoplasms (17.7).
Discussion In this population-based follow-up study of 32,308 one-year survivors of childhood cancer in the five Nordic countries, survivors had an overall twofold increased lifetime risk for hospital admission for cardiovascular disease. The RR varied considerably by age, from 19 in early life to 1.3 for survivors 60 years. This reduction in relative risk by age was mainly a consequence of an age-dependent increase in cardiovascular disease in the general population rather than a modification of the damaging effects associated with childhood cancer treatment. Thus the AER, attributable to status as a childhood cancer survivor, remained at 3–6 excess cardiovascular diseases per 1,000 person-years throughout life. For survivors diagnosed with cancer in 1975–1989, the cumulative risk for a hospitalization for cardiovascular disease was 26.9% at the age of 50 years. One-year survivors of leukemia, Hodgkin lymphoma, sympathetic nervous system neoplasms, and hepatic tumors had the highest overall risks. Particularly, high risks were seen in survivors of leukemia and lymphoma for heart failure, in survivors of Hodgkin lymphoma for C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
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Figure 1. Age-specific observed and expected hospitalization rates for a selected set of cardiovascular diseases among 32,308 one-year survivors of childhood cancer in the Nordic countries, to illustrate the different disease-pattern by age (note that three different scales are used).
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CVD in Nordic childhood cancer survivors
Table 3. Standardized hospitalization rate ratios (RR) for any and for selected1 diagnostic categories of cardiovascular disease by main diagnostic group of childhood cancer ICCC group
Childhood cancer2/Cardiovascular disease3
I
Leukemia (n 5 6,796) Any cardiovascular disease
IIa
328
3.5
3.1–3.9
20.8
15.5–28.1
Cerebrovascular disease
72
8.6
6.7–11.1
Hypertension
66
4.4
3.4–5.6
Pulmonary heart disease
14
4.4
2.5–7.6
Peri-, myo- and endocardial disease
26
3.6
2.4–5.4
Valvular disease
8
2.7
1.3–5.4
Hodgkin lymphoma (n 5 2,388) 333
3.2
2.9–3.6
Valvular disease
104
34.3
27.5–42.8
Heart failure
65
12.1
9.4–15.7
Peri-, myo- and endocardial disease
42
8.4
6.1–11.5
Ischemic heart disease
104
5.9
4.9–7.2
Pulmonary heart disease
17
5.5
3.4–8.9
Conduction disorders
72
3.7
3.0–4.7
Cerebrovascular disease
39
3.2
2.3–4.4
Venous and lymphatic disease
78
2.2
1.7–2.7
Non-Hodgkin lymphoma (n 5 1,750) 146
2.0
1.7–2.4
41
9.1
6.6–12.5
672
2.2
2.0–2.4
Cerebrovascular disease
282
7.0
6.2–8.0
Hemorrhage
99
17.7
13.9–22.7
Infarction
110
7.0
5.7–8.6
Heart failure Central nervous system neoplasm (n 5 7,723)
Epidemiology
Any cardiovascular disease
IV
Sympathetic nervous system neoplasm (n 5 1,281) Any cardiovascular disease
80
3.4
2.7–4.2
Heart failure
14
16.2
9.4–27.9
Pulmonary heart disease
9
11.8
6.0–23.1
Cerebrovascular disease
19
8.1
5.1–12.7
Hypertension
20
4.1
2.6–6.4
46
1.2
0.9–1.7
V
Retinoblastoma (n 5 819)
VI
Renal tumor (n 5 1,376)
Any cardiovascular disease
Any cardiovascular disease
VII
95% CI
62
Any cardiovascular disease
III
RR
Heart failure
Any cardiovascular disease
IIb
No. of first hospital admissions
108
2.8
2.3–3.4
Heart failure
24
15.1
9.9–22.9
Arterial disease
10
5.9
3.1–11.0
Hypertension
37
4.6
3.3–6.3
13
5.1
2.9–8.7
Hepatic tumor (n 5 231) Any cardiovascular disease Heart failure
4
58.0
21.4–157
Arterial disease
2
17.7
4.4–71.4
Venous and lymphatic disease
7
7.1
3.4–15.0
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Table 3. Standardized hospitalization rate ratios (RR) for any and for selected1 diagnostic categories of cardiovascular disease by main diagnostic group of childhood cancer (Continued) ICCC group
Childhood cancer2/Cardiovascular disease3
VIII
Malignant bone tumor (n 5 1,519) Any cardiovascular disease Heart failure
IX
No. of first hospital admissions
RR
95% CI
154
2.1
1.8–2.4
33
7.1
5.0–10.0
173
1.6
1.4–1.9
26
3.5
2.4–5.2
178
1.8
1.5–2.0
344
1.3
1.2–1.5
45
2.2
1.6–2.9
Soft-tissue sarcoma (n 5 1,972) Any cardiovascular disease Heart failure
X
Germ-cell and gonadal neoplasm (n 5 2,100)
XI
Malignant epithelial neoplasm (n 5 3,648)
XII
Other and unspecified neoplasm (n 5 461)
Any cardiovascular disease
Any cardiovascular disease
Any cardiovascular disease
valvular disease and in survivors of central nervous system neoplasms for cerebral hemorrhage. Cardiac disease associated with radiation was described as early as 1924.20 Subsequent clinical studies of patients with a variety of early onset cancers showed long-term adverse cardiovascular effects, including left ventricular dysfunction (resulting in congestive heart failure), ischemic heart disease and valvular and pericardial disease, mainly ascribed to the cardiotoxic effects of chemotherapeutic agents (especially anthracyclines) and radiotherapy.21,22 In general, these reports were based on relatively small, uncontrolled series of survivors, which obviated accurate calculation of risk estimates.23 More recently, the risks for a selected set of cardiovascular diseases and for hospitalization for cardiovascular disease of any type were investigated in the CCSS cohort of about 14,000 five-year survivors treated at 26 institutions in the USA and Canada during 1970–1986 and 4,000 sibling comparisons.4 Despite major methodological differences between our study (use of outcome data from hospital discharge records and of a population-based comparison cohort) and the CCSS (use of outcome data from patient questionnaires and of a comparison sibling cohort), where some 30% of survivors were lost to follow-up or did not respond to the first questionnaire in the CCSS,8 the increases in many of the outcomes were of the same order of magnitude. Table 4 shows the risk estimates for equivalent diagnoses or groups of diagnoses for the two cohorts. In the analyses of CCSS data by Oeffinger et al., Bowers et al. and Kurt et al.,8,24–26 the risk estimates for cardiovascular disease were in general compatible with ours (Table 4). Notable differences were seen, however, when we compared our results with the estimates obtained by Mulrooney et al. in their analysis of CCSS C 2015 UICC Int. J. Cancer: 137, 1176–1186 (2015) V
data, not least with regard to heart failure (14.1 in ALiCCS and 5.9 in CCSS) and valvular dysfunction (11.6 in ALiCCS and 4.8 in CCSS).27 In a population-based study from British Columbia, Canada, with 1,374 five-year survivors diagnosed in 1981–1995 or a somewhat younger cohort than ours, the authors reported a RR of 4.9 (2.9–8.4) for hospital-related diseases of the circulatory system,28 which is comparable with our overall estimate of 2.9 (2.7–3.0) for survivors under follow-up in the age-range 1–39 years. In a study from the Netherlands of 1,362 five-year survivors of childhood cancer, who were followed for symptomatic cardiac events (congestive heart failure, cardiac ischemia, valvular disease, arrhythmia and/or pericarditis), the authors reported a cumulative risk of 7.2% 40 years from cancer diagnosis.29 This estimate is to be compared with a cumulative risk of 10.4% at age 50 for the same outcomes seen in our Nordic study. In a recently published record linkage study from the UK of 1,367 five-year survivors of childhood cancer, the authors reported a 7.5% cumulative risk of cardiovascular late effects at 20 years from diagnosis.30 This estimate is to be compared with a cumulative risk of 11.1% in our study. Recently, two smaller studies of five-year survivors of childhood cancer from Finland (n 5 4,459) and Denmark (n 5 2,243), respectively, reported risk estimates for common cardiac diseases similar in magnitude to ours; however, in either study the patient material was to a large extent a subset of that included in this study.31,32 Moreover, Armstrong et al. have reported a potentiation of the effect of modifiable cardiovascular risk factors on the risk of major cardiac events among survivors and therefore further emphasize the need for studies on cardiovascular late-effects among childhood cancer survivors.33
Epidemiology
Abbreviations: ICCC: international classification of childhood cancer; RR: standardized hospitalization rate ratio; CI: confidence Interval. 1 Distinguished by a lower 95% confidence limit of 2. 2 According to the International Classification of Childhood Cancer (ICCC).14 3 According to International classification of diseases (ICD).
1.7 (1.1–2.7) 1.4 (0.8–2.2)
Bone tumor
STS
2.0 (0.6–6.3)
8.6 (6.6–11.2) 11.0 (6.7–18.2) 4.4 (2.2–9.0) 15.2 (11.1–20.8)
All cancers
Leukemia
HD
CNS tumors
49.2 (27.7–87.5)
HD
3.0 (1.2–7.3) 11.6 (6.6–20.2)
CNS tumors
All cancers
16.2 (8.7–30.4)
HD
4.5 (2.7–7.3)
CNS tumors
All cancers
9.8 (5.1–18.6)
HD
STS 3.5 (2.0–6.2)
12.3 (5.0–30.5)
Renal tumors
All cancers
29.0 (11.2–74.8)
Neuroblastoma
1.8 (1.3–2.6)
2.7 (2.0–3.5)
1.4 (0.9–2.0)
1.3 (0.7–2.0)
2.7 (2.1–3.4)
2.5 (1.8–3.4)
6.6 (5.6–7.6)
1.5 (1.3–1.8)
–
RR2 (95% CI)
29.0 (13.8–60.7)
4.3 (2.0–9.3)
6.4 (3.0–13.8)
9.3 (4.1–21.2)
10.4 (4.1–25.9)
15.1 (4.8–47.9)
HR3 (95% CI)
10.5 (6.1–17.9)
4.8 (3.0–7.6)
2.9 (1.2–6.8)
10.4 (5.4–19.9)
6.3 (2.2–11.9)
6.1 (2.3–16.2)
12.2 (5.2–28.2)
5.0 (2.3–10.4)
4.6 (2.4–8.8)
4.9 (2.4–10.0)
4.1 (1.7–9.7)
5.1 (2.6–10.0)
6.8 (3.9–11.7)
4.2 (2.3–7.4)
5.9 (3.4–9.6)
HR4 (95% CI)
CCSS Author
Bowers et al. 2006
Bowers et al. 2005
Bowers et al. 2006
Oeffinger et al. 2006
Mulrooney et al. 2009
Mulrooney et al. 2009
Mulrooney et al. 2009
Oeffinger et al. 20063/ Mulrooney et al. 20094
Mulrooney et al. 2009
Oeffinger et al. 20063/ Mulrooney et al. 20094
Kurt et al. 2012
Kurt et al. 2012
Abbreviations: CCSS: childhood cancer survivor study; CI: confidence interval; CNS: central nervous system; HD: Hodgkin disease; HR: hazard ratio; NHL: non-Hodgkin lymphoma; RR: standardized hospitalization rate ratio; STS: soft-tissue sarcoma. 1 The ALiCCS cohort restricted to the same inclusion criteria as in the CCSS: 5-year survivors diagnosed with cancer in 1970–1986 and followed throughout year 2002. All cancers, as those cancer types included in the CCSS: leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, neuroblastoma, soft-tissue sarcoma and bone cancer. 2 Using annual U.S. population hospitalization rates and adjusted for calendar year only.26 3 HR, adjusting for age, sex and race. Accounting for within-family correlations with the use of sandwich standard-error estimates.8,24,25 4 HR, with adjustments for gender, race, household income, education and tobacco use. Potential within family correlation accounted for by the use of sandwich variance estimates. Multiple imputation methodology used for event-time relations when age at cardiac event was not reported.27
Cerebrovascular disease
Valvular dysfunction
Pericardial disease
Myocardial infarction
22.9 (11.5–45.8) 54.2 (20.7–141.8)
NHL
18.8 (10.5–33.7)
3.0 (1.9–4.8)
Renal tumors
28.4 (15.6–51.4)
5.9 (3.8–9.1)
Neuroblastoma
HD
2.8 (2.3–3.3)
CNS tumors
Leukemia
2.0 (1.3–3.2)
NHL
14.1 (9.7–20.4)
4.1 (3.3–5.0)
HD
All cancers
3.0 (2.3–3.9)
Leukemia
Heart failure
2.8 (2.5–3.2)
All cancers
Hospitalization for any cardiovascular disease
RR (95% CI)
Cancer
Outcome
ALiCCS1
Table 4. Relative risk estimates for compatible cardiovascular outcomes observed in this Nordic study (ALiCCS) in a restricted 5-year survivor cohort1 and in the North American CCSS
Epidemiology
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medical records of cancer survivors need to be organized. Such studies, designed to quantify the damaging effects of the various components of the childhood cancer treatment in regard to a selected set of cardiovascular outcomes, are ongoing within the Nordic childhood cancer cohort. This long-term follow-up study of one-year survivors of childhood cancer from northern Europe underscores the importance of following childhood cancer survivors regularly throughout life as it reveals a persistent excess risk for a broad range of cardiovascular diseases requiring hospital admission, the composition of which, however, changes with increasing age. An aggregated risk of nearly 30% for being admitted to a hospital for a cardiovascular disease before the age of 50 demonstrates that this group of diseases adds substantially to the total burden of chronic diseases among childhood cancer survivors. The combination of cardiovascular diseases as a persistent and lifelong health problem and a rapidly growing population of childhood cancer survivors represent a distinct challenge for the general health care system. This calls for the development of a risk-based, targeted follow-up care that can promote early detection of adverse late effects and deliver appropriate interventions. In particular, modifiable cardiovascular risk factors need to be identified during follow-up to prevent further increase in risk of major cardiac events.
Acknowledgements The authors thank Andrea Bautz for valuable contribution to data management, Klaus Kaae Andersen for statistical advice, Dr Lasse Wegener Lund for discussions, Dr Hj€ ortur Oddsson, cardiologist at the University Hospital in Iceland, for his input on conduction disorders, and members of the ALiCCS board (Catherine Rechnitzer, Kirsi Jahnukainen and Lars Hjorth) for their valuable guidance and discussions.
Contributors ThG is the principal investigator and has significantly contributed to study design, collection and assembly of data, data analysis and interpretation. She has written all manuscript drafts, tables and figures and the final version of the manuscript. JHO, JFW, HH and HA contributed to the conception and design. JHO, JFW, LT, HA and FW contributed to collection and assembly of data. JHO, JFW, SDFL, TGB, PHA, FW, NM and HH contributed to data analysis and interpretation. All authors have contributed to the manuscript writing and approval of the final version. The corresponding author (ThG) is the study guarantor and had full access to all the data and final responsibility to submit for publication.
Competing Interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Epidemiology
Previous studies of cardiovascular late effects after childhood cancer have either been limited to specific types of cardiovascular disease and/or hampered by a small sample size. To our knowledge, this is the largest population-based study conducted so far, which gives a full picture of cardiovascular late effects in childhood cancer survivors. We used hospital-based diagnoses by physicians as markers of disease outcome. While this increased the validity of the diagnostic information,18 less severe cases of cardiovascular complications treated in the primary health care system were missed. As this limitation also applies to the comparison cohort, however, the validity of the risk estimates is acceptable, although they are restricted to complications that require hospital admission. To obtain the most appropriate date of diagnosis for cardiovascular disease, we began follow-up of childhood cancer survivors one year after the date of cancer diagnosis. However, cardiovascular outcomes that occurred 1–4 years after cancer diagnosis might to some extent have been attributable to reversible side-effects of prolonged treatment for cancer or relapse, and this difference should be taken into account in comparisons of our results with those of the CCSS and others.22 The virtual completeness of nationwide cancer registration in all the Nordic countries and the prospective nature of our study, with registration of malignant disease before and independent of registration of cardiovascular outcomes, reduce the risk for bias due to selection of study subjects or differential reporting of cardiovascular outcomes. The unique personal identifiers ensured both random selection of population comparison subjects and virtually complete long-term follow-up. Nevertheless, we cannot exclude the possibility that our results were influenced by closer medical surveillance of survivors than of population comparison subjects. Surveillance bias would preferentially affect less well-defined, less severe conditions, such as hypertension without complications or venous and lymphatic disease and might—in addition to changes in treatment over time—have contributed to the increasing agespecific cumulative risk observed during the study period. The various types of cardiovascular diagnoses are in their essence not uniformly defined and since we covered all types of cardiovascular diagnoses in this study, we included estimates not only for overall cardiovascular disease, but also for each main diagnostic category and for each specific subcategory/diagnosis. This implies that diagnostic criteria differ, also because they follow general clinical practice in hospitals in the Nordic countries exercised over a time window of more than 30 years. However, most of these cardiovascular diagnoses signify serious illness and validation studies conducted in some of the national hospital registries have shown high positive predictive value for the majority of diagnoses and a good sensitivity.17,18 The usefulness of the Nordic cancer registry files in research of late effects in childhood cancer survivors are limited by lacking information on treatment variables in the individual patient. To compensate for this problem, casecohort studies with collection of treatment data from the
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Ethical Approval Human subjects research approval was obtained in each country from the respective national bioethics committee, data protection agency or national institute for health and
welfare (Denmark: 2010-41-4334, Finland: THL/183/5.05.00/ 2012, Iceland: VSN 10-041; Norway: REC 2011/884 and € 10-2010, 2011/19). Sweden: O
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