- Email: [email protected]
Risk of haemorrhagic and ischaemic stroke in patients with cancer: A nationwide follow-up study from Sweden
European Journal of Cancer (2012) 48, 1875– 1883
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Risk of haemorrhagic and ischaemic stroke in patients with cancer: A nationwide follow-up study from Sweden Bengt Zo¨ller a,⇑, Jianguang Ji a, Jan Sundquist a,b, Kristina Sundquist a a
Center for Primary Health Care Research, Lund University/Region Ska˚ne, Clinical Research Centre, Floor 11, Building 28, Entrance 72, Ska˚ne University Hospital, 205 02 Malmo¨, Sweden b Stanford Prevention Research Centre, Stanford University School of Medicine, Medical School Office Building, 251 Campus Drive, Mail Code 5411, Stanford, CA 94305-5411, USA Available online 30 January 2012
KEYWORDS Cancer Ischaemic stroke Haemorrhagic stroke Epidemiology Risk factors
Background: Stroke is common in cancer patients, but risk estimates for different cancer sites/types have not been determined. The aim of this nationwide study was to examine whether there is an association between cancer and first hospitalisation for haemorrhagic or ischaemic stroke. Methods: All 820,491 individuals in Sweden with a diagnosis of cancer between 1st January 1987 and 31st December 2008 were followed for first hospitalisation for haemorrhagic or ischaemic stroke. The reference population was the total population of Sweden without cancer. Standardised incidence ratios (SIRs) for haemorrhagic and ischaemic strokes were calculated. Results: Overall risk of haemorrhagic stroke and ischaemic stroke during the first 6 months after diagnosis of cancer was 2.2 (95% confidence interval (CI) = 2.0–2.3) and 1.6 (CI = 1.5– 1.6), respectively. For 18 and 20 of the 34 cancers studied, respectively, risk of haemorrhagic and ischaemic strokes was increased. Overall stroke risk decreased rapidly, but remained elevated, even 10+ years after diagnosis of cancer 1.2 (CI = 1.1–1.3) for haemorrhagic stroke and 1.1 (CI = 1.1–1.2) for ischaemic stroke. The risk of stroke was highest during the first 6 months after diagnosis of cancer of the nervous system (29 (CI = 25–34) for haemorrhagic stroke and 4.1 (CI = 3.4–4.8) for ischaemic stroke)) or leukaemia (13 (CI = 10–16) for haemorrhagic stroke and 3.0 (CI = 2.5–3.7) for ischaemic stroke)). Metastasis was associated with an increased risk of haemorrhagic stroke 2.2 (CI = 1.8–2.7) and ischaemic stroke 1.5 (CI = 1.3–1.7). Interpretation: Several cancer sites/types are associated with an increased risk of haemorrhagic and ischaemic strokes. Ó 2012 Elsevier Ltd. All rights reserved. Abstract
⇑ Corresponding author: Mobile: +46 70 6691476; fax: +46 40 391370.
E-mail address: [email protected] (B. Zo¨ller). 0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2012.01.005
1876
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
1. Introduction Haemorrhagic and ischaemic strokes are major causes of morbidity and mortality worldwide.1 In an autopsy study from 1985, 14.6% of cancer patients suffered from ischaemic stroke.2 However, the clinical significance of these findings is not clear, as the study included silent infarcts and diffuse vascular encephalopathies.2 Cancer is also overrepresented in stroke patients.3 Notably, a more than 10-fold increase in the risk of brain tumours within the first year after diagnosis of stroke was reported in a previous study.3 However, diagnostic misinterpretation of a brain tumour as a stroke may have been possible with the study design use.3 Minor increases in the risk of cancer at other sites were also found in the first year of follow-up.3 In a retrospective study of 96 patients with confirmed stroke, lung cancer was the most common primary tumour (30%), followed by brain malignancy and prostate cancer (9% each).4 Cerebral haemorrhage has been reported frequently in cancer patients, especially those with haematological malignancies. In patients with leukaemia and lymphoma, 72% and 36% of strokes, respectively, were haemorrhagic.5 A number of cancer-related causes of stroke have been suggested,2,6,7 including treatment-related sideeffects, direct tumour compressing or invasion of blood vessels, tumour-induced haemostatic activation8 or an alteration in blood viscosity, and non-bacterial thrombotic endocarditis.2,6,7 Tumour cells produce various cytokines and chemokines that attract leucocytes, which may trigger an inflammatory response.9 This may in turn have prothrombotic and atherosclerotic effects.10,11 However, there is no consensus as to whether cancer is an independent risk factor for stroke like traditional risk factors such as hypertension and smoking. It has been proposed that conventional stroke etiologies account for the majority of cerebral ischaemic events in the adult cancer population.12,13 Moreover, cancer and ischaemic stroke share a common risk factor (tobacco smoke), and an increased risk of ischaemic stroke would be expected among patients with smoking-related cancers (i.e. cancers of the lung, larynx, oesophagus, mouth and tongue, pharynx, urinary bladder, pancreas and kidney).14–17 Other suspected smoking-related cancers sites include lip, liver, cervix, stomach and salivary gland; leukaemia is also suspected to be cancer-related Thus, cancer and ischaemic stroke share a number of risk factors, and an increased risk of ischaemic stroke among cancer patients might be expected. We hypothesised that cancer may affect risk of haemorrhagic and ischaemic strokes. In a nationwide followup study of data from 1987 to 2008, we estimated risk of hospitalisation for haemorrhagic and ischaemic strokes in patients with different cancers. An important novel contribution of the study is the use of nationwide
validated registers such as the Swedish Cancer Registry and the Hospital Discharge Register, thereby eliminating the risk of selection and recall bias. 2. Methods 2.1. MigMed 2 Database This study was approved by the Ethics Committee of Lund University, Sweden. Data used in this study were retrieved from the MigMed 2 Database (an updated version of the original MigMed database), maintained at the Center for Primary Health Care Research, Lund University/Region Ska˚ne, Malmo¨. MigMed 2 contains data on all individuals registered as residents of Sweden. It contains individual-level information on age, sex, occupation, geographic region of residence, hospital diagnoses and dates of hospital admissions in Sweden, as well as country of birth, parents’ country of birth, date of emigration and date and cause of death. The database was constructed using several national Swedish data registers (reviewed by Rosen and Hakulinen),18 including, but not limited to, the Swedish Cancer Registry,19 the Swedish National Population and Housing Census, the Total Population Register, the Multi-Generation Register20 and the Swedish Hospital Discharge Register.21 Information retrieved from the various registers in the MigMed 2 Database is linked, at the individual level, via the 10-digit personal identification number assigned to each resident of Sweden for his or her lifetime. Registration numbers were replaced by serial numbers to preserve anonymity. As well as being used to track all records in the database at the individual level, these serial numbers were used to check that individuals with hospital diagnoses of haemorrhagic and ischaemic strokes appeared only once in the dataset (for the first hospital diagnosis of haemorrhagic or ischaemic stroke during the study period). The follow-up period for analysis of data in the present study started on 1st January 1987 and continued until hospitalisation for haemorrhagic or ischaemic stroke, death, emigration or the end of the study period (31st December 2008). Data for first hospitalisation for haemorrhagic and ischaemic strokes during the study period were retrieved from the Hospital Discharge Register (1987–2008). This register does not include data for hospital outpatients or patients treated at primary health care centres. 2.2. Predictor variable The predictor variable was diagnosis of cancer in the Swedish Cancer Registry. Cancer site/type was identified according to the 7th revision of the International
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Classification of Diseases (ICD-7).22 The Swedish Cancer Registry records all new cases of cancer. Close to 100% of all cases nationwide have been histologically or cytologically confirmed.19 Information on metastasis has been included in the Swedish Cancer Registry since 2002.
1877
(1) chronic obstructive pulmonary disease (COPD) (490–496 (ICD-9) and J40–J49 (ICD-10)); (2) obesity (278A (ICD-9) and E65–E68 (ICD-10)); (3) alcoholism (291 and 303 (ICD-9) and F10 (ICD-10)); (4) diabetes mellitus (250 (ICD-9) and E10–E14 (ICD-10)) and (5) hypertension (401–405 (ICD-9) and I10-I15 (ICD-10)).
2.3. Outcome variables 2.5. Statistical analysis Diagnoses of haemorrhagic and ischaemic strokes were based on the 9th and 10th revisions of the International Classification of Diseases (ICD-9 and ICD-10). Cases of ischaemic stroke were identified using the following ICD codes: 433, 434, 435, 437.0, and 437.1 (ICD-9) and I63 (not I636), I65, I66, I67.2 and I67.8 (ICD-10). Cases of haemorrhagic stroke were identified using the following ICD codes: 431 and 432 (ICD-9) and I61 and I62 (ICD-10). 2.4. Individual-level variables The individual-level variables were sex, age, time period, geographic region of residence, socioeconomic status (SES) and comorbidity. Sex: male or female. Age was divided into 5-year categories. Subjects of all ages were included in the study. Time period was divided into five categories: 1987– 1990, 1991–1994, 1995–1999, 2000–2004 and 2005–2008. Geographic region of residence was included as an individual-level variable to allow adjustment for possible differences in hospital admissions for haemorrhagic and ischaemic strokes between different geographic regions in Sweden. It was categorised as (1) large city (city with a population of >200,000 (i.e. Stockholm, Gothenburg or Malmo)); (2) Southern Sweden (rural and urban); (3) Northern Sweden (rural and urban); or (4) unknown (if geographic region of residence could not be determined). Note: the three ‘large cities’ all lie in Southern Sweden, but were excluded from the Southern Sweden category. Occupation was used as a proxy for socioeconomic status (SES). Occupational data were retrieved from national census records in the MigMed 2 Database. We classified each individual’s occupation into one of six categories: (1) blue-collar worker, (2) whitecollar worker, (3) professional, (4) self-employed, (5) farmer and (6) non-employed (individuals without paid employment). Students without an occupation were categorised on the basis of their father’s or mother’s occupation. If that was not possible, they were included in the ‘non-employed’ category. For individuals aged <20 years, parental occupation was used. Comorbidity was defined as first hospital diagnosis at follow-up (1987–2008) for the following conditions:
Person-years of risk (i.e. number of persons at risk multiplied by time at risk) were calculated from the time at which subjects were included in the study (1987 or later) until first hospitalisation for haemorrhagic or ischaemic stroke, death and emigration or the end of the study period. The expected number of cases was based on the number of cases in the reference group. Standardised incidence ratios (SIRs) were calculated as the ratio of observed (O) and expected (E) number of haemorrhagic or ischaemic stroke cases using the indirect standardisation method.23 Expected numbers were calculated for anyone without cancer, that is, for the whole Swedish population without cancer. The expected numbers were calculated as age (5-year groups), sex, period (5-year groups), region and socioeconomic status (=SES)-specific standard incidence rates. An additional adjustment was made for hospitalisation for comorbidities: (1) chronic obstructive pulmonary disease (COPD); (2) obesity; (3) alcoholism; (4) diabetes mellitus and (5) hypertension. Ninety-five percent confidence intervals (95% CI) were calculated assuming a Poisson distribution,23 All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA). 3. Results Totally 820,491 cancer cases were identified between 1987 and 2008, 51.9% males (n = 425899) and 48.1% females (n = 394.592).22 The four most common cancers among males were prostate cancer (n = 139,510), lung cancer (n = 36,424), urinary bladder (n = 29,705) and colon cancer (29,633).22 The four most common cancers among females were breast cancer (115,705), colon cancer (32,169), endometrium cancer (n = 23,479) and lung cancer (23,220).22 Table 1 shows the basic characteristics of patients with and without cancer who were hospitalised with haemorrhagic or ischaemic stroke during the study period. A total of 77,031 and 396,702 individuals without cancer were hospitalised with a main diagnosis of haemorrhagic and ischaemic strokes, respectively (Table 1), while 6926 and 31,524 individuals with cancer were subsequently hospitalised for haemorrhagic and ischaemic strokes (Table 1), respectively.
1878
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Table 1 Basic characteristics of the stroke patients. Parameter
Ischaemic stroke With cancer
Haemorrhagic stroke Without cancer
With cancer
Without cancer
Number
%
Number
%
Number
%
Number
%
<60 60–69 70–79 P80
1106 3658 11,002 15,758
3.5 11.6 34.9 50.0
37,836 66,302 136,376 156,188
9.5 16.7 34.4 39.4
530 1000 2373 3023
7.7 14.4 34.3 43.6
12,544 13,969 25,147 25,371
16.3 18.1 32.6 32.9
Male Female
17,671 13,853
56.1 43.9
200,144 196,558
50.5 49.5
4282 2644
61.8 38.2
42,586 34,445
55.3 44.7
1987–1989 1990–1994 1995–1999 2000–2004 2005–2008
848 4663 7917 9334 8762
2.7 14.8 25.1 29.6 27.8
48,437 92,026 99,140 88,708 68,391
12.2 23.2 25.0 22.4 17.2
206 892 1644 2091 2093
3.0 12.9 23.7 30.2 30.2
8352 16,292 18,634 18,843 14,910
10.8 21.1 24.2 24.5 19.4
Region of residence Large city South North Unknown
11,211 13,515 6112 686
35.6 42.9 19.4 2.2
127,898 162,456 85,193 21,146
32.2 41.0 21.5 5.3
2341 2971 1368 246
33.8 42.9 19.8 3.6
24,090 29,868 17,077 5996
31.3 38.8 22.2 7.8
All
31,524
100.0
396,702
100.0
6926
100.0
77,031
100.0
Age (years)
Sex
Time period
3.1. Ischaemic stroke Risk of ischaemic stroke was increased during the first 6 months after diagnosis of 23 of the 34 cancers studied (Tables 2). Overall risk of ischaemic stroke during the first 6 months after diagnosis of cancer was 1.6 (95% CI 1.5–1.6). It decreased thereafter, but remained relatively constant after 6 months over time (SIR 1.1 after 6–12 months (95% CI 1.1–1.2), 1.1 after 1–5 years (95% CI 1.1–1.2), 1.2 after 5–10 years (95% CI 1.2–1.2) and 1.1 after 10+ years (95% CI 1.1–1.2)). Risk of ischaemic stroke was P2 during the first 6 months after diagnosis of cancers of six sites/types: small intestine, pancreas, lung, nervous system, endocrine glands and leukaemia (Table 2). For 11 cancer sites/types—upper aerodigestive tract, salivary gland, colon, rectum, nose, breast, prostate, urinary bladder, skin (squamous cell), nervous system and non-Hodgkin lymphoma—risk of ischaemic stroke was increased 10+ years after hospitalisation (Table 2).
3.2. Haemorrhagic stroke Risk of haemorrhagic stroke was increased during the first 6 months after diagnosis of 15 of the 34 cancers studied (Table 3). Overall risk of haemorrhagic stroke during the first 6 months after diagnosis of cancer was 2.2 (95% CI 2.0–2.3). It was much lower between 6 and 12 months, but thereafter remained relatively con-
stant over time (SIR 1.4 after 6–12 months (95% CI 1.3–1.5), 1.3 after 1–5 years (95% CI 1.2–1.3), 1.3 after 5–10 years (95% CI 1.2–1.4), and 1.2 after 10+ years (95% CI 1.1–1.3)). Risk of haemorrhagic stroke was P2 during the first 6 months after diagnosis of cancers of 10 sites/types: small intestine, liver, kidney, nervous system, thyroid gland, endocrine glands, connective tissue, non-Hodgkin lymphoma, myeloma and leukaemia (Table 2). For six cancer sites/types—prostate, kidney, urinary bladder, skin (squamous cell), non-Hodgkin lymphoma and leukaemia—risk of CHD was increased 10+ years after hospitalisation (Table 3). 3.3. Cancer sites unrelated to tobacco smoking Several cancer sites/types unrelated to tobacco smoking—small intestine, colon, rectum, breast, endometrium, ovary, other female genital, prostate, melanoma, skin (squamous cell), nervous system, endocrine glands, connective tissue, non-Hodgkin lymphoma and myeloma—were associated with increased ischaemic stroke risk during the first 6 months after cancer diagnosis (Table 2). Several cancer sites/types unrelated to tobacco smoking—small intestine, colon, prostate, melanoma, skin (squamous cell), nervous system, thyroid gland, endocrine glands, connective tissue, non-Hodgkin lymphoma and myeloma—were associated with increased haemorrhagic stroke risk the first 6 months after cancer diagnosis (Table 3).
Table 2 Standardised incidence ratio (SIRs) for subsequent ischaemic stroke in cancer patients by follow-up time. Cancer site/type
Follow-up interval <6 months O
*
1.3 1.5 1.5 1.8 2.2 1.6 1.6 1.5 1.3 2.2 1.1 2.2 1.5 1.6 1.7 1.8 1.7 1.2 2.0 2.0 1.5 1.7 * 1.3 * 1.2 1.3 4.1 1.6 2.1 1.2 * 1.6 1.6 1.3 1.5 3.0 1.6
1.0* 0.6 1.1 1.5 1.4 1.5 1.3 0.6 1.0 1.8 0.3 1.9 1.3 1.0 1.4 1.4 1.1 1.1 0.4 1.0 1.2 1.5 1.0 1.0 0.5 3.4 0.8 1.6 0.1 1.0 1.4 0.4 1.1 2.5 1.5
1.7 3.2 2.2 2.2 3.4 1.8 1.8 3.0 1.7 2.7 2.8 2.4 1.6 2.4 2.0 2.4 2.7 1.3 5.9 3.8 1.9 1.9 1.6 1.4 2.7 4.8 2.6 2.7 4.3 2.5 1.8 3.0 2.0 3.7 1.6
41 5 11 40 10 194 106 6 29 14 4 99 266 15 61 19 19 596 2 3 46 160 61 185 4 32 10 39 0 10 94 7 25 30 2243
1–5 years
5–10 years
10+ years
All
SIR 95% CI
O
SIR 95% CI
O
O
O
1.0 0.7 1.2 04 1.1 0.5 1.0 0.7 1.4 0.6 1.1 1.0 1.1 0.9 1.3 0.5 1.8 1.2 1.0 0.6 1.3 0.3 1.3 1.0 1.2 1.0 1.3 0.8 1.0 0.8 0.7 0.4 2.0 1.2 * 1.1 1.0 1.4 0.1 0.7 0.1 1.1 0.8 1.2 1.1 0.9 0.7 * 1.2 1.0 0.8 0.2 1.3 0.9 1.3 0.6 1.3 0.9
272 25 21 158 33 1126 529 24 38 28 20 230 1588 74 407 121 50 3640 9 27 264 874 398 1192 25 181 59 266 4 63 483 24 136 125 12515
*
1.0 1.1 2.2 0.8 1.2 1.1
0.4 0.9 0.9 0.5 0.8 1.1
1.3 2.9 1.9 1.4 2.5 1.3 1.3 2.8 2.6 1.7 3.2 1.6 1.3 2.2 1.3 1.1 3.1 1.2 5.1 2.1 1.4 1.4 1.2 1.4 2.0 1.9 2.5 1.8 1.8 1.3 4.6 1.2 1.7 1.2
1.1 1.1 0.8 1.1 0.8 1.2 1.0 1.0 0.9 1.4 1.2 1.1 1.1 1.2 1.0 0.9 1.1 1.2 0.8 1.2 1.1 1.2 1.0 1.4 0.8 1.3 1.2 1.2 0.5 1.1 1.0 1.3 1.0 1.1 1.1
1.0 0.7 0.5 1.0 0.6 1.1 0.9 0.6 0.6 0.9 0.7 0.99 1.0 1.0 0.9 0.7 0.8 1.1 0.4 0.76 1.0 1.1 0.9 1.3 0.5 1.4 0.9 1.1 0.1 0.9 0.9 0.8 0.9 0.9 1.1
1.3 248 1.6 21 1.3 12 1.3 101 1.2 21 1.3 700 1.1 385 1.5 15 1.2 23 2.0 6 1.8 17 1.3 104 1.1 1316 1.6 60 1.1 335 1.1 94 1.4 41 1.2 1935 1.6 6 1.7 18 1.2 206 1.3 605 1.1 346 1.4 678 1.2 22 1.5 140 1.5 46 1.4 277 1.3 9 1.4 41 1.1 322 1.9 12 1.2 45 1.3 88 1.2 8295
SIR 95% CI 1.5 1.3 1.0 * 1.2 0.9 1.2 1.2 0.9 1.1 0.9 1.5 1.1 * 1.1 1.3 1.0 1.0 1.3 1.2 0.5 1.2 1.2 1.2 1.1 1.3 1.1 1.1 1.0 1.4 1.4 1.1 * 1.2 0.8 1.0 1.5 1.2
1.3 0.8 0.5 1.0 0.5 1.1 1.1 0.5 0.7 0.3 0.9 0.9 1.0 1.0 0.9 0.8 1.0 1.2 0.2 0.7 1.1 1.1 1.0 1.2 0.7 0.9 0.8 1.2 0.6 0.8 1.0 0.4 0.8 1.2 1.2
1.7 148 2.0 20 1.8 6 1.5 52 1.3 14 1.3 428 1.3 229 1.5 13 1.7 13 2.0 1 2.4 14 1.3 63 1.1 1023 1.6 47 1.1 263 1.2 97 1.8 18 1.3 636 1.0 12 1.8 6 1.4 104 1.3 377 1.2 229 1.4 293 1.6 10 1.3 149 1.4 42 1.5 185 2.6 5 1.5 20 1.3 175 1.4 18 1.4 16 1.8 37 1.2 4763
SIR 95% CI 1.5 1.7 1.2 1.0 1.0 1.3 * 1.2 1.2 1.0 0.3 2.1 1.3 * 1.1 1.1 1.0 1.2 1.0 1.2 0.7 0.7 0.9 1.2 0.9 * 1.1 0.7 1.3 1.0 1.1 0.9 0.8 1.2 1.5 1.1 1.3 1.1
1.2 1.1 0.4 0.8 0.5 1.2 1.0 0.6 0.5 0.0 1.2 1.0 1.0 0.8 0.9 1.0 0.6 1.1 0.4 0.2 0.8 1.1 0.8 1.0 0.3 1.1 0.7 0.9 0.3 0.5 1.1 0.9 0.6 0.9 1.1
1.7 776 2.7 78 2.5 81 1.4 471 1.7 99 1.4 2786 1.4 1430 2.1 66 1.7 158 1.6 139 3.6 59 1.6 809 1.1 4551 1.4 217 1.1 1175 1.5 392 1.6 148 1.3 7495 1.2 32 1.4 64 1.1 703 1.4 2269 1.1 1124 1.3 2549 1.3 68 1.6 642 1.3 171 1.3 831 2.1 20 1.2 155 1.4 1238 2.4 66 1.8 276 1.8 385 1.2 31524
1+ years SIR 95% CI O 1.3 1.3 1.1 1.2 1.1 1.3 1.1 1.1 1.2 1.6 1.4 1.4 1.1 1.2 * 1.1 1.1 1.3 1.2 0.7 1.1 1.1 1.2 1.0 1.3 0.9 1.4 1.1 1.3 0.8 1.1 1.1 1.3 1.1 1.5 1.2 *
1.2 1.0 0.9 1.1 0.9 1.2 1.1 0.8 1.0 1.4 1.1 1.3 1.1 1.1 1.0 1.0 1.1 1.2 0.5 0.9 1.1 1.2 1.0 1.2 0.7 1.3 1.0 1.2 0.5 0.9 1.1 1.0 1.0 1.3 1.2
1.4 668 1.6 66 1.4 39 1.4 311 1.3 68 1.3 2254 1.2 1143 1.4 52 1.4 74 1.9 35 1.8 51 1.5 397 1.1 3927 1.4 181 1.1 1005 1.2 312 1.5 109 1.2 6211 1.0 27 1.4 51 1.2 574 1.3 1856 1.1 973 1.3 2163 1.1 57 1.6 470 1.3 147 1.4 728 1.3 18 1.3 124 1.2 980 1.6 54 1.2 197 1.6 250 1.2 25573
SIR 95% CI 1.3 1.3 0.9 * 1.2 0.9 1.2 * 1.1 1.0 1.0 1.1 1.5 * 1.2 * 1.1 * 1.2 1.0 1.0 1.2 1.2 0.7 1.1 * 1.1 1.2 1.0 1.3 0.9 1.2 1.1 1.2 0.9 1.1 * 1.1 1.2 1.0 1.2 1.2 *
1.2 1.0 0.7 1.0 0.7 1.2 1.0 0.8 0.8 0.8 1.1 1.0 1.0 1.0 1.0 0.9 0.9 1.2 0.4 0.8 1.0 1.1 0.9 1.2 0.7 1.1 0.9 1.1 0.5 0.9 1.0 0.9 0.9 1.1 1.1
1.4 1.7 1.3 1.3 1.1 1.3 1.2 1.3 1.2 1.6 1.9 1.3 1.1 1.4 1.1 1.1 1.4 1.2 1.0 1.4 1.2 1.2 1.1 1.4 1.1 1.3 1.2 1.3 1.4 1.2 1.2 1.6 1.2 1.4 1.2
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Upper aerodigestive tract 67 Salivary gland 7 Oesophagus 31 Stomach 120 Small intestine 21 Colon 338 Rectum 181 Anus 8 Liver 55 Pancreas 90 Nose 4 Lung 313 Breast 358 Cervix 21 Endometrium 109 Ovary 61 Other female genital 20 Prostate 688 Testis 3 Other male genital 10 Kidney 83 Urinary bladder 253 Melanoma 90 Skin, squamous cell 201 Eye 7 Nervous system 140 Thyroid gland 14 Endocrine glands 64 Bone 2 Connective tissue 21 Non-Hodgkin lymphoma 164 Hodgkin’s disease 5 Myeloma 54 Leukaemia 105 All 3708
6–12 months
SIR 95% Confidence O interval (CI)
Bold type, 95% CI does not include 1.00. 1879
1880
Table 3 SIRs for subsequent haemorrhagic stroke in cancer patients by follow-up time. Cancer site/type
Follow-up interval <6 months O
*
9 2 8 19 6 55 20 0 18 9 3 49 37 5 15 8 1 164 0 1 41 32 26 43 2 199 6 30 0 8 45 2 19 82 965
95% CI
0.9 2.4 2.0 1.5 3.4 1.5 0.9
0.4 0.2 0.9 0.9 1.2 1.1 0.6
1.8 8.7 4.1 2.4 7.4 1.9 1.4
2.4 1.2 4.2 1.8 0.9 2.2 1.4 1.4 0.5 1.4
1.4 0.6 0.8 1.3 0.6 0.7 0.8 0.6 0.0 1.2
3.8 2.4 12 2.3 1.2 5.1 2.3 2.8 3.0 1.6
1.0 4.1 1.1 1.9 * 1.4 2.0 29 3.6 5.6
0.0 2.9 0.8 1.3 1.0 0.2 25 1.3 3.8
5.8 5.6 1.6 2.8 1.9 7.3 34 7.9 8.0
3.2 2.3 2.6 2.9 13 2.2
1.4 1.7 0.2 1.8 10 2.0
6.5 3.1 9.6 4.6 16 2.3
Bold type, 95% CI does not include 1.00.
6–12 months
1–5 years
O
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
61 8 8 41 9 228 105 8 10 6 4 44 242 9 63 26 10 807 5 7 91 160 152 201 9 51 6 59 3 13 96 8 47 73 2671
*
1.0 0.8 0.7 1.1 0.6 1.2 0.9 0.8 0.6 0.6 0.3 0.8 0.8 0.4 0.7 0.7 0.6 1.2 0.5 0.6 1.6 1.0 1.6 1.1 0.7 1.4 0.2 1.2 0.4 0.6 0.9 0.9 1.4 2.6 1.2
42 6 2 38 9 153 96 8 3 2 6 11 231 11 53 17 8 420 5 2 54 117 96 122 5 59 10 67 2 8 70 4 11 21 1769
1.3 1.9 0.9 2.5 1.9 1.4 1.5 2.7 0.8 1.6 2.8 0.6 1.1 1.2 1.0 1.1 1.6 1.3 1.4 0.6 1.6 1.2 1.5 * 1.2 1.3 2.3 1.2 1.8 1.5 1.1 * 1.3 1.3 1.3 1.8 1.3
0.9 0.7 0.1 1.8 0.9 1.2 1.2 1.2 0.2 0.2 1.0 0.3 1.0 0.6 0.7 0.6 0.7 1.2 0.5 0.1 1.2 1.0 1.2 1.0 0.4 1.7 0.6 1.4 0.2 0.5 1.0 0.4 0.7 1.1 1.2
30 1 1 9 4 80 40 0 3 1 3 9 178 5 44 13 2 151 6 1 35 89 63 73 1 33 9 36 4 3 43 2 5 16 993
1.4 0.4 1.0 0.9 1.4 1.2 1.1
1.0 0.0 0.0 0.4 0.4 1.0 0.8
2.0 2.5 5.4 1.7 3.6 1.5 1.4
1.2 1.4 2.1 0.9 1.1 0.6 1.0 0.9 0.6 1.3 1.3 0.5 1.6 1.4 1.2 1.4 0.4 1.4 1.1 1.1 3.4 0.6 1.5 0.7 1.7 2.6 1.2
0.2 0.0 0.4 0.4 0.9 0.2 0.7 0.5 0.1 1.1 0.5 0.0 1.1 1.1 1.0 1.1 0.0 1.0 0.5 0.8 0.9 0.1 1.1 0.1 0.5 1.5 1.1
3.6 8.2 6.2 1.8 1.2 1.4 1.3 1.6 2.3 1.6 2.9 2.8 2.2 1.7 1.6 1.8 2.1 2.0 2.1 1.5 8.8 1.6 2.0 2.7 4.0 4.3 1.3
148 17 22 116 28 567 289 17 39 21 17 131 721 33 186 68 21 1684 16 11 237 435 359 476 18 368 32 201 9 36 268 17 93 223 6926
1.3 1.5 1.6 1.6 * 1.6 1.4 1.2 1.5 1.6 1.4 2.1 * 1.2 1.0 1.0 1.0 1.1 1.1 1.3 1.4 0.9 2.0 1.2 1.6 1.3 1.2 4.2 1.1 1.7 1.9 1.3 1.3 1.6 2.0 4.4 1.4
1.1 0.9 1.0 1.4 1.0 1.3 1.1 0.9 1.1 0.8 1.2 1.0 0.9 0.7 0.9 0.8 0.7 1.2 0.8 0.5 1.8 1.1 1.5 1.2 0.7 3.8 0.8 1.5 0.9 0.9 1.2 0.9 1.6 3.8 1.3
133 15 11 88 22 461 241 16 16 9 13 64 651 25 160 56 20 1378 16 10 180 366 311 396 15 143 25 162 9 24 209 14 63 110 5433
1.3 1.6 1.3 1.7 1.5 1.4 1.2 1.7 1.1 1.6 * 1.9 1.0 1.0 0.9 1.0 1.0 1.3 1.3 1.4 1.0 1.8 1.2 1.6 1.2 1.2 1.9 1.0 1.5 * 2.2 1.0 1.2 1.5 1.8 2.8 1.3
1.1 09 0.7 1.4 0.9 1.2 1.1 1.0 0.6 0.7 1.0 0.7 0.9 0.6 0.8 0.8 0.8 1.2 0.8 0.5 1.6 1.1 1.4 1.1 0.7 1.6 0.6 1.3 1.0 0.7 1.1 0.8 1.4 2.3 1.2
6 0 3 9 0 51 28 1 5 3 1 18 33 3 11 4 0 142 0 0 16 37 22 37 1 26 1 9 0 4 14 1 11 31 528
SIR
95% CI
0.7
0.3
1.6
1.5 1.2
0.3 0.6
4.4 2.4
1.6 1.5 1.2 1.7 1.2 1.6 1.2 0.8 1.5 1.1 0.8
1.2 1.0 0.0 0.5 0.2 0.0 0.7 0.6 0.3 0.6 0.2
2.1 2.2 6.8 4.0 3.6 9.4 1.9 1.2 4.5 2.0 2.2
1.3
1.1
1.6
2.0 1.5 1.7 1.3 1.0 5.5 0.7 1.8
1.1 1.1 1.1 0.9 0.0 3.6 0.0 0.8
3.2 2.1 2.6 1.8 5.9 8.0 4.1 3.3
2.0 0.9 1.6 2.0 6.5 1.4
0.5 0.5 0.0 1.0 4.4 1.3
5.2 1.5 9.2 3.6 9.3 1.5
1.3 1.9 1.6 1.6 1.2 1.4 1.1 1.8 1.2 1.6 1.3 1.1 0.9 0.8 1.0 1.1 1.3 1.3 1.7 1.5 2.0 1.1 1.9 1.2 1.5 1.8 0.6 1.5 1.9 1.2 1.1 2.1 1.9 3.3 1.3
5–10 years
1.7 3.7 3.2 2.2 2.3 1.5 1.3 3.6 2.3 3.5 3.3 1.5 1.1 1.6 1.2 1.6 2.4 1.4 3.9 3.1 2.5 1.3 2.2 1.4 2.9 2.4 1.4 2.0 5.7 2.1 1.3 4.2 2.6 4.2 1.3
10+ years
1.8 4.2 3.2 3.4 3.7 1.7 1.9 5.3 2.3 5.9 6.1 1.1 1.2 2.2 1.3 1.7 3.1 1.4 3.4 2.3 2.2 1.4 1.9 1.4 3.0 2.9 2.2 2.3 5.7 2.2 1.6 3.4 2.4 2.7 1.4
All
1+ years
1.5 2.4 2.4 2.0 2.2 1.5 1.4 2.4 2.1 2.1 3.4 1.4 1.1 1.4 1.2 1.4 1.7 1.4 2.2 1.7 2.3 1.3 1.8 1.4 2.0 4.6 1.6 2.0 3.7 1.8 1.5 2.5 2.4 5.0 1.4
16 2.6 2.4 2.1 2.2 1.5 1.4 2.8 1.8 3.0 3.3 1.2 1.1 1.3 1.1 1.4 1.9 1.4 2.4 1.8 2.1 1.3 1.8 1.4 2.0 2.2 1.4 1.8 4.2 1.6 1.4 2.5 2.3 3.3 1.3
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Upper aerodigestive tract Salivary gland Oesophagus Stomach Small intestine Colon Rectum Anus Liver Pancreas Nose Lung Breast Cervix Endometrium Ovary Other female genitals Prostate Testis Other male genitals Kidney Urinary bladder Melanoma Skin, squamous cell Eye Nervous system Thyroid gland Endocrine glands Bone Connective tissue Non-Hodgkin lymphoma Hodgkin’s disease Myeloma Leukaemia All
SIR
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
1881
Table 4 SIRs for subsequent stroke in cancer patients by metastasis. Cancer site/type
Ischaemic stroke
Haemorrhagic stroke
No metastasis
Upper aerodigestive tract Oesophagus Stomach Colon Rectum Liver Pancreas Nose Lung Breast Prostate Other male genitals Kidney Urinary bladder Melanoma Skin, squamous cell Thyroid gland Endocrine glands Connective tissue All *
With metastasis
No metastasis O
SIR
95% CI
O
6 2 5 45 12 5 2 1 20 44 78 1 7 6 20 44 1 0 1 304
0.7 1.6 1.7 * 1.4 0.71 3.9 2.0 2.2 1.1 0.8 1.1 1.1 1.4 0.6 2.2 1.6 0.8
0.3 0.2 0.5 1.0 0.4 1.2 0.2 0.0 0.7 0.6 0.9 0.0 0.6 0.2 1.4 1.2 0.0
1.6 6.0 4.0 1.8 1.2 9.1 7.2 13 1.8 1.1 1.4 6.3 2.9 1.3 3.4 2.2 4.6
0.9 1.2
0.0 1.0
5.1 1.3
0 0 1 8 1 0 1 0 18 0 47 0 7 0 0 0 0 0 0 83
O
SIR
95% CI
O
56 6 20 230 84 10 10 5 136 310 294 14 28 61 39 153 7 0 10 1499
1.5 1.1 1.4 1.5 1.0 1.6 2.0 2.4 1.6 * 1.1 1.0 3.6 1.2 * 1.3 0.9 1.2 1.2
1.1 0.4 0.9 1.3 0.8 0.8 1.0 0.8 1.4 1.0 0.8 2.0 0.8 1.0 0.6 1.0 0.5
1.9 2.3 2.2 1.7 1.3 3.0 3.7 5.6 1.9 1.3 1.1 6.1 1.7 1.7 1.3 1.4 2.5
2.0 1.2
0.9 1.1
3.6 1.3
0 3 7 35 9 3 16 0 64 8 97 0 5 3 2 1 2 0 0 258
SIR
95% CI
2.0 2.3 1.8 0.9 1.8 5.8
0.4 0.9 1.3 0.4 0.4 3.3
6.0 4.8 2.5 1.7 5.4 9.4
2.1 1.1 1.1
1.6 0.5 0.9
2.6 2.1 1.4
1.2 1.6 2.9 3.3 3.0
0.4 0.3 0.3 0.0 0.3
2.7 4.6 10 19 11
1.5
1.3
1.7
*
With metastasis SIR
95% CI
1.5 2.0 0.5
0.0 0.9 0.0
8.7 4.0 2.7
1.7
0.0
9.9
2.8
1.6
4.4
2.4
1.8
3.2
7.6
3.0
2.2
1.8
16
2.7
Bold type, 95% CI does not include 1.00.
3.4. Metastasis and haemorrhagic and ischaemic strokes’ risk The Swedish Cancer Registry only contains data on metastasis since 2002. Between 2002 and 2008, overall risk of haemorrhagic and ischaemic strokes was higher in cancer patients with metastasis than in those without metastasis (Table 4). 4. Discussion The present study is the first nationwide study of cancer and risk of haemorrhagic and ischaemic strokes to present precise risk estimates for multiple different cancer sites/types. The results indicate that many cancer sites/ types are associated with an increased risk of hospitalisation for haemorrhagic and ischaemic strokes. This is consistent with previous studies that have shown stroke to be common among cancer patients.2–7 Moreover, the association is not limited to smoking-related cancers. Several non-smoking-related cancers were also associated with increased risk of haemorrhagic and ischaemic strokes (Tables 2 and 3). Although it declines rapidly after 6 months, the overall risk of haemorrhagic and ischaemic strokes remains slightly raised for 10 or more years. Overall risk of haemorrhagic and ischaemic strokes is additionally related to the presence of metastasis (Table 4). The results of the present study suggest that there is a general association between cancer, especially newly diagnosed cancer, and increased risk of subsequent haemorrhagic and ischaemic strokes. We have recently reported increased risk of coronary heart disease
and myocardial infarction in cancer patients.22 Thus, arterial cardiovascular disease just like venous thromboembolism appears to be associated with cancer.8 Some cancer sites/types, notably the nervous system and leukaemia, are especially strongly associated with the development of ischaemic and haemorrhagic strokes, and it is of especial clinical relevance to consider them. The increased risks of haemorrhagic and ischaemic strokes for different cancer sites/types may have different underlying causes. Unfortunately, we were unable to determine the mechanisms involved due to lack of access to laboratory and treatment data. One possible cause of the increased stroke risk among cancer patients might be that cardiovascular risk factors like hypertension and diabetes and other comorbidities have been reported to be common among cancer patients.24–26 Since inflammation has been linked to both atherosclerosis and haemostatic activation, cancer-associated inflammation/ haemostatic activation may constitute a general link between cancer and haemorrhagic and ischaemic strokes.8–11 The observed association of tumour metastasis with haemorrhagic and ischaemic strokes’ risk indicates that this hypothesis is plausible (i.e. increased inflammation and haemostatic activation) due to presence of metastasis (i.e. increased tumour burden) (Table 3). As well as reducing tumour size, efficient cancer treatment might also reduce associated inflammation, haemostatic activation and, thus, risk of haemorrhagic and ischaemic strokes. The fact that the risk of haemorrhagic and ischaemic strokes decreases rapidly suggests that haemorrhagic and ischaemic strokes’ risk could be linked to tumour size, which is likely to decrease over
1882
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
time due to treatment. However, as we lack treatment data, we cannot test this hypothesis. The decreased risk after 6 months could also be due to the cessation of treatment with cytostatics.27 Cytostatics could not only promote thrombosis, but also bleeding due to thrombocytopenia.27 The rapid decrease could also be due to death of patients with cerebral metastasis or successful treatment of cerebral metastasis. Indeed, the risks for both haemorrhagic and ischaemic strokes were highest in patients with primary brain tumour (i.e. nervous system tumours). In smoking-related cancers, the increased haemorrhagic and ischaemic strokes’ risk may be due to tobacco smoking.14–17 Thus, smoking cessation—a confounder for which we could not adjust—may also contribute to the rapid decrease in the incidence of haemorrhagic and ischaemic strokes after diagnosis of cancer. Thus, a number of mechanisms are possible. The effects of treatment (cerebral or neck irradiation)28,29 may also contribute to the identified associations, especially in the case of primary brain tumour or cerebral metastasis. Risk for stroke was previously shown to be increased in survivors of paediatric CNS tumours, Hodgkin’s disease and acute lymphoblastic leukaemia,29 in agreement with our study, in which the highest risks were observed for brain tumours and leukaemia. However, the stroke risk was not increased in patients with Hodgkin’s disease in the present study. Another potential confounder that could contribute to the increased haemorrhagic and ischaemic strokes’ risk during the first 6 months after diagnosis is the stress of having cancer. Although we were unable to evaluate the impact of psychosocial stress, psychosocial factors have been suggested to be risk factors for cardiovascular disease.30 The present study has certain limitations. For example, we had no data on general cardiovascular disease risk factors such as weight, smoking and diet. It is unrealistic to gather such data for an entire national population. However, we did adjust for socioeconomic status, which is associated with risk factors such as smoking and alcohol. Adjustment was also made for comorbidities (COPD, obesity, alcoholism, hypertension and diabetes mellitus). A further limitation is that we had no access to outpatient data, which means that only the most severe cases of haemorrhagic and ischaemic strokes (i.e. those requiring hospitalisation) were included in the analyses. However, almost all cases of haemorrhagic and ischaemic strokes should, according to official guidelines, be treated at hospitals in Sweden.31 Computed tomography of the brain should also be performed in patients with stroke symptoms.31 Moreover, incidence rates were calculated for the whole follow-up period, divided into five time periods, and adjustments were made for possible changes in incidence rates over time. A further limitation was our lack of access to treatment data.
The study also had a number of strengths. For instance, the study population included all individuals in Sweden diagnosed with cancer and hospitalised with haemorrhagic or ischaemic stroke during the study period. Because of the personal identification number assigned to each resident in Sweden, it was possible to trace every subject for the whole follow-up period. Data on occupation were 99.2% complete (1980 and 1990 censuses), which enabled us to adjust our models for socioeconomic status. Moreover, the Swedish Cancer Registry records all new cases of cancer, with almost all cases being histologically or cytologically confirmed.19 A further strength of the present study was the use of validated hospital discharge data.18,32,33 The Hospital Discharge Register has high validity,18,32,33 especially for cardiovascular disorders such as haemorrhagic and ischaemic strokes, for which approximately 95% of diagnoses have been shown to be correct.32,33 Another advantage was that the exclusive use of hospital diagnoses eliminated recall bias. In summary, risk of hospitalisation for haemorrhagic and ischaemic strokes was, for a number of cancer sites/ types, found to be significantly increased during the first 6 months after diagnosis of cancer. The risk of haemorrhagic and ischaemic strokes decreased rapidly thereafter, but for many cancer sites remained elevated for more than 10 years. Overall risk of haemorrhagic and ischaemic strokes was related to the presence of metastasis, suggesting that haemorrhagic and ischaemic strokes’ risk is affected by the severity of cancer. The findings of the present study indicate that newly diagnosed cancer in general is associated with increased risk of ischaemic and haemorrhagic strokes. Role of the funding source None. Contributors All authors contributed to the conception and design of the study; JS and KS acquired; all authors contributed to the analysis and interpretation of data; BZ drafted the manuscript and all authors revised it critically and approved the final version. All authors had full access to all of the data (including statistical reports and tables) and take responsibility for their integrity and the accuracy of their analysis. Conflict of interest statement None declared.
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Acknowledgements The authors wish to thank the CPF’s Science Editor Stephen Gilliver for his useful comments on the text. The registers used in the present study are maintained by Statistics Sweden and the National Board of Health and Welfare. This work was supported by grants awarded to Kristina and Jan Sundquist by the Swedish Research Council (2008-3110 and 2008-2638), the Swedish Council for Working Life and Social Research (2006-0386, 2007-1754 and 2007-1962), Formas (20064255-6596-99 and 2007-1352), and to Bengt Zo¨ller by the Swedish Heart and Lung Foundation and Region Ska˚ne (REGSKANE-124611). References 1. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371:1612–23. 2. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16–35. 3. Lindvig K, Moller H, Mosbech J, Jensen OM. The pattern of cancer in a large cohort of stroke patients. Int J Epidemiol 1990;19:498–504. 4. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology 2004;62:2025–30. 5. Rogers LR. Cerebrovascular complications in cancer patients. Oncology (Williston Park) 1994;8:23–30. 6. Nguyen T, DeAngelis LM. Stroke in cancer patients. Curr Neurol Neurosci Rep 2006;6:187–92. 7. Haller S, Lyrer P. Malignancy and stroke. Semin Cerebrovasc Dis Stroke 2005;5:47–54. 8. Franchini M, Montagnana M, Favaloro EJ, Lippi G. The bidirectional relationship of cancer and hemostasis and the potential role of anticoagulant therapy in moderating thrombosis and cancer spread. Semin Thromb Hemost 2009;35:644–53. 9. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7. 10. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. 11. van Leuven SI, Franssen R, Kastelein JJ, et al. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology 2008;47:3–7. 12. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology 2004;62:2025–30. 13. Chaturvedi S, Ansell J, Recht L. Should cerebral ischemic events in cancer patients be considered a manifestation of hypercoagulability? Stroke 1994;25:1215–8. 14. Dreyer L, Olsen JH. Cancer risk of patients discharged with acute myocardial infarct. Epidemiology 1998;9:178–83. 15. Dreyer L, Olsen JH. Risk for non-smoking-related cancer in atherosclerotic patients. Cancer Epidemiol Biomarkers Prev 1999;8:915–8.
1883
16. Horn-Ross PL, Ljung BM, Morrow M. Environmental factors and the risk of salivary gland cancer. Epidemiology 1997;8:414–9. 17. Fernberg P, Odenbro A, Bellocco R, et al. Tobacco use, body mass index, and the risk of leukemia and multiple myeloma: a nationwide cohort study in Sweden. Cancer Res 2007;67:5983–6. 18. Rosen M, Hakulinen T. Use of disease registers. In: Ahrens W, Pigeot I, editors. Handbook of epidemiology. Berlin: SpringerVerlag; 2005. p. 231–52. 19. Cancer incidence in Sweden 2005. Stockholm: The National Board of Health and Welfare; 2007. 20. The multi-generation register 2009. A description of contents and quality. Statistics Sweden. Available from: [accessed 22.03.11]. 21. The Swedish Hospital Discharge Register 1987–1996: quality and contents. Stockholm: The National Board of Health and Welfare; 1998. 22. Zo¨ller B, Ji J, Sundquist J, Sundquist K. Risk of coronary heart disease in patients with cancer: a nationwide follow-up study from Sweden Eur J Cancer 2012; 48:121–8. 23. Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia: Lippincott-Raven; 1998. 24. Coebergh JW, Janssen-Heijnen ML, Razenberg PP. Prevalence of co-morbidity in newly diagnosed patients with cancer: a population-based study. Crit Rev Oncol Hematol 1998;27:97–100. 25. Janssen-Heijnen ML, Houterman S, Lemmens VE, et al. Prognostic impact of increasing age and co-morbidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol 2005;55:231–40. 26. Janssen-Heijnen ML, Szerencsi K, van de Schans SA, et al. Cancer patients with cardiovascular disease have survival rates comparable to cancer patients within the age-cohort of 10 years older without cardiovascular morbidity. Crit Rev Oncol Hematol 2010;76:196–207. 27. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231–47. 28. Dubec JJ, Munk PL, Tsang V, et al. Carotid artery stenosis in patients who have undergone radiation therapy for head and neck malignancy. Br J Radiol 1998;7:872–5. 29. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors: a Children’s Oncology Group Report. Neurology 2009;73:1906–13. 30. Rozanski A, Blumenthal JA, Davidson KW, Saab PG, Kubzansky L. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005;45:637–51. 31. National guidelines for stroke care 2005. Basis for prioritisation. Stockholm: The National Board of Health and Welfare; 2005 [in Swedish]. 32. Validity of the diagnoses from the Swedish in-care register 1987 and 1995. Stockholm: The National Board of Health and Welfare; 2000 [in Swedish]. 33. Lindblad U, Ra˚stam L, Ranstam J, Peterson M. Validity of register data on acute myocardial infarction and acute stroke: the Skaraborg Hypertension Project. Scand J Soc Med 1993;21:3–9.
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Risk of haemorrhagic and ischaemic stroke in patients with cancer: A nationwide follow-up study from Sweden Bengt Zo¨ller a,⇑, Jianguang Ji a, Jan Sundquist a,b, Kristina Sundquist a a
Center for Primary Health Care Research, Lund University/Region Ska˚ne, Clinical Research Centre, Floor 11, Building 28, Entrance 72, Ska˚ne University Hospital, 205 02 Malmo¨, Sweden b Stanford Prevention Research Centre, Stanford University School of Medicine, Medical School Office Building, 251 Campus Drive, Mail Code 5411, Stanford, CA 94305-5411, USA Available online 30 January 2012
KEYWORDS Cancer Ischaemic stroke Haemorrhagic stroke Epidemiology Risk factors
Background: Stroke is common in cancer patients, but risk estimates for different cancer sites/types have not been determined. The aim of this nationwide study was to examine whether there is an association between cancer and first hospitalisation for haemorrhagic or ischaemic stroke. Methods: All 820,491 individuals in Sweden with a diagnosis of cancer between 1st January 1987 and 31st December 2008 were followed for first hospitalisation for haemorrhagic or ischaemic stroke. The reference population was the total population of Sweden without cancer. Standardised incidence ratios (SIRs) for haemorrhagic and ischaemic strokes were calculated. Results: Overall risk of haemorrhagic stroke and ischaemic stroke during the first 6 months after diagnosis of cancer was 2.2 (95% confidence interval (CI) = 2.0–2.3) and 1.6 (CI = 1.5– 1.6), respectively. For 18 and 20 of the 34 cancers studied, respectively, risk of haemorrhagic and ischaemic strokes was increased. Overall stroke risk decreased rapidly, but remained elevated, even 10+ years after diagnosis of cancer 1.2 (CI = 1.1–1.3) for haemorrhagic stroke and 1.1 (CI = 1.1–1.2) for ischaemic stroke. The risk of stroke was highest during the first 6 months after diagnosis of cancer of the nervous system (29 (CI = 25–34) for haemorrhagic stroke and 4.1 (CI = 3.4–4.8) for ischaemic stroke)) or leukaemia (13 (CI = 10–16) for haemorrhagic stroke and 3.0 (CI = 2.5–3.7) for ischaemic stroke)). Metastasis was associated with an increased risk of haemorrhagic stroke 2.2 (CI = 1.8–2.7) and ischaemic stroke 1.5 (CI = 1.3–1.7). Interpretation: Several cancer sites/types are associated with an increased risk of haemorrhagic and ischaemic strokes. Ó 2012 Elsevier Ltd. All rights reserved. Abstract
⇑ Corresponding author: Mobile: +46 70 6691476; fax: +46 40 391370.
E-mail address: [email protected] (B. Zo¨ller). 0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2012.01.005
1876
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
1. Introduction Haemorrhagic and ischaemic strokes are major causes of morbidity and mortality worldwide.1 In an autopsy study from 1985, 14.6% of cancer patients suffered from ischaemic stroke.2 However, the clinical significance of these findings is not clear, as the study included silent infarcts and diffuse vascular encephalopathies.2 Cancer is also overrepresented in stroke patients.3 Notably, a more than 10-fold increase in the risk of brain tumours within the first year after diagnosis of stroke was reported in a previous study.3 However, diagnostic misinterpretation of a brain tumour as a stroke may have been possible with the study design use.3 Minor increases in the risk of cancer at other sites were also found in the first year of follow-up.3 In a retrospective study of 96 patients with confirmed stroke, lung cancer was the most common primary tumour (30%), followed by brain malignancy and prostate cancer (9% each).4 Cerebral haemorrhage has been reported frequently in cancer patients, especially those with haematological malignancies. In patients with leukaemia and lymphoma, 72% and 36% of strokes, respectively, were haemorrhagic.5 A number of cancer-related causes of stroke have been suggested,2,6,7 including treatment-related sideeffects, direct tumour compressing or invasion of blood vessels, tumour-induced haemostatic activation8 or an alteration in blood viscosity, and non-bacterial thrombotic endocarditis.2,6,7 Tumour cells produce various cytokines and chemokines that attract leucocytes, which may trigger an inflammatory response.9 This may in turn have prothrombotic and atherosclerotic effects.10,11 However, there is no consensus as to whether cancer is an independent risk factor for stroke like traditional risk factors such as hypertension and smoking. It has been proposed that conventional stroke etiologies account for the majority of cerebral ischaemic events in the adult cancer population.12,13 Moreover, cancer and ischaemic stroke share a common risk factor (tobacco smoke), and an increased risk of ischaemic stroke would be expected among patients with smoking-related cancers (i.e. cancers of the lung, larynx, oesophagus, mouth and tongue, pharynx, urinary bladder, pancreas and kidney).14–17 Other suspected smoking-related cancers sites include lip, liver, cervix, stomach and salivary gland; leukaemia is also suspected to be cancer-related Thus, cancer and ischaemic stroke share a number of risk factors, and an increased risk of ischaemic stroke among cancer patients might be expected. We hypothesised that cancer may affect risk of haemorrhagic and ischaemic strokes. In a nationwide followup study of data from 1987 to 2008, we estimated risk of hospitalisation for haemorrhagic and ischaemic strokes in patients with different cancers. An important novel contribution of the study is the use of nationwide
validated registers such as the Swedish Cancer Registry and the Hospital Discharge Register, thereby eliminating the risk of selection and recall bias. 2. Methods 2.1. MigMed 2 Database This study was approved by the Ethics Committee of Lund University, Sweden. Data used in this study were retrieved from the MigMed 2 Database (an updated version of the original MigMed database), maintained at the Center for Primary Health Care Research, Lund University/Region Ska˚ne, Malmo¨. MigMed 2 contains data on all individuals registered as residents of Sweden. It contains individual-level information on age, sex, occupation, geographic region of residence, hospital diagnoses and dates of hospital admissions in Sweden, as well as country of birth, parents’ country of birth, date of emigration and date and cause of death. The database was constructed using several national Swedish data registers (reviewed by Rosen and Hakulinen),18 including, but not limited to, the Swedish Cancer Registry,19 the Swedish National Population and Housing Census, the Total Population Register, the Multi-Generation Register20 and the Swedish Hospital Discharge Register.21 Information retrieved from the various registers in the MigMed 2 Database is linked, at the individual level, via the 10-digit personal identification number assigned to each resident of Sweden for his or her lifetime. Registration numbers were replaced by serial numbers to preserve anonymity. As well as being used to track all records in the database at the individual level, these serial numbers were used to check that individuals with hospital diagnoses of haemorrhagic and ischaemic strokes appeared only once in the dataset (for the first hospital diagnosis of haemorrhagic or ischaemic stroke during the study period). The follow-up period for analysis of data in the present study started on 1st January 1987 and continued until hospitalisation for haemorrhagic or ischaemic stroke, death, emigration or the end of the study period (31st December 2008). Data for first hospitalisation for haemorrhagic and ischaemic strokes during the study period were retrieved from the Hospital Discharge Register (1987–2008). This register does not include data for hospital outpatients or patients treated at primary health care centres. 2.2. Predictor variable The predictor variable was diagnosis of cancer in the Swedish Cancer Registry. Cancer site/type was identified according to the 7th revision of the International
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Classification of Diseases (ICD-7).22 The Swedish Cancer Registry records all new cases of cancer. Close to 100% of all cases nationwide have been histologically or cytologically confirmed.19 Information on metastasis has been included in the Swedish Cancer Registry since 2002.
1877
(1) chronic obstructive pulmonary disease (COPD) (490–496 (ICD-9) and J40–J49 (ICD-10)); (2) obesity (278A (ICD-9) and E65–E68 (ICD-10)); (3) alcoholism (291 and 303 (ICD-9) and F10 (ICD-10)); (4) diabetes mellitus (250 (ICD-9) and E10–E14 (ICD-10)) and (5) hypertension (401–405 (ICD-9) and I10-I15 (ICD-10)).
2.3. Outcome variables 2.5. Statistical analysis Diagnoses of haemorrhagic and ischaemic strokes were based on the 9th and 10th revisions of the International Classification of Diseases (ICD-9 and ICD-10). Cases of ischaemic stroke were identified using the following ICD codes: 433, 434, 435, 437.0, and 437.1 (ICD-9) and I63 (not I636), I65, I66, I67.2 and I67.8 (ICD-10). Cases of haemorrhagic stroke were identified using the following ICD codes: 431 and 432 (ICD-9) and I61 and I62 (ICD-10). 2.4. Individual-level variables The individual-level variables were sex, age, time period, geographic region of residence, socioeconomic status (SES) and comorbidity. Sex: male or female. Age was divided into 5-year categories. Subjects of all ages were included in the study. Time period was divided into five categories: 1987– 1990, 1991–1994, 1995–1999, 2000–2004 and 2005–2008. Geographic region of residence was included as an individual-level variable to allow adjustment for possible differences in hospital admissions for haemorrhagic and ischaemic strokes between different geographic regions in Sweden. It was categorised as (1) large city (city with a population of >200,000 (i.e. Stockholm, Gothenburg or Malmo)); (2) Southern Sweden (rural and urban); (3) Northern Sweden (rural and urban); or (4) unknown (if geographic region of residence could not be determined). Note: the three ‘large cities’ all lie in Southern Sweden, but were excluded from the Southern Sweden category. Occupation was used as a proxy for socioeconomic status (SES). Occupational data were retrieved from national census records in the MigMed 2 Database. We classified each individual’s occupation into one of six categories: (1) blue-collar worker, (2) whitecollar worker, (3) professional, (4) self-employed, (5) farmer and (6) non-employed (individuals without paid employment). Students without an occupation were categorised on the basis of their father’s or mother’s occupation. If that was not possible, they were included in the ‘non-employed’ category. For individuals aged <20 years, parental occupation was used. Comorbidity was defined as first hospital diagnosis at follow-up (1987–2008) for the following conditions:
Person-years of risk (i.e. number of persons at risk multiplied by time at risk) were calculated from the time at which subjects were included in the study (1987 or later) until first hospitalisation for haemorrhagic or ischaemic stroke, death and emigration or the end of the study period. The expected number of cases was based on the number of cases in the reference group. Standardised incidence ratios (SIRs) were calculated as the ratio of observed (O) and expected (E) number of haemorrhagic or ischaemic stroke cases using the indirect standardisation method.23 Expected numbers were calculated for anyone without cancer, that is, for the whole Swedish population without cancer. The expected numbers were calculated as age (5-year groups), sex, period (5-year groups), region and socioeconomic status (=SES)-specific standard incidence rates. An additional adjustment was made for hospitalisation for comorbidities: (1) chronic obstructive pulmonary disease (COPD); (2) obesity; (3) alcoholism; (4) diabetes mellitus and (5) hypertension. Ninety-five percent confidence intervals (95% CI) were calculated assuming a Poisson distribution,23 All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA). 3. Results Totally 820,491 cancer cases were identified between 1987 and 2008, 51.9% males (n = 425899) and 48.1% females (n = 394.592).22 The four most common cancers among males were prostate cancer (n = 139,510), lung cancer (n = 36,424), urinary bladder (n = 29,705) and colon cancer (29,633).22 The four most common cancers among females were breast cancer (115,705), colon cancer (32,169), endometrium cancer (n = 23,479) and lung cancer (23,220).22 Table 1 shows the basic characteristics of patients with and without cancer who were hospitalised with haemorrhagic or ischaemic stroke during the study period. A total of 77,031 and 396,702 individuals without cancer were hospitalised with a main diagnosis of haemorrhagic and ischaemic strokes, respectively (Table 1), while 6926 and 31,524 individuals with cancer were subsequently hospitalised for haemorrhagic and ischaemic strokes (Table 1), respectively.
1878
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Table 1 Basic characteristics of the stroke patients. Parameter
Ischaemic stroke With cancer
Haemorrhagic stroke Without cancer
With cancer
Without cancer
Number
%
Number
%
Number
%
Number
%
<60 60–69 70–79 P80
1106 3658 11,002 15,758
3.5 11.6 34.9 50.0
37,836 66,302 136,376 156,188
9.5 16.7 34.4 39.4
530 1000 2373 3023
7.7 14.4 34.3 43.6
12,544 13,969 25,147 25,371
16.3 18.1 32.6 32.9
Male Female
17,671 13,853
56.1 43.9
200,144 196,558
50.5 49.5
4282 2644
61.8 38.2
42,586 34,445
55.3 44.7
1987–1989 1990–1994 1995–1999 2000–2004 2005–2008
848 4663 7917 9334 8762
2.7 14.8 25.1 29.6 27.8
48,437 92,026 99,140 88,708 68,391
12.2 23.2 25.0 22.4 17.2
206 892 1644 2091 2093
3.0 12.9 23.7 30.2 30.2
8352 16,292 18,634 18,843 14,910
10.8 21.1 24.2 24.5 19.4
Region of residence Large city South North Unknown
11,211 13,515 6112 686
35.6 42.9 19.4 2.2
127,898 162,456 85,193 21,146
32.2 41.0 21.5 5.3
2341 2971 1368 246
33.8 42.9 19.8 3.6
24,090 29,868 17,077 5996
31.3 38.8 22.2 7.8
All
31,524
100.0
396,702
100.0
6926
100.0
77,031
100.0
Age (years)
Sex
Time period
3.1. Ischaemic stroke Risk of ischaemic stroke was increased during the first 6 months after diagnosis of 23 of the 34 cancers studied (Tables 2). Overall risk of ischaemic stroke during the first 6 months after diagnosis of cancer was 1.6 (95% CI 1.5–1.6). It decreased thereafter, but remained relatively constant after 6 months over time (SIR 1.1 after 6–12 months (95% CI 1.1–1.2), 1.1 after 1–5 years (95% CI 1.1–1.2), 1.2 after 5–10 years (95% CI 1.2–1.2) and 1.1 after 10+ years (95% CI 1.1–1.2)). Risk of ischaemic stroke was P2 during the first 6 months after diagnosis of cancers of six sites/types: small intestine, pancreas, lung, nervous system, endocrine glands and leukaemia (Table 2). For 11 cancer sites/types—upper aerodigestive tract, salivary gland, colon, rectum, nose, breast, prostate, urinary bladder, skin (squamous cell), nervous system and non-Hodgkin lymphoma—risk of ischaemic stroke was increased 10+ years after hospitalisation (Table 2).
3.2. Haemorrhagic stroke Risk of haemorrhagic stroke was increased during the first 6 months after diagnosis of 15 of the 34 cancers studied (Table 3). Overall risk of haemorrhagic stroke during the first 6 months after diagnosis of cancer was 2.2 (95% CI 2.0–2.3). It was much lower between 6 and 12 months, but thereafter remained relatively con-
stant over time (SIR 1.4 after 6–12 months (95% CI 1.3–1.5), 1.3 after 1–5 years (95% CI 1.2–1.3), 1.3 after 5–10 years (95% CI 1.2–1.4), and 1.2 after 10+ years (95% CI 1.1–1.3)). Risk of haemorrhagic stroke was P2 during the first 6 months after diagnosis of cancers of 10 sites/types: small intestine, liver, kidney, nervous system, thyroid gland, endocrine glands, connective tissue, non-Hodgkin lymphoma, myeloma and leukaemia (Table 2). For six cancer sites/types—prostate, kidney, urinary bladder, skin (squamous cell), non-Hodgkin lymphoma and leukaemia—risk of CHD was increased 10+ years after hospitalisation (Table 3). 3.3. Cancer sites unrelated to tobacco smoking Several cancer sites/types unrelated to tobacco smoking—small intestine, colon, rectum, breast, endometrium, ovary, other female genital, prostate, melanoma, skin (squamous cell), nervous system, endocrine glands, connective tissue, non-Hodgkin lymphoma and myeloma—were associated with increased ischaemic stroke risk during the first 6 months after cancer diagnosis (Table 2). Several cancer sites/types unrelated to tobacco smoking—small intestine, colon, prostate, melanoma, skin (squamous cell), nervous system, thyroid gland, endocrine glands, connective tissue, non-Hodgkin lymphoma and myeloma—were associated with increased haemorrhagic stroke risk the first 6 months after cancer diagnosis (Table 3).
Table 2 Standardised incidence ratio (SIRs) for subsequent ischaemic stroke in cancer patients by follow-up time. Cancer site/type
Follow-up interval <6 months O
*
1.3 1.5 1.5 1.8 2.2 1.6 1.6 1.5 1.3 2.2 1.1 2.2 1.5 1.6 1.7 1.8 1.7 1.2 2.0 2.0 1.5 1.7 * 1.3 * 1.2 1.3 4.1 1.6 2.1 1.2 * 1.6 1.6 1.3 1.5 3.0 1.6
1.0* 0.6 1.1 1.5 1.4 1.5 1.3 0.6 1.0 1.8 0.3 1.9 1.3 1.0 1.4 1.4 1.1 1.1 0.4 1.0 1.2 1.5 1.0 1.0 0.5 3.4 0.8 1.6 0.1 1.0 1.4 0.4 1.1 2.5 1.5
1.7 3.2 2.2 2.2 3.4 1.8 1.8 3.0 1.7 2.7 2.8 2.4 1.6 2.4 2.0 2.4 2.7 1.3 5.9 3.8 1.9 1.9 1.6 1.4 2.7 4.8 2.6 2.7 4.3 2.5 1.8 3.0 2.0 3.7 1.6
41 5 11 40 10 194 106 6 29 14 4 99 266 15 61 19 19 596 2 3 46 160 61 185 4 32 10 39 0 10 94 7 25 30 2243
1–5 years
5–10 years
10+ years
All
SIR 95% CI
O
SIR 95% CI
O
O
O
1.0 0.7 1.2 04 1.1 0.5 1.0 0.7 1.4 0.6 1.1 1.0 1.1 0.9 1.3 0.5 1.8 1.2 1.0 0.6 1.3 0.3 1.3 1.0 1.2 1.0 1.3 0.8 1.0 0.8 0.7 0.4 2.0 1.2 * 1.1 1.0 1.4 0.1 0.7 0.1 1.1 0.8 1.2 1.1 0.9 0.7 * 1.2 1.0 0.8 0.2 1.3 0.9 1.3 0.6 1.3 0.9
272 25 21 158 33 1126 529 24 38 28 20 230 1588 74 407 121 50 3640 9 27 264 874 398 1192 25 181 59 266 4 63 483 24 136 125 12515
*
1.0 1.1 2.2 0.8 1.2 1.1
0.4 0.9 0.9 0.5 0.8 1.1
1.3 2.9 1.9 1.4 2.5 1.3 1.3 2.8 2.6 1.7 3.2 1.6 1.3 2.2 1.3 1.1 3.1 1.2 5.1 2.1 1.4 1.4 1.2 1.4 2.0 1.9 2.5 1.8 1.8 1.3 4.6 1.2 1.7 1.2
1.1 1.1 0.8 1.1 0.8 1.2 1.0 1.0 0.9 1.4 1.2 1.1 1.1 1.2 1.0 0.9 1.1 1.2 0.8 1.2 1.1 1.2 1.0 1.4 0.8 1.3 1.2 1.2 0.5 1.1 1.0 1.3 1.0 1.1 1.1
1.0 0.7 0.5 1.0 0.6 1.1 0.9 0.6 0.6 0.9 0.7 0.99 1.0 1.0 0.9 0.7 0.8 1.1 0.4 0.76 1.0 1.1 0.9 1.3 0.5 1.4 0.9 1.1 0.1 0.9 0.9 0.8 0.9 0.9 1.1
1.3 248 1.6 21 1.3 12 1.3 101 1.2 21 1.3 700 1.1 385 1.5 15 1.2 23 2.0 6 1.8 17 1.3 104 1.1 1316 1.6 60 1.1 335 1.1 94 1.4 41 1.2 1935 1.6 6 1.7 18 1.2 206 1.3 605 1.1 346 1.4 678 1.2 22 1.5 140 1.5 46 1.4 277 1.3 9 1.4 41 1.1 322 1.9 12 1.2 45 1.3 88 1.2 8295
SIR 95% CI 1.5 1.3 1.0 * 1.2 0.9 1.2 1.2 0.9 1.1 0.9 1.5 1.1 * 1.1 1.3 1.0 1.0 1.3 1.2 0.5 1.2 1.2 1.2 1.1 1.3 1.1 1.1 1.0 1.4 1.4 1.1 * 1.2 0.8 1.0 1.5 1.2
1.3 0.8 0.5 1.0 0.5 1.1 1.1 0.5 0.7 0.3 0.9 0.9 1.0 1.0 0.9 0.8 1.0 1.2 0.2 0.7 1.1 1.1 1.0 1.2 0.7 0.9 0.8 1.2 0.6 0.8 1.0 0.4 0.8 1.2 1.2
1.7 148 2.0 20 1.8 6 1.5 52 1.3 14 1.3 428 1.3 229 1.5 13 1.7 13 2.0 1 2.4 14 1.3 63 1.1 1023 1.6 47 1.1 263 1.2 97 1.8 18 1.3 636 1.0 12 1.8 6 1.4 104 1.3 377 1.2 229 1.4 293 1.6 10 1.3 149 1.4 42 1.5 185 2.6 5 1.5 20 1.3 175 1.4 18 1.4 16 1.8 37 1.2 4763
SIR 95% CI 1.5 1.7 1.2 1.0 1.0 1.3 * 1.2 1.2 1.0 0.3 2.1 1.3 * 1.1 1.1 1.0 1.2 1.0 1.2 0.7 0.7 0.9 1.2 0.9 * 1.1 0.7 1.3 1.0 1.1 0.9 0.8 1.2 1.5 1.1 1.3 1.1
1.2 1.1 0.4 0.8 0.5 1.2 1.0 0.6 0.5 0.0 1.2 1.0 1.0 0.8 0.9 1.0 0.6 1.1 0.4 0.2 0.8 1.1 0.8 1.0 0.3 1.1 0.7 0.9 0.3 0.5 1.1 0.9 0.6 0.9 1.1
1.7 776 2.7 78 2.5 81 1.4 471 1.7 99 1.4 2786 1.4 1430 2.1 66 1.7 158 1.6 139 3.6 59 1.6 809 1.1 4551 1.4 217 1.1 1175 1.5 392 1.6 148 1.3 7495 1.2 32 1.4 64 1.1 703 1.4 2269 1.1 1124 1.3 2549 1.3 68 1.6 642 1.3 171 1.3 831 2.1 20 1.2 155 1.4 1238 2.4 66 1.8 276 1.8 385 1.2 31524
1+ years SIR 95% CI O 1.3 1.3 1.1 1.2 1.1 1.3 1.1 1.1 1.2 1.6 1.4 1.4 1.1 1.2 * 1.1 1.1 1.3 1.2 0.7 1.1 1.1 1.2 1.0 1.3 0.9 1.4 1.1 1.3 0.8 1.1 1.1 1.3 1.1 1.5 1.2 *
1.2 1.0 0.9 1.1 0.9 1.2 1.1 0.8 1.0 1.4 1.1 1.3 1.1 1.1 1.0 1.0 1.1 1.2 0.5 0.9 1.1 1.2 1.0 1.2 0.7 1.3 1.0 1.2 0.5 0.9 1.1 1.0 1.0 1.3 1.2
1.4 668 1.6 66 1.4 39 1.4 311 1.3 68 1.3 2254 1.2 1143 1.4 52 1.4 74 1.9 35 1.8 51 1.5 397 1.1 3927 1.4 181 1.1 1005 1.2 312 1.5 109 1.2 6211 1.0 27 1.4 51 1.2 574 1.3 1856 1.1 973 1.3 2163 1.1 57 1.6 470 1.3 147 1.4 728 1.3 18 1.3 124 1.2 980 1.6 54 1.2 197 1.6 250 1.2 25573
SIR 95% CI 1.3 1.3 0.9 * 1.2 0.9 1.2 * 1.1 1.0 1.0 1.1 1.5 * 1.2 * 1.1 * 1.2 1.0 1.0 1.2 1.2 0.7 1.1 * 1.1 1.2 1.0 1.3 0.9 1.2 1.1 1.2 0.9 1.1 * 1.1 1.2 1.0 1.2 1.2 *
1.2 1.0 0.7 1.0 0.7 1.2 1.0 0.8 0.8 0.8 1.1 1.0 1.0 1.0 1.0 0.9 0.9 1.2 0.4 0.8 1.0 1.1 0.9 1.2 0.7 1.1 0.9 1.1 0.5 0.9 1.0 0.9 0.9 1.1 1.1
1.4 1.7 1.3 1.3 1.1 1.3 1.2 1.3 1.2 1.6 1.9 1.3 1.1 1.4 1.1 1.1 1.4 1.2 1.0 1.4 1.2 1.2 1.1 1.4 1.1 1.3 1.2 1.3 1.4 1.2 1.2 1.6 1.2 1.4 1.2
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Upper aerodigestive tract 67 Salivary gland 7 Oesophagus 31 Stomach 120 Small intestine 21 Colon 338 Rectum 181 Anus 8 Liver 55 Pancreas 90 Nose 4 Lung 313 Breast 358 Cervix 21 Endometrium 109 Ovary 61 Other female genital 20 Prostate 688 Testis 3 Other male genital 10 Kidney 83 Urinary bladder 253 Melanoma 90 Skin, squamous cell 201 Eye 7 Nervous system 140 Thyroid gland 14 Endocrine glands 64 Bone 2 Connective tissue 21 Non-Hodgkin lymphoma 164 Hodgkin’s disease 5 Myeloma 54 Leukaemia 105 All 3708
6–12 months
SIR 95% Confidence O interval (CI)
Bold type, 95% CI does not include 1.00. 1879
1880
Table 3 SIRs for subsequent haemorrhagic stroke in cancer patients by follow-up time. Cancer site/type
Follow-up interval <6 months O
*
9 2 8 19 6 55 20 0 18 9 3 49 37 5 15 8 1 164 0 1 41 32 26 43 2 199 6 30 0 8 45 2 19 82 965
95% CI
0.9 2.4 2.0 1.5 3.4 1.5 0.9
0.4 0.2 0.9 0.9 1.2 1.1 0.6
1.8 8.7 4.1 2.4 7.4 1.9 1.4
2.4 1.2 4.2 1.8 0.9 2.2 1.4 1.4 0.5 1.4
1.4 0.6 0.8 1.3 0.6 0.7 0.8 0.6 0.0 1.2
3.8 2.4 12 2.3 1.2 5.1 2.3 2.8 3.0 1.6
1.0 4.1 1.1 1.9 * 1.4 2.0 29 3.6 5.6
0.0 2.9 0.8 1.3 1.0 0.2 25 1.3 3.8
5.8 5.6 1.6 2.8 1.9 7.3 34 7.9 8.0
3.2 2.3 2.6 2.9 13 2.2
1.4 1.7 0.2 1.8 10 2.0
6.5 3.1 9.6 4.6 16 2.3
Bold type, 95% CI does not include 1.00.
6–12 months
1–5 years
O
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
61 8 8 41 9 228 105 8 10 6 4 44 242 9 63 26 10 807 5 7 91 160 152 201 9 51 6 59 3 13 96 8 47 73 2671
*
1.0 0.8 0.7 1.1 0.6 1.2 0.9 0.8 0.6 0.6 0.3 0.8 0.8 0.4 0.7 0.7 0.6 1.2 0.5 0.6 1.6 1.0 1.6 1.1 0.7 1.4 0.2 1.2 0.4 0.6 0.9 0.9 1.4 2.6 1.2
42 6 2 38 9 153 96 8 3 2 6 11 231 11 53 17 8 420 5 2 54 117 96 122 5 59 10 67 2 8 70 4 11 21 1769
1.3 1.9 0.9 2.5 1.9 1.4 1.5 2.7 0.8 1.6 2.8 0.6 1.1 1.2 1.0 1.1 1.6 1.3 1.4 0.6 1.6 1.2 1.5 * 1.2 1.3 2.3 1.2 1.8 1.5 1.1 * 1.3 1.3 1.3 1.8 1.3
0.9 0.7 0.1 1.8 0.9 1.2 1.2 1.2 0.2 0.2 1.0 0.3 1.0 0.6 0.7 0.6 0.7 1.2 0.5 0.1 1.2 1.0 1.2 1.0 0.4 1.7 0.6 1.4 0.2 0.5 1.0 0.4 0.7 1.1 1.2
30 1 1 9 4 80 40 0 3 1 3 9 178 5 44 13 2 151 6 1 35 89 63 73 1 33 9 36 4 3 43 2 5 16 993
1.4 0.4 1.0 0.9 1.4 1.2 1.1
1.0 0.0 0.0 0.4 0.4 1.0 0.8
2.0 2.5 5.4 1.7 3.6 1.5 1.4
1.2 1.4 2.1 0.9 1.1 0.6 1.0 0.9 0.6 1.3 1.3 0.5 1.6 1.4 1.2 1.4 0.4 1.4 1.1 1.1 3.4 0.6 1.5 0.7 1.7 2.6 1.2
0.2 0.0 0.4 0.4 0.9 0.2 0.7 0.5 0.1 1.1 0.5 0.0 1.1 1.1 1.0 1.1 0.0 1.0 0.5 0.8 0.9 0.1 1.1 0.1 0.5 1.5 1.1
3.6 8.2 6.2 1.8 1.2 1.4 1.3 1.6 2.3 1.6 2.9 2.8 2.2 1.7 1.6 1.8 2.1 2.0 2.1 1.5 8.8 1.6 2.0 2.7 4.0 4.3 1.3
148 17 22 116 28 567 289 17 39 21 17 131 721 33 186 68 21 1684 16 11 237 435 359 476 18 368 32 201 9 36 268 17 93 223 6926
1.3 1.5 1.6 1.6 * 1.6 1.4 1.2 1.5 1.6 1.4 2.1 * 1.2 1.0 1.0 1.0 1.1 1.1 1.3 1.4 0.9 2.0 1.2 1.6 1.3 1.2 4.2 1.1 1.7 1.9 1.3 1.3 1.6 2.0 4.4 1.4
1.1 0.9 1.0 1.4 1.0 1.3 1.1 0.9 1.1 0.8 1.2 1.0 0.9 0.7 0.9 0.8 0.7 1.2 0.8 0.5 1.8 1.1 1.5 1.2 0.7 3.8 0.8 1.5 0.9 0.9 1.2 0.9 1.6 3.8 1.3
133 15 11 88 22 461 241 16 16 9 13 64 651 25 160 56 20 1378 16 10 180 366 311 396 15 143 25 162 9 24 209 14 63 110 5433
1.3 1.6 1.3 1.7 1.5 1.4 1.2 1.7 1.1 1.6 * 1.9 1.0 1.0 0.9 1.0 1.0 1.3 1.3 1.4 1.0 1.8 1.2 1.6 1.2 1.2 1.9 1.0 1.5 * 2.2 1.0 1.2 1.5 1.8 2.8 1.3
1.1 09 0.7 1.4 0.9 1.2 1.1 1.0 0.6 0.7 1.0 0.7 0.9 0.6 0.8 0.8 0.8 1.2 0.8 0.5 1.6 1.1 1.4 1.1 0.7 1.6 0.6 1.3 1.0 0.7 1.1 0.8 1.4 2.3 1.2
6 0 3 9 0 51 28 1 5 3 1 18 33 3 11 4 0 142 0 0 16 37 22 37 1 26 1 9 0 4 14 1 11 31 528
SIR
95% CI
0.7
0.3
1.6
1.5 1.2
0.3 0.6
4.4 2.4
1.6 1.5 1.2 1.7 1.2 1.6 1.2 0.8 1.5 1.1 0.8
1.2 1.0 0.0 0.5 0.2 0.0 0.7 0.6 0.3 0.6 0.2
2.1 2.2 6.8 4.0 3.6 9.4 1.9 1.2 4.5 2.0 2.2
1.3
1.1
1.6
2.0 1.5 1.7 1.3 1.0 5.5 0.7 1.8
1.1 1.1 1.1 0.9 0.0 3.6 0.0 0.8
3.2 2.1 2.6 1.8 5.9 8.0 4.1 3.3
2.0 0.9 1.6 2.0 6.5 1.4
0.5 0.5 0.0 1.0 4.4 1.3
5.2 1.5 9.2 3.6 9.3 1.5
1.3 1.9 1.6 1.6 1.2 1.4 1.1 1.8 1.2 1.6 1.3 1.1 0.9 0.8 1.0 1.1 1.3 1.3 1.7 1.5 2.0 1.1 1.9 1.2 1.5 1.8 0.6 1.5 1.9 1.2 1.1 2.1 1.9 3.3 1.3
5–10 years
1.7 3.7 3.2 2.2 2.3 1.5 1.3 3.6 2.3 3.5 3.3 1.5 1.1 1.6 1.2 1.6 2.4 1.4 3.9 3.1 2.5 1.3 2.2 1.4 2.9 2.4 1.4 2.0 5.7 2.1 1.3 4.2 2.6 4.2 1.3
10+ years
1.8 4.2 3.2 3.4 3.7 1.7 1.9 5.3 2.3 5.9 6.1 1.1 1.2 2.2 1.3 1.7 3.1 1.4 3.4 2.3 2.2 1.4 1.9 1.4 3.0 2.9 2.2 2.3 5.7 2.2 1.6 3.4 2.4 2.7 1.4
All
1+ years
1.5 2.4 2.4 2.0 2.2 1.5 1.4 2.4 2.1 2.1 3.4 1.4 1.1 1.4 1.2 1.4 1.7 1.4 2.2 1.7 2.3 1.3 1.8 1.4 2.0 4.6 1.6 2.0 3.7 1.8 1.5 2.5 2.4 5.0 1.4
16 2.6 2.4 2.1 2.2 1.5 1.4 2.8 1.8 3.0 3.3 1.2 1.1 1.3 1.1 1.4 1.9 1.4 2.4 1.8 2.1 1.3 1.8 1.4 2.0 2.2 1.4 1.8 4.2 1.6 1.4 2.5 2.3 3.3 1.3
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Upper aerodigestive tract Salivary gland Oesophagus Stomach Small intestine Colon Rectum Anus Liver Pancreas Nose Lung Breast Cervix Endometrium Ovary Other female genitals Prostate Testis Other male genitals Kidney Urinary bladder Melanoma Skin, squamous cell Eye Nervous system Thyroid gland Endocrine glands Bone Connective tissue Non-Hodgkin lymphoma Hodgkin’s disease Myeloma Leukaemia All
SIR
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
1881
Table 4 SIRs for subsequent stroke in cancer patients by metastasis. Cancer site/type
Ischaemic stroke
Haemorrhagic stroke
No metastasis
Upper aerodigestive tract Oesophagus Stomach Colon Rectum Liver Pancreas Nose Lung Breast Prostate Other male genitals Kidney Urinary bladder Melanoma Skin, squamous cell Thyroid gland Endocrine glands Connective tissue All *
With metastasis
No metastasis O
SIR
95% CI
O
6 2 5 45 12 5 2 1 20 44 78 1 7 6 20 44 1 0 1 304
0.7 1.6 1.7 * 1.4 0.71 3.9 2.0 2.2 1.1 0.8 1.1 1.1 1.4 0.6 2.2 1.6 0.8
0.3 0.2 0.5 1.0 0.4 1.2 0.2 0.0 0.7 0.6 0.9 0.0 0.6 0.2 1.4 1.2 0.0
1.6 6.0 4.0 1.8 1.2 9.1 7.2 13 1.8 1.1 1.4 6.3 2.9 1.3 3.4 2.2 4.6
0.9 1.2
0.0 1.0
5.1 1.3
0 0 1 8 1 0 1 0 18 0 47 0 7 0 0 0 0 0 0 83
O
SIR
95% CI
O
56 6 20 230 84 10 10 5 136 310 294 14 28 61 39 153 7 0 10 1499
1.5 1.1 1.4 1.5 1.0 1.6 2.0 2.4 1.6 * 1.1 1.0 3.6 1.2 * 1.3 0.9 1.2 1.2
1.1 0.4 0.9 1.3 0.8 0.8 1.0 0.8 1.4 1.0 0.8 2.0 0.8 1.0 0.6 1.0 0.5
1.9 2.3 2.2 1.7 1.3 3.0 3.7 5.6 1.9 1.3 1.1 6.1 1.7 1.7 1.3 1.4 2.5
2.0 1.2
0.9 1.1
3.6 1.3
0 3 7 35 9 3 16 0 64 8 97 0 5 3 2 1 2 0 0 258
SIR
95% CI
2.0 2.3 1.8 0.9 1.8 5.8
0.4 0.9 1.3 0.4 0.4 3.3
6.0 4.8 2.5 1.7 5.4 9.4
2.1 1.1 1.1
1.6 0.5 0.9
2.6 2.1 1.4
1.2 1.6 2.9 3.3 3.0
0.4 0.3 0.3 0.0 0.3
2.7 4.6 10 19 11
1.5
1.3
1.7
*
With metastasis SIR
95% CI
1.5 2.0 0.5
0.0 0.9 0.0
8.7 4.0 2.7
1.7
0.0
9.9
2.8
1.6
4.4
2.4
1.8
3.2
7.6
3.0
2.2
1.8
16
2.7
Bold type, 95% CI does not include 1.00.
3.4. Metastasis and haemorrhagic and ischaemic strokes’ risk The Swedish Cancer Registry only contains data on metastasis since 2002. Between 2002 and 2008, overall risk of haemorrhagic and ischaemic strokes was higher in cancer patients with metastasis than in those without metastasis (Table 4). 4. Discussion The present study is the first nationwide study of cancer and risk of haemorrhagic and ischaemic strokes to present precise risk estimates for multiple different cancer sites/types. The results indicate that many cancer sites/ types are associated with an increased risk of hospitalisation for haemorrhagic and ischaemic strokes. This is consistent with previous studies that have shown stroke to be common among cancer patients.2–7 Moreover, the association is not limited to smoking-related cancers. Several non-smoking-related cancers were also associated with increased risk of haemorrhagic and ischaemic strokes (Tables 2 and 3). Although it declines rapidly after 6 months, the overall risk of haemorrhagic and ischaemic strokes remains slightly raised for 10 or more years. Overall risk of haemorrhagic and ischaemic strokes is additionally related to the presence of metastasis (Table 4). The results of the present study suggest that there is a general association between cancer, especially newly diagnosed cancer, and increased risk of subsequent haemorrhagic and ischaemic strokes. We have recently reported increased risk of coronary heart disease
and myocardial infarction in cancer patients.22 Thus, arterial cardiovascular disease just like venous thromboembolism appears to be associated with cancer.8 Some cancer sites/types, notably the nervous system and leukaemia, are especially strongly associated with the development of ischaemic and haemorrhagic strokes, and it is of especial clinical relevance to consider them. The increased risks of haemorrhagic and ischaemic strokes for different cancer sites/types may have different underlying causes. Unfortunately, we were unable to determine the mechanisms involved due to lack of access to laboratory and treatment data. One possible cause of the increased stroke risk among cancer patients might be that cardiovascular risk factors like hypertension and diabetes and other comorbidities have been reported to be common among cancer patients.24–26 Since inflammation has been linked to both atherosclerosis and haemostatic activation, cancer-associated inflammation/ haemostatic activation may constitute a general link between cancer and haemorrhagic and ischaemic strokes.8–11 The observed association of tumour metastasis with haemorrhagic and ischaemic strokes’ risk indicates that this hypothesis is plausible (i.e. increased inflammation and haemostatic activation) due to presence of metastasis (i.e. increased tumour burden) (Table 3). As well as reducing tumour size, efficient cancer treatment might also reduce associated inflammation, haemostatic activation and, thus, risk of haemorrhagic and ischaemic strokes. The fact that the risk of haemorrhagic and ischaemic strokes decreases rapidly suggests that haemorrhagic and ischaemic strokes’ risk could be linked to tumour size, which is likely to decrease over
1882
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
time due to treatment. However, as we lack treatment data, we cannot test this hypothesis. The decreased risk after 6 months could also be due to the cessation of treatment with cytostatics.27 Cytostatics could not only promote thrombosis, but also bleeding due to thrombocytopenia.27 The rapid decrease could also be due to death of patients with cerebral metastasis or successful treatment of cerebral metastasis. Indeed, the risks for both haemorrhagic and ischaemic strokes were highest in patients with primary brain tumour (i.e. nervous system tumours). In smoking-related cancers, the increased haemorrhagic and ischaemic strokes’ risk may be due to tobacco smoking.14–17 Thus, smoking cessation—a confounder for which we could not adjust—may also contribute to the rapid decrease in the incidence of haemorrhagic and ischaemic strokes after diagnosis of cancer. Thus, a number of mechanisms are possible. The effects of treatment (cerebral or neck irradiation)28,29 may also contribute to the identified associations, especially in the case of primary brain tumour or cerebral metastasis. Risk for stroke was previously shown to be increased in survivors of paediatric CNS tumours, Hodgkin’s disease and acute lymphoblastic leukaemia,29 in agreement with our study, in which the highest risks were observed for brain tumours and leukaemia. However, the stroke risk was not increased in patients with Hodgkin’s disease in the present study. Another potential confounder that could contribute to the increased haemorrhagic and ischaemic strokes’ risk during the first 6 months after diagnosis is the stress of having cancer. Although we were unable to evaluate the impact of psychosocial stress, psychosocial factors have been suggested to be risk factors for cardiovascular disease.30 The present study has certain limitations. For example, we had no data on general cardiovascular disease risk factors such as weight, smoking and diet. It is unrealistic to gather such data for an entire national population. However, we did adjust for socioeconomic status, which is associated with risk factors such as smoking and alcohol. Adjustment was also made for comorbidities (COPD, obesity, alcoholism, hypertension and diabetes mellitus). A further limitation is that we had no access to outpatient data, which means that only the most severe cases of haemorrhagic and ischaemic strokes (i.e. those requiring hospitalisation) were included in the analyses. However, almost all cases of haemorrhagic and ischaemic strokes should, according to official guidelines, be treated at hospitals in Sweden.31 Computed tomography of the brain should also be performed in patients with stroke symptoms.31 Moreover, incidence rates were calculated for the whole follow-up period, divided into five time periods, and adjustments were made for possible changes in incidence rates over time. A further limitation was our lack of access to treatment data.
The study also had a number of strengths. For instance, the study population included all individuals in Sweden diagnosed with cancer and hospitalised with haemorrhagic or ischaemic stroke during the study period. Because of the personal identification number assigned to each resident in Sweden, it was possible to trace every subject for the whole follow-up period. Data on occupation were 99.2% complete (1980 and 1990 censuses), which enabled us to adjust our models for socioeconomic status. Moreover, the Swedish Cancer Registry records all new cases of cancer, with almost all cases being histologically or cytologically confirmed.19 A further strength of the present study was the use of validated hospital discharge data.18,32,33 The Hospital Discharge Register has high validity,18,32,33 especially for cardiovascular disorders such as haemorrhagic and ischaemic strokes, for which approximately 95% of diagnoses have been shown to be correct.32,33 Another advantage was that the exclusive use of hospital diagnoses eliminated recall bias. In summary, risk of hospitalisation for haemorrhagic and ischaemic strokes was, for a number of cancer sites/ types, found to be significantly increased during the first 6 months after diagnosis of cancer. The risk of haemorrhagic and ischaemic strokes decreased rapidly thereafter, but for many cancer sites remained elevated for more than 10 years. Overall risk of haemorrhagic and ischaemic strokes was related to the presence of metastasis, suggesting that haemorrhagic and ischaemic strokes’ risk is affected by the severity of cancer. The findings of the present study indicate that newly diagnosed cancer in general is associated with increased risk of ischaemic and haemorrhagic strokes. Role of the funding source None. Contributors All authors contributed to the conception and design of the study; JS and KS acquired; all authors contributed to the analysis and interpretation of data; BZ drafted the manuscript and all authors revised it critically and approved the final version. All authors had full access to all of the data (including statistical reports and tables) and take responsibility for their integrity and the accuracy of their analysis. Conflict of interest statement None declared.
B. Zo¨ller et al. / European Journal of Cancer 48 (2012) 1875–1883
Acknowledgements The authors wish to thank the CPF’s Science Editor Stephen Gilliver for his useful comments on the text. The registers used in the present study are maintained by Statistics Sweden and the National Board of Health and Welfare. This work was supported by grants awarded to Kristina and Jan Sundquist by the Swedish Research Council (2008-3110 and 2008-2638), the Swedish Council for Working Life and Social Research (2006-0386, 2007-1754 and 2007-1962), Formas (20064255-6596-99 and 2007-1352), and to Bengt Zo¨ller by the Swedish Heart and Lung Foundation and Region Ska˚ne (REGSKANE-124611). References 1. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371:1612–23. 2. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16–35. 3. Lindvig K, Moller H, Mosbech J, Jensen OM. The pattern of cancer in a large cohort of stroke patients. Int J Epidemiol 1990;19:498–504. 4. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology 2004;62:2025–30. 5. Rogers LR. Cerebrovascular complications in cancer patients. Oncology (Williston Park) 1994;8:23–30. 6. Nguyen T, DeAngelis LM. Stroke in cancer patients. Curr Neurol Neurosci Rep 2006;6:187–92. 7. Haller S, Lyrer P. Malignancy and stroke. Semin Cerebrovasc Dis Stroke 2005;5:47–54. 8. Franchini M, Montagnana M, Favaloro EJ, Lippi G. The bidirectional relationship of cancer and hemostasis and the potential role of anticoagulant therapy in moderating thrombosis and cancer spread. Semin Thromb Hemost 2009;35:644–53. 9. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7. 10. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. 11. van Leuven SI, Franssen R, Kastelein JJ, et al. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology 2008;47:3–7. 12. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis LM. Stroke in patients with cancer: incidence and etiology. Neurology 2004;62:2025–30. 13. Chaturvedi S, Ansell J, Recht L. Should cerebral ischemic events in cancer patients be considered a manifestation of hypercoagulability? Stroke 1994;25:1215–8. 14. Dreyer L, Olsen JH. Cancer risk of patients discharged with acute myocardial infarct. Epidemiology 1998;9:178–83. 15. Dreyer L, Olsen JH. Risk for non-smoking-related cancer in atherosclerotic patients. Cancer Epidemiol Biomarkers Prev 1999;8:915–8.
1883
16. Horn-Ross PL, Ljung BM, Morrow M. Environmental factors and the risk of salivary gland cancer. Epidemiology 1997;8:414–9. 17. Fernberg P, Odenbro A, Bellocco R, et al. Tobacco use, body mass index, and the risk of leukemia and multiple myeloma: a nationwide cohort study in Sweden. Cancer Res 2007;67:5983–6. 18. Rosen M, Hakulinen T. Use of disease registers. In: Ahrens W, Pigeot I, editors. Handbook of epidemiology. Berlin: SpringerVerlag; 2005. p. 231–52. 19. Cancer incidence in Sweden 2005. Stockholm: The National Board of Health and Welfare; 2007. 20. The multi-generation register 2009. A description of contents and quality. Statistics Sweden. Available from: