- Email: [email protected]
Cancer risk in asthmatic populations
Cancer risk in asthmatic populations Patricia Tennis, PhD*; Beth Sherrill, MS*; Carlos Fernandez, MD, MPH†; and Chantal Dolan, PhD‡
Objective: To conduct a meta-analysis of epidemiologic studies to derive a pooled estimate of the association between asthma and cancer incidence and between allergy and cancer incidence. Data Sources: Five cohort studies and 1 case-control study of cancer incidence in asthma, 4 studies of cancer mortality in asthma, and 3 studies of cancer incidence in allergy. Study Selection: We searched the National Library of Medicine Gateway to identify observational studies of cancer incidence in asthma and included any case-control or cohort study of incident cancers or of cancer mortality that met the predefined inclusion criteria. Results: There was no significant association between asthma and cancer incidence. A single large cohort study demonstrated a protective effect of asthma; the remaining cohort studies demonstrated a slightly elevated risk of cancer associated with asthma. Inconsistencies in study design features included control of smoking in analyses, use of a control group, and methods to identify asthma status. Conclusions: The method of asthma identification affects the validity of asthma classification and the severity of asthma examined. The inconsistency in study designs could have contributed to the variability in results and the underestimation of the impact of asthma on cancer incidence. Ann Allergy Asthma Immunol. 2005;95:354–360.
INTRODUCTION Innate and adaptive immunity are known to play key roles in tumor immunosurveillance (ie, the ability of the immune system to detect and destroy new, malignantly transformed cells), and the process has been studied extensively.1,2 To test hypotheses about the effect of IgE levels on cancer incidence, some early studies3–5 evaluated the relationship between IgE level and cancer, but these studies were cross-sectional and did not evaluate the IgE levels that preceded the development of cancer. Other studies6,7 evaluated the association of cancer incidence with conditions related to atopy, but definitions of exposures varied and included various combinations of asthma, hives, seasonal rhinitis, urticaria, and other conditions. To synthesize the literature and to perform a meta-analysis, we focused on 1 condition—asthma—as a potential risk factor for cancer. We performed a systematic review of observational studies that met the predefined study design inclusion criteria. This meta-analysis focuses on studies that explicitly included patients with asthma and evaluated the incidence of all cancer or cancer mortality. METHODS To identify all relevant published articles written in English, we conducted 2 literature searches in the National Library of Medicine Gateway. The first search was conducted in Octo-
* RTI Health Solutions, Research Triangle Park, North Carolina. † Novartis Pharmaceutical SA, Barcelona, Spain. ‡ Genentech, South San Francisco, California. Received for publication September 24, 2004. Accepted for publication in revised form February 24, 2005.
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ber 2002 and covered January 1, 1970, to October 31, 2002. Three hundred twenty-six articles were identified. The search terms included asthma combined with the following terms: human, epidemiology, cancer, neoplasia, neoplasm, casecontrol study, or cohort study. A second search was performed in October 2003, and 149 additional articles were identified. An epidemiologist (P.T.) reviewed the abstracts from each search to identify any formal study that evaluated the association between the incidence of all cancers and asthma. Any case-control or cohort study of incident cancers or of cancer mortality was initially reviewed to evaluate the methods used. Cohort studies followed up patients with asthma for several years and compared the incidence of cancer with that in a specified comparison group or population. The resultant measure of association was usually a relative risk or an incidence ratio, which reflected the ratio of cancer incidence in patients with asthma divided by the incidence in the comparison group. Case-control studies identified individuals with cancer (cases) and compared the prevalence of asthma or a history of asthma in these patients with that in a group of individuals without cancer (controls). These articles generally presented an odds ratio, which approximated the ratio of cancer incidence in patients with asthma relative to patients without asthma. For any article that identified all cancers and patients with asthma or patients with other conditions that explicitly included asthma, eg, allergy or atopy, we abstracted the methods documented to determine whether the studies met the following inclusion criteria to be considered in the metaanalysis: (1) age was controlled through stratification, matching, or analysis; (2) sex was controlled through stratification, matching, or analysis; (3) incidence was based on person-
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 1. Cohort Studies of the Association Between Asthma and Cancer Incidence or Mortality Source
Study years and location
Asthma and comparison groups, No.
Asthma ascertainment
Cancer ascertainment
Covariates matched or otherwise controlled
Cancer Incidence McWhorter,22 1971–1984 1,840 (includes 348 with Asthma was assessed as Cancer ⬎5 y after interview Age group, sex, race, 1988 US population asthma and others part of the NHANES I was assessed through smoking status with any other allergy) interview; self-report on hospital or nursing home 5,760 with no asthma having been told by a records or on the death 4,268 with no allergy physician that they had certificate if hospital asthma, hay fever, hives, records were unavailable. food allergy, or other Cancer was defined as allergy ICD-9 codes 140-208 Reynolds and 1965–1983 217 with asthma Asthma was assessed using Cancer was assessed Age, smoking, sex Kaplan,19 Alameda 6,608 with no asthma a survey with a self-report through a record linkage 1987 County, CA of asthma during the past to statewide vital 12 mo statistics and the California Tumor Registry Vesterinen et 1970–1987 77,952 with asthma Asthma was assessed Cancer was assessed Age, sex, period al,21 1993 Finland General population through the Finnish Social through the Finnish (1970–1975, Insurance Institution Cancer Registry 1976–1981, registry and was defined 1982–1987) as a diagnosis of bronchial 5-y age group, asthma by a specialist in follow-up from allergy, pulmonary the beginning of diseases, internal the entitlement medicine, or pediatrics or to reimbursed based on suitable hospital medication examination Eriksson et 1976–1989 6,593 with asthma or Allergy clinic patients Cancer was assessed Age group, calendar al,23 1995 Allergy clinic rhinitis or urticaria reporting symptoms such through the Swedish period, atopy, sex in Sweden (includes 2,512 with as dyspnea or wheezing National Tumor Registry asthma and 2,397 on exposure to allergens, and was identified by ICD with atopy [including unspecific irritants, or codes asthma]) exercise or showing General population reversible airway obstruction on spirometry Mills et al,24 1976–1982 16,244 with asthma or Asthma was ascertained Cancer was assessed Age, sex, smoking 1992 Seventh Day other allergies through use of a using a questionnaire to history, time since Adventists in 2,189 with asthma questionnaire asking, ascertain hospitalization last physician California 32,009 with no asthma “Have you been bothered and medical records and contact, number 17,954 with no asthma by any of the following the Cancer Surveillance of allergies or other allergies enough to seek treatment Program and Resources from a physician: asthma, for Cancer Epidemiology hay fever, reactions to in the San Francisco Bay medications, chemicals, area bee sting, and poison oak (or ivy) or other plants?” Kallen et al,20 1969–1987 64,346 with asthma Asthma was ascertained Cancer was ascertained Age, sex, period of 1993 Sweden General population through the Hospital through the Swedish cancer development Discharge Registry and Cancer Registry and the (first 5 y vs last 5 y) was defined by a hospital Death Registry in Sweden diagnosis of asthma and was defined as a malignant tumor occurring after the first known treatment period for asthma Continued
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Table 1. Continued Source
Study years and location
Cancer Mortality Robinette and 1944–1974 Fraumeni,25 US Army 1978
Asthma and comparison groups, No. 9,550 with asthma 9,550 with no asthma
Alderson,26 1974
1936–1970 1,892 with asthma Asthma clinic General population at Manchester Royal Infirmary (England)
Markowe et al,27 1987
1970–1985 60 general practices in Great Britain
Vandentorren 1974–1998 et al,28 2003 Households in France
2,158 with asthma 2,046 with no asthma
940 with asthma 13,346 without asthma in 1974–1976
Asthma ascertainment
Cancer ascertainment
Asthma was ascertained Cancer was ascertained through patients through death certificates hospitalized for asthma in and was defined by ICDthe US Army between 8–adapted codes 1944 and 1945 Asthma was ascertained Cancer was ascertained through medical records through the National and was defined as having Health Service Central a history of wheezing, Register and was defined dyspnea with intervening as death by malignant periods of complete cancer symptomatic remission, and a normal chest radiograph; most had a reaction on skin testing and had been recommended for desensitization or other conventional treatment for asthma Asthma was ascertained Cancer was ascertained through clinics that through medical records identified patients who and the National Health had consulted their Service Central Register general practitioner for and was defined as asthma during the national malignant neoplasm (ICD morbidity survey code 140-208) Asthma was ascertained by Deaths were ascertained the questions, “Have you via computerized national ever had asthma?” and register, and ICD codes “Have you ever had for causes of death were attacks of breathlessness obtained from the associated with National Institute of wheezing?” Health and Medical Research (INSERM)
Covariates matched or otherwise controlled Age at admission to hospital, calendar year of death
Age, sex, geographic area, year of entry into study (asthma diagnosis)
Age, sex, general practice
Age, sex, educational level, smoking habit, occupational exposure, FEV1 where appropriate
Abbreviation: FEV1, forced expiratory volume in 1 second; ICD, International Classification of Diseases; NHANES I, First National Health and Nutrition Examination Survey.
years of follow-up (in cohort studies); (4) identification of cancer outcomes was identical for exposed and unexposed individuals (in cohort studies); (5) identification of individuals with asthma was identical for cases and controls (in case-control studies); (6) the asthma definition reflected exposure before the diagnosis of cancer (in case-control studies); and (7) point estimates and variance estimates controlled for key covariates were reported. Where only sex-specific estimates were available, these were collected and used to derive an overall estimate. We recorded all covariates, including whether the study controlled for the smoking status of individuals. Statistical Methods We used measures of association and confidence limits provided by the individual study authors to generate combined
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estimates of the incidence ratio. Suitable measures included relative risk, odds ratio, and standardized incidence ratio. All included studies provided measures of association adjusted for sex and age, either through matching or original study analysis. Analyses were performed separately for cancer incidence in asthma, cancer incidence in allergy, and cancer mortality in asthma. Articles on allergy were included only if they explicitly mentioned that patients with asthma were included in the definition of allergy or atopy. Across-study estimates for the relative incidence of all cancers among asthmatic vs nonasthmatic populations or allergic vs nonallergic populations were generated using a random-effects approach.8 The random-effects approach incorporates between-study variance and consequently weights the studies more evenly than does a fixed-effects approach. The random-
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 2. Results Reported From Studies of Asthma and Cancer Incidence Source 22
McWhorter, 1988 Mills et al,24 1992 Kallen et al,20 1993 Vesterinen et al,21 1993 Eriksson et al,23 1995
Relative risk (95% CI)
Asthma group, No.
Males
Females
Total sample
348 2,189 64,346 77,952 2,512
NR 0.78 (0.48–1.27) 0.69 (0.66–0.71) 1.12 (1.07–1.17) NR
NR 0.96 (0.69–1.34) 0.62 (0.59–0.65) 1.03 (0.98–1.07) NR
1.02 (0.63–1.65) NR 0.66 (0.64–0.68) NR 1.27 (0.93–1.74)
Abbreviations: CI, confidence interval; NR, not reported.
effects approach is thus preferred when study results are shown to be heterogeneous. 2 Tests of heterogeneity and forest plots were generated by sex or sex combined, depending on the data reported from each study. For 2 studies that provided only sex-specific estimates of association, we calculated a within-study overall estimate of association as the weighted average of the estimates for men and for women. These values were used in place of missing values so that a single estimate could be generated across all studies for sex combined. We evaluated the effect of any single study by sequentially removing each study from the pool and recomputing the combined estimate of association across the remaining studies. We pursued meta-regression in an exploratory manner to evaluate whether study design characteristics affected measures of association. We used weighted measures of association from individual studies in general linear models as dependent variables, and we used study design differences (such as whether adjustments were made for smoking) as independent variables in the meta-regression. We used a software program (Stata version 7.0; StataCorp LP, College Station, TX) for performing analyses.9 –14 Analysis commands included META for generating summary estimates, METAINF for conducting influence evaluation, and METAREG for meta-regression models. RESULTS We identified 4 case-control studies and 10 cohort studies that evaluated the association between asthma and cancer incidence or cancer mortality. Excluded published articles included studies of individual cancer types, cross-sectional studies, and studies that did not evaluate both cancer and asthma. Case-Control Studies We identified 4 case-control studies that evaluated the association between asthma and all cancers. Of these studies, the 3 earliest15–17 did not adjust for age or did not specify how patients with cancer or controls were chosen and therefore did not meet the inclusion criteria for further analysis. In the remaining study,18 3.8% of 6,494 men with cancer and 3.0% of 7,077 women with cancer had a history of asthma, whereas 3.8% of the 1,562 male controls and 3.2% of the 2,477 female controls had a history of asthma. These findings resulted in age- and smoking-adjusted odds ratios of 0.96 and 0.92 for
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cancer in asthma among men and women, respectively, which were not significantly different from 1.0. Because there was only 1 eligible case-control study, no meta-analysis of casecontrol studies was performed. Cohort Studies Of the 10 identified cohort studies, 6 evaluated cancer incidence and 4 evaluated cancer mortality (Table 1). Of the studies that evaluated cancer incidence, that by Reynolds and Kaplan19 did not provide adequate data for assessing variance and was not included in the meta-analyses of cancer incidence. Methods for identifying asthma status and definitions of asthma were different across the cohort studies. Some studies were based on a physician diagnosis or prescription for treatment, and others were self-reported in a survey or interview. Table 2 summarizes the data available for meta-analysis of cancer incidence in asthmatic populations. The 2 large cohort studies that reported significant associations between asthma and cancer incidence gave contradictory results. The study by Kallen et al20 showed a significant negative association, and the study by Vesterinen et al21 reported a significant positive association among males; the overall sex-combined relative risk estimated for this study was significant (1.07; 95% confidence interval [CI], 1.04 –1.10). Combined-study estimates of the association between asthma and cancer incidence were not significant in any of the preliminary metaanalyses of studies with results from all patients (3 studies) or in sex-specific analyses (3 studies; P ⬎ .05) (Table 3). Results were affected little by the inclusion of imputed combined-sex estimates from the studies by Mills et al24 and Vesterinen et al21 (5 studies). The incidence ratio showed significant variability among the 5 studies (P ⬍ .001), and the pooled incidence ratio was 0.95 (95% CI, 0.69 –1.30) (Table 3 and Fig 1). Influence evaluation confirmed that the study by Kallen et al20 contributed most of the variability among studies. When the study by Kallen et al20 was excluded from the analysis because of lack of homogeneity, the 4 other studies were shown to provide homogeneous measures of association (test for heterogeneity, P ⬎ .20). These 4 studies gave a significant combined incidence ratio of 1.07 (95% CI, 1.04 –1.10). We attempted to identify factors that could explain the differing study results. However, the key study methods were 100% correlated in the following manner: (1) studies that used medical record– or medical service–related diagnosis of
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Table 3. Summary Results From Meta-analyses of Cohort Studies Assessing the Association Between Asthma and Cancer Incidence Meta-analysis subset Combined sexes reported Males only Females only Combined sexes imputed Combined sexes imputed*
Studies, No.
Relative risk (95% CI)
3 3 3 5 4
0.93 (0.57–1.51) 0.85 (0.57–1.29) 0.84 (0.56–1.28) 0.95 (0.69–1.30) 1.07 (1.04–1.10)
Abbreviation: CI, confidence interval. *The study by Kallen et al20 was excluded.
asthma did not control for smoking status, were conducted in Europe, and used population-based comparator data and (2) studies that used self-reported asthma ascertainment controlled for individual smoking status, were conducted in the United States, and had individuals without asthma identified for the comparator group. Therefore, it was impossible to determine which of the study design features (ascertainment method, control for smoking, location of study, and whether population-based comparator data were used) contributed to the between-study differences in incidence ratios. Examination of other factors that might explain heterogeneity across studies was limited owing to incomplete reporting. The 4 cohort studies that examined cancer mortality were evaluated separately from those that studied the incidence of cancers. One study25 included only males and demonstrated a significant association in males, 1 study26 demonstrated a significant negative association, and 2 studies27,28 did not detect any significant association (Table 4). Limited data were available for meta-analysis, and variance estimates or data to estimate variance were not reported in the 2 earlier studies.25,26 The latter 2 studies27,28 were combined to give a pooled estimate of relative risk of 1.03 (95% CI, 0.81–1.30). Three studies22–24 of allergy and cancer met the inclusion criteria, including explicit mention of asthma (Table 5). The study by McWhorter22 showed an excess of risk in people who reported having allergies, and the other 2 studies23,24 failed to show an association. Among these 3 studies, there was no significant heterogeneity in measures of association after imputing a sex-combined association for the study by Mills et al24 (relative risk, 1.05; 95% CI, 0.92–1.18; P ⫽ .10). The combined-study measure for the relative incidence of all cancers in patients with allergies compared with those without allergies was not significant (incidence ratio, 1.16; 95% CI, 0.94 –1.44). DISCUSSION Meta-analysis did not show a significant association when all the studies that met the methodological inclusion criteria were pooled. It is difficult to conclude whether asthma is associated with an increased or decreased incidence of cancer given the heterogeneity of the studies. Although a single large cohort study20 showed a protective effect of asthma on overall cancer incidence, the pooled results of the 4 other studies showed excess cancer risk in people with asthma.
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Figure 1. Forest plot of the incidence ratio for all cancer in individuals with asthma and those without asthma (all studies). The horizontal centers of the dark and light boxes represent the point estimates for relative risk in each study, and the areas of the boxes represent the sample size of each study. The width of the horizontal lines on the dark boxes and within the light boxes represent the 95% confidence intervals for each relative risk; the solid vertical line shows where relative risk is 1, representing no association; and the horizontal center of the diamond and the vertical dotted line represent the combined relative risk, and the horizontal width of the diamond represents the 95% confidence interval of the combined relative risk.
Some studies controlled for smoking status; patients with asthma may represent a heterogeneous group regarding age at onset and avoidance of exposure, which may partially explain the heterogeneity of the findings. Although smoking is a significant risk factor for asthma, some cancers, and cancer mortality, we could not control for smoking in a metaregression because control for smoking status was confounded by other important potential confounders. To our knowledge, age at asthma onset was not a controlled variable in any of the studies. All the European studies had the same design characteristics, which differed across the board from those of US studies. This confounding of key factors made it impossible to distinguish whether individual factors such as location, control for smoking status, or choice of comparator group affected study results. We expect that the methods used, such as how asthma was defined, how patients with asthma were identified, how cancer was identified, and how the comparison group was chosen, may affect individual study results. The use of asthma status or asthma history at one point in time to represent a specific state of the immune system for the long term is fraught with assumptions about the exposure of interest. Eriksson and colleagues23 showed that only 45% of patients with asthma had positive skin prick test reactions at one point in time, and none of these studies accounted for the temporal variability in symptoms. In the studies that also identified patients with allergies, patients with allergy and asthma overlapped, but neither was totally subsumed within the other. The lack of association of cancer incidence in patients with diagnosed allergies, after combining the studies, suggests that there is no strong positive or negative association of cancer incidence with heightened immune system activity.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 4. Results Reported From Studies of Asthma and Cancer Mortality Source 26
Alderson, 1974 Robinette and Fraumeni,25 1978* Markowe et al,27 1987 Vandentorren et al,28 2003
Relative risk (95% CI)
Asthma group, No.
Males
Females
Total sample
1,892 9,550 2,547 940
NR 1.28† 0.70 (0.30–1.40) NR
NR NR 1.20 (0.60–2.50) NR
0.71† NR 0.90 (0.50–1.50) 1.06 (0.81–1.40)
Abbreviations: CI, confidence interval; NR, not reported. *Females are not included in the study population. †P ⬍ .05.
Method of asthma ascertainment was a key study design difference. These studies ascertained asthma based on either clinical diagnosis, hospitalization for asthma, self-report, or referral for skin prick testing. These approaches can result in the inclusion of individuals with varying degrees of asthma severity and may, in some situations (eg, when self-reported), result in misclassification of asthma status. Such misclassification is generally expected to lessen the strength of the observed association. Severity of asthma could have been related to the method used to classify asthma status. The study by Vandentorren28 was the only study that accounted for clinical measures of severity (forced expiratory volume in 1 second); this study focused on mortality. The study by Kallen et al,20 in which patients with asthma were identified as having been hospitalized for asthma, had a substantial effect on the pooled association of cancer incidence and asthma and showed the strongest result in the predicted direction under the immunosurveillance hypothesis. Members of this group may have had more severe asthma, measured as asthma exacerbations, than the patients with asthma in the other cohort studies. This severity could account for the observed protective effect of asthma. However, it is also possible that the association could be biased given that the expected number of cancers was derived from the population data and there was no control for individual risk factors such as smoking. The other 4 studies included in the analysis of asthma and all cancers displayed a small but statistically significant effect in the opposite direction. This result was dominated by the study by Vesterinen et al,21 which was similar in size to the study by Kallen et al20 and was conducted in a neighboring country (Finland).
Except for asthma definition, the Kallen et al20 and Vesterinen et al21 study designs were similar. In the study by Vesterinen et al,21 asthma diagnosis was made by a specialist, and these patients did not seem to be at elevated risk compared with the general population. Studies also differed in period and countries where the studies were conducted. Asthma prevalence varies across time, with increasing prevalence noted across several decades.29 In addition, asthma prevalence varies substantially across various countries.30 The source of this variability is unclear, but it suggests that the asthma populations in these studies may be exposed to different factors across time and across countries, including different treatment approaches. Whether these factors could also affect observed risk for all cancers and confound the meta-analysis is unknown. The results on asthma and cancer mortality did not account for the possibility of competing causes of death. As demonstrated in the study by Robinette and Fraumeni,25 patients with asthma, especially those who have been hospitalized for asthma, may be more likely to experience other causes of mortality. This meta-analysis focused on the incidence of all cancers and did not address whether asthma is associated with the decreased risk of any specific cancer. Unless the excess risk of a specific cancer associated with asthma is very high, an analysis of all cancers would likely fail to detect such an association. One recent study31 of specific cancers evaluated the association of asthma and atopy (as measured by skin prick testing) with prostate cancer, breast cancer, colorectal cancer, lung cancer, melanoma, leukemia, and lymphoma. They found a small significant association of asthma with
Table 5. Results of Cohort Studies Quantifying the Association Between Allergy and All Cancers Source
Allergy patients, No.*
Cancers in allergy patients, No.
Relative risk (95% CI)
Covariates matched or otherwise controlled
1,840 2,397 NR
118 17 NR
1.40 (1.10–1.77) 1.07 (0.63–1.73) Males: 1.13 (0.92–1.39) Females: 1.00 (0.85–1.17)
Race, sex, smoking, age Sex, calendar year Age, sex, smoking history, time since last physician contact, number of allergies
McWhorter, 198822 Eriksson et al, 199523 Mills et al, 199224
Abbreviations: CI, confidence interval; NR, not reported stratified by sex. *Includes patients with asthma.
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prostate cancer only. Although other outcomes were associated with a point estimate suggesting a protective effect of asthma or atopy, the CIs were very wide and covered the null hypothesis of no association. In other words, any increased risk that may exist for a particular cancer is so small that it will be undetectable when all cancers are combined. In conclusion, the meta-analysis did not show a significant association between asthma and cancer incidence or cancer mortality. One large cohort study that showed a significant protective effect on cancer incidence was counterbalanced by 4 studies that, when combined, showed a significant increased risk. Only 2 studies could be included in the metaanalysis of cancer mortality, and no association was detected. The individual cohort study methods varied substantially by type of asthma ascertainment, possible confounding of treatment, and other factors, and the meta-analysis was constrained by the limited data available in the published articles. The ideal study design to test the hypothesis of interest would be a cohort study that measured specific aspects of immune system activity at baseline and at regular intervals throughout a long follow-up period. If one uses patients with asthma as a surrogate for hypersensitive immune systems, the identification of important confounding variables, including treatment, would be essential to understanding whether there is an association between cancer and asthma. REFERENCES 1. Severson R, Davis S, Thomas DB, Stevens RG, Heuser L, Sever LE. Acute myelocytic leukemia and prior allergies. J Clin Epidemiol. 1989;42:995–1001. 2. Smyth M, Godfrey D, Trapani J. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001;2: 293–299. 3. Hallgren R, Arrendal H, Hiesche K, Lundquist G, Nou E, Zetterstrom O. Elevated serum immunoglobulin E in bronchial carcinoma: its relation to the histology and prognosis of the cancer. J Allergy Clin Immunol. 1981;67:398 – 406. 4. Hallgren R, Nou E, Arrendal H, Hiesche K. Smoking and circulating IgE in bronchial carcinoma. Acta Med Scand. 1982; 211:269 –273. 5. Winters W, Heiner D. IgE levels in sera of cancer patients. J Allergy Clin Immunol. 1976;57:181–186. 6. Meers PD. Allergy and cancer. Lancet. 1973;1973:884 – 885. 7. Cockcroft DW, Klein GJ, Donevan RE, Copland GM. Is there a negative correlation between malignancy and respiratory atopy? Ann Allergy. 1979;43:345–347. 8. Cochrane Reviewers’ Handbook 4.1. Oxford, England: The Cochrane Collaboration; 2000. 9. Sharp S, Sterne J. sbe16: meta-analysis. Stata Tech Bull. 1997; 38:9 –14. 10. Sharp S, Sterne J. sbe16.1: new syntax and output for the meta-analysis command. Stata Tech Bull. 1998;42:6 – 8. 11. Sharp S, Sterne J. sbe16.2: corrections to the meta-analysis command. Stata Tech Bull. 1998;43:15. 12. Sharp S. sbe23: meta-analysis regression. Stata Tech Bull. 1998; 42:16 –24.
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13. Tobias A. sbe26: assessing the influence of a single study in meta-analysis. Stata Tech Bull. 1999;47:15–17. 14. Sterne J, Bradburn MJ, Egger M. Meta-analysis in Stata™. In: Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta Analysis in Context. London, England: BMJ Publishing Group; 2000:347–349. 15. Johnson KJ. The relation of cancer to allergy. J Lancet. 1966; 86:5–11. 16. Mackay WD. The incidence of allergic disorders and cancer. Br J Cancer. 1966;20:434 – 437. 17. Logan J, Saker D. The incidence of allergic disorders in cancer. N Z Med J. 1953;52:210 –212. 18. Vena JE, Bona JR, Byers TE, Middleton E Jr, Swanson MK, Graham S. Allergy-related diseases and cancer: an inverse association. Am J Epidemiol. 1985;122:66 –74. 19. Reynolds P, Kaplan GA. Asthma and cancer. Am J Epidemiol. 1987;125:539 –540. 20. Kallen B, Gunnarskog J, Conradson TB. Cancer risk in asthmatic subjects selected from hospital discharge registry. Eur Respir J. 1993;6:694 – 697. 21. Vesterinen E, Pukkala E, Timonen T, Aromaa A. Cancer incidence among 78,000 asthmatic patients. Int J Epidemiol. 1993; 22:976 –982. 22. McWhorter WP. Allergy and risk of cancer: a prospective study using NHANESI follow-up data. Cancer. 1988;62:451– 455. 23. Eriksson NE, Holmen A, Hogstedt B, Mikoczy Z, Hagmar L. A prospective study of cancer incidence in a cohort examined for allergy. Allergy. 1995;50:718 –722. 24. Mills PK, Beeson WL, Fraser GE, Phillips RL. Allergy and cancer: organ site-specific results from the Adventist Health Study. Am J Epidemiol. 1992;136:287–295. 25. Robinette CD, Fraumeni JF Jr. Asthma and subsequent mortality in World War II veterans. J Chronic Dis. 1978;31:619 – 624. 26. Alderson M. Mortality from malignant disease in patients with asthma. Lancet. 1974;2:1475–1477. 27. Markowe HL, Bulpitt CJ, Shipley MJ, Rose G, Crombie DL, Fleming DM. Prognosis in adult asthma: a national study. BMJ (Clin Res Ed). 1987;295:949 –952. 28. Vandentorren S, Bladi I, Maesano IA, et al. Long-term mortality among adults with or without asthma in the PAARC study. Eur Respir J. 2003;21:462– 467. 29. American Lung Association. Trends in asthma morbidity and mortality: 2002 [monograph]. Available at: http://www. lungusa.org/data/asthma/ASTHMAdt.pdf. Accessed October 15, 2002. 30. European Community Respiratory Health Survey. Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996;9:687– 695. 31. Talbot-Smith A, Frtischi L, Divitini ML, et al. Allergy, atopy, and cancer: a prospective study of the 1981 Brusselton cohort. Am J Epidemiol. 2003;157:606 – 612. Requests for reprints should be addressed to: Patricia Tennis, PhD RTI Health Solutions 3040 Cornwallis Rd Research Triangle Park, NC 27709-2194 E-mail: [email protected]
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Objective: To conduct a meta-analysis of epidemiologic studies to derive a pooled estimate of the association between asthma and cancer incidence and between allergy and cancer incidence. Data Sources: Five cohort studies and 1 case-control study of cancer incidence in asthma, 4 studies of cancer mortality in asthma, and 3 studies of cancer incidence in allergy. Study Selection: We searched the National Library of Medicine Gateway to identify observational studies of cancer incidence in asthma and included any case-control or cohort study of incident cancers or of cancer mortality that met the predefined inclusion criteria. Results: There was no significant association between asthma and cancer incidence. A single large cohort study demonstrated a protective effect of asthma; the remaining cohort studies demonstrated a slightly elevated risk of cancer associated with asthma. Inconsistencies in study design features included control of smoking in analyses, use of a control group, and methods to identify asthma status. Conclusions: The method of asthma identification affects the validity of asthma classification and the severity of asthma examined. The inconsistency in study designs could have contributed to the variability in results and the underestimation of the impact of asthma on cancer incidence. Ann Allergy Asthma Immunol. 2005;95:354–360.
INTRODUCTION Innate and adaptive immunity are known to play key roles in tumor immunosurveillance (ie, the ability of the immune system to detect and destroy new, malignantly transformed cells), and the process has been studied extensively.1,2 To test hypotheses about the effect of IgE levels on cancer incidence, some early studies3–5 evaluated the relationship between IgE level and cancer, but these studies were cross-sectional and did not evaluate the IgE levels that preceded the development of cancer. Other studies6,7 evaluated the association of cancer incidence with conditions related to atopy, but definitions of exposures varied and included various combinations of asthma, hives, seasonal rhinitis, urticaria, and other conditions. To synthesize the literature and to perform a meta-analysis, we focused on 1 condition—asthma—as a potential risk factor for cancer. We performed a systematic review of observational studies that met the predefined study design inclusion criteria. This meta-analysis focuses on studies that explicitly included patients with asthma and evaluated the incidence of all cancer or cancer mortality. METHODS To identify all relevant published articles written in English, we conducted 2 literature searches in the National Library of Medicine Gateway. The first search was conducted in Octo-
* RTI Health Solutions, Research Triangle Park, North Carolina. † Novartis Pharmaceutical SA, Barcelona, Spain. ‡ Genentech, South San Francisco, California. Received for publication September 24, 2004. Accepted for publication in revised form February 24, 2005.
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ber 2002 and covered January 1, 1970, to October 31, 2002. Three hundred twenty-six articles were identified. The search terms included asthma combined with the following terms: human, epidemiology, cancer, neoplasia, neoplasm, casecontrol study, or cohort study. A second search was performed in October 2003, and 149 additional articles were identified. An epidemiologist (P.T.) reviewed the abstracts from each search to identify any formal study that evaluated the association between the incidence of all cancers and asthma. Any case-control or cohort study of incident cancers or of cancer mortality was initially reviewed to evaluate the methods used. Cohort studies followed up patients with asthma for several years and compared the incidence of cancer with that in a specified comparison group or population. The resultant measure of association was usually a relative risk or an incidence ratio, which reflected the ratio of cancer incidence in patients with asthma divided by the incidence in the comparison group. Case-control studies identified individuals with cancer (cases) and compared the prevalence of asthma or a history of asthma in these patients with that in a group of individuals without cancer (controls). These articles generally presented an odds ratio, which approximated the ratio of cancer incidence in patients with asthma relative to patients without asthma. For any article that identified all cancers and patients with asthma or patients with other conditions that explicitly included asthma, eg, allergy or atopy, we abstracted the methods documented to determine whether the studies met the following inclusion criteria to be considered in the metaanalysis: (1) age was controlled through stratification, matching, or analysis; (2) sex was controlled through stratification, matching, or analysis; (3) incidence was based on person-
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 1. Cohort Studies of the Association Between Asthma and Cancer Incidence or Mortality Source
Study years and location
Asthma and comparison groups, No.
Asthma ascertainment
Cancer ascertainment
Covariates matched or otherwise controlled
Cancer Incidence McWhorter,22 1971–1984 1,840 (includes 348 with Asthma was assessed as Cancer ⬎5 y after interview Age group, sex, race, 1988 US population asthma and others part of the NHANES I was assessed through smoking status with any other allergy) interview; self-report on hospital or nursing home 5,760 with no asthma having been told by a records or on the death 4,268 with no allergy physician that they had certificate if hospital asthma, hay fever, hives, records were unavailable. food allergy, or other Cancer was defined as allergy ICD-9 codes 140-208 Reynolds and 1965–1983 217 with asthma Asthma was assessed using Cancer was assessed Age, smoking, sex Kaplan,19 Alameda 6,608 with no asthma a survey with a self-report through a record linkage 1987 County, CA of asthma during the past to statewide vital 12 mo statistics and the California Tumor Registry Vesterinen et 1970–1987 77,952 with asthma Asthma was assessed Cancer was assessed Age, sex, period al,21 1993 Finland General population through the Finnish Social through the Finnish (1970–1975, Insurance Institution Cancer Registry 1976–1981, registry and was defined 1982–1987) as a diagnosis of bronchial 5-y age group, asthma by a specialist in follow-up from allergy, pulmonary the beginning of diseases, internal the entitlement medicine, or pediatrics or to reimbursed based on suitable hospital medication examination Eriksson et 1976–1989 6,593 with asthma or Allergy clinic patients Cancer was assessed Age group, calendar al,23 1995 Allergy clinic rhinitis or urticaria reporting symptoms such through the Swedish period, atopy, sex in Sweden (includes 2,512 with as dyspnea or wheezing National Tumor Registry asthma and 2,397 on exposure to allergens, and was identified by ICD with atopy [including unspecific irritants, or codes asthma]) exercise or showing General population reversible airway obstruction on spirometry Mills et al,24 1976–1982 16,244 with asthma or Asthma was ascertained Cancer was assessed Age, sex, smoking 1992 Seventh Day other allergies through use of a using a questionnaire to history, time since Adventists in 2,189 with asthma questionnaire asking, ascertain hospitalization last physician California 32,009 with no asthma “Have you been bothered and medical records and contact, number 17,954 with no asthma by any of the following the Cancer Surveillance of allergies or other allergies enough to seek treatment Program and Resources from a physician: asthma, for Cancer Epidemiology hay fever, reactions to in the San Francisco Bay medications, chemicals, area bee sting, and poison oak (or ivy) or other plants?” Kallen et al,20 1969–1987 64,346 with asthma Asthma was ascertained Cancer was ascertained Age, sex, period of 1993 Sweden General population through the Hospital through the Swedish cancer development Discharge Registry and Cancer Registry and the (first 5 y vs last 5 y) was defined by a hospital Death Registry in Sweden diagnosis of asthma and was defined as a malignant tumor occurring after the first known treatment period for asthma Continued
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Table 1. Continued Source
Study years and location
Cancer Mortality Robinette and 1944–1974 Fraumeni,25 US Army 1978
Asthma and comparison groups, No. 9,550 with asthma 9,550 with no asthma
Alderson,26 1974
1936–1970 1,892 with asthma Asthma clinic General population at Manchester Royal Infirmary (England)
Markowe et al,27 1987
1970–1985 60 general practices in Great Britain
Vandentorren 1974–1998 et al,28 2003 Households in France
2,158 with asthma 2,046 with no asthma
940 with asthma 13,346 without asthma in 1974–1976
Asthma ascertainment
Cancer ascertainment
Asthma was ascertained Cancer was ascertained through patients through death certificates hospitalized for asthma in and was defined by ICDthe US Army between 8–adapted codes 1944 and 1945 Asthma was ascertained Cancer was ascertained through medical records through the National and was defined as having Health Service Central a history of wheezing, Register and was defined dyspnea with intervening as death by malignant periods of complete cancer symptomatic remission, and a normal chest radiograph; most had a reaction on skin testing and had been recommended for desensitization or other conventional treatment for asthma Asthma was ascertained Cancer was ascertained through clinics that through medical records identified patients who and the National Health had consulted their Service Central Register general practitioner for and was defined as asthma during the national malignant neoplasm (ICD morbidity survey code 140-208) Asthma was ascertained by Deaths were ascertained the questions, “Have you via computerized national ever had asthma?” and register, and ICD codes “Have you ever had for causes of death were attacks of breathlessness obtained from the associated with National Institute of wheezing?” Health and Medical Research (INSERM)
Covariates matched or otherwise controlled Age at admission to hospital, calendar year of death
Age, sex, geographic area, year of entry into study (asthma diagnosis)
Age, sex, general practice
Age, sex, educational level, smoking habit, occupational exposure, FEV1 where appropriate
Abbreviation: FEV1, forced expiratory volume in 1 second; ICD, International Classification of Diseases; NHANES I, First National Health and Nutrition Examination Survey.
years of follow-up (in cohort studies); (4) identification of cancer outcomes was identical for exposed and unexposed individuals (in cohort studies); (5) identification of individuals with asthma was identical for cases and controls (in case-control studies); (6) the asthma definition reflected exposure before the diagnosis of cancer (in case-control studies); and (7) point estimates and variance estimates controlled for key covariates were reported. Where only sex-specific estimates were available, these were collected and used to derive an overall estimate. We recorded all covariates, including whether the study controlled for the smoking status of individuals. Statistical Methods We used measures of association and confidence limits provided by the individual study authors to generate combined
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estimates of the incidence ratio. Suitable measures included relative risk, odds ratio, and standardized incidence ratio. All included studies provided measures of association adjusted for sex and age, either through matching or original study analysis. Analyses were performed separately for cancer incidence in asthma, cancer incidence in allergy, and cancer mortality in asthma. Articles on allergy were included only if they explicitly mentioned that patients with asthma were included in the definition of allergy or atopy. Across-study estimates for the relative incidence of all cancers among asthmatic vs nonasthmatic populations or allergic vs nonallergic populations were generated using a random-effects approach.8 The random-effects approach incorporates between-study variance and consequently weights the studies more evenly than does a fixed-effects approach. The random-
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 2. Results Reported From Studies of Asthma and Cancer Incidence Source 22
McWhorter, 1988 Mills et al,24 1992 Kallen et al,20 1993 Vesterinen et al,21 1993 Eriksson et al,23 1995
Relative risk (95% CI)
Asthma group, No.
Males
Females
Total sample
348 2,189 64,346 77,952 2,512
NR 0.78 (0.48–1.27) 0.69 (0.66–0.71) 1.12 (1.07–1.17) NR
NR 0.96 (0.69–1.34) 0.62 (0.59–0.65) 1.03 (0.98–1.07) NR
1.02 (0.63–1.65) NR 0.66 (0.64–0.68) NR 1.27 (0.93–1.74)
Abbreviations: CI, confidence interval; NR, not reported.
effects approach is thus preferred when study results are shown to be heterogeneous. 2 Tests of heterogeneity and forest plots were generated by sex or sex combined, depending on the data reported from each study. For 2 studies that provided only sex-specific estimates of association, we calculated a within-study overall estimate of association as the weighted average of the estimates for men and for women. These values were used in place of missing values so that a single estimate could be generated across all studies for sex combined. We evaluated the effect of any single study by sequentially removing each study from the pool and recomputing the combined estimate of association across the remaining studies. We pursued meta-regression in an exploratory manner to evaluate whether study design characteristics affected measures of association. We used weighted measures of association from individual studies in general linear models as dependent variables, and we used study design differences (such as whether adjustments were made for smoking) as independent variables in the meta-regression. We used a software program (Stata version 7.0; StataCorp LP, College Station, TX) for performing analyses.9 –14 Analysis commands included META for generating summary estimates, METAINF for conducting influence evaluation, and METAREG for meta-regression models. RESULTS We identified 4 case-control studies and 10 cohort studies that evaluated the association between asthma and cancer incidence or cancer mortality. Excluded published articles included studies of individual cancer types, cross-sectional studies, and studies that did not evaluate both cancer and asthma. Case-Control Studies We identified 4 case-control studies that evaluated the association between asthma and all cancers. Of these studies, the 3 earliest15–17 did not adjust for age or did not specify how patients with cancer or controls were chosen and therefore did not meet the inclusion criteria for further analysis. In the remaining study,18 3.8% of 6,494 men with cancer and 3.0% of 7,077 women with cancer had a history of asthma, whereas 3.8% of the 1,562 male controls and 3.2% of the 2,477 female controls had a history of asthma. These findings resulted in age- and smoking-adjusted odds ratios of 0.96 and 0.92 for
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cancer in asthma among men and women, respectively, which were not significantly different from 1.0. Because there was only 1 eligible case-control study, no meta-analysis of casecontrol studies was performed. Cohort Studies Of the 10 identified cohort studies, 6 evaluated cancer incidence and 4 evaluated cancer mortality (Table 1). Of the studies that evaluated cancer incidence, that by Reynolds and Kaplan19 did not provide adequate data for assessing variance and was not included in the meta-analyses of cancer incidence. Methods for identifying asthma status and definitions of asthma were different across the cohort studies. Some studies were based on a physician diagnosis or prescription for treatment, and others were self-reported in a survey or interview. Table 2 summarizes the data available for meta-analysis of cancer incidence in asthmatic populations. The 2 large cohort studies that reported significant associations between asthma and cancer incidence gave contradictory results. The study by Kallen et al20 showed a significant negative association, and the study by Vesterinen et al21 reported a significant positive association among males; the overall sex-combined relative risk estimated for this study was significant (1.07; 95% confidence interval [CI], 1.04 –1.10). Combined-study estimates of the association between asthma and cancer incidence were not significant in any of the preliminary metaanalyses of studies with results from all patients (3 studies) or in sex-specific analyses (3 studies; P ⬎ .05) (Table 3). Results were affected little by the inclusion of imputed combined-sex estimates from the studies by Mills et al24 and Vesterinen et al21 (5 studies). The incidence ratio showed significant variability among the 5 studies (P ⬍ .001), and the pooled incidence ratio was 0.95 (95% CI, 0.69 –1.30) (Table 3 and Fig 1). Influence evaluation confirmed that the study by Kallen et al20 contributed most of the variability among studies. When the study by Kallen et al20 was excluded from the analysis because of lack of homogeneity, the 4 other studies were shown to provide homogeneous measures of association (test for heterogeneity, P ⬎ .20). These 4 studies gave a significant combined incidence ratio of 1.07 (95% CI, 1.04 –1.10). We attempted to identify factors that could explain the differing study results. However, the key study methods were 100% correlated in the following manner: (1) studies that used medical record– or medical service–related diagnosis of
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Table 3. Summary Results From Meta-analyses of Cohort Studies Assessing the Association Between Asthma and Cancer Incidence Meta-analysis subset Combined sexes reported Males only Females only Combined sexes imputed Combined sexes imputed*
Studies, No.
Relative risk (95% CI)
3 3 3 5 4
0.93 (0.57–1.51) 0.85 (0.57–1.29) 0.84 (0.56–1.28) 0.95 (0.69–1.30) 1.07 (1.04–1.10)
Abbreviation: CI, confidence interval. *The study by Kallen et al20 was excluded.
asthma did not control for smoking status, were conducted in Europe, and used population-based comparator data and (2) studies that used self-reported asthma ascertainment controlled for individual smoking status, were conducted in the United States, and had individuals without asthma identified for the comparator group. Therefore, it was impossible to determine which of the study design features (ascertainment method, control for smoking, location of study, and whether population-based comparator data were used) contributed to the between-study differences in incidence ratios. Examination of other factors that might explain heterogeneity across studies was limited owing to incomplete reporting. The 4 cohort studies that examined cancer mortality were evaluated separately from those that studied the incidence of cancers. One study25 included only males and demonstrated a significant association in males, 1 study26 demonstrated a significant negative association, and 2 studies27,28 did not detect any significant association (Table 4). Limited data were available for meta-analysis, and variance estimates or data to estimate variance were not reported in the 2 earlier studies.25,26 The latter 2 studies27,28 were combined to give a pooled estimate of relative risk of 1.03 (95% CI, 0.81–1.30). Three studies22–24 of allergy and cancer met the inclusion criteria, including explicit mention of asthma (Table 5). The study by McWhorter22 showed an excess of risk in people who reported having allergies, and the other 2 studies23,24 failed to show an association. Among these 3 studies, there was no significant heterogeneity in measures of association after imputing a sex-combined association for the study by Mills et al24 (relative risk, 1.05; 95% CI, 0.92–1.18; P ⫽ .10). The combined-study measure for the relative incidence of all cancers in patients with allergies compared with those without allergies was not significant (incidence ratio, 1.16; 95% CI, 0.94 –1.44). DISCUSSION Meta-analysis did not show a significant association when all the studies that met the methodological inclusion criteria were pooled. It is difficult to conclude whether asthma is associated with an increased or decreased incidence of cancer given the heterogeneity of the studies. Although a single large cohort study20 showed a protective effect of asthma on overall cancer incidence, the pooled results of the 4 other studies showed excess cancer risk in people with asthma.
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Figure 1. Forest plot of the incidence ratio for all cancer in individuals with asthma and those without asthma (all studies). The horizontal centers of the dark and light boxes represent the point estimates for relative risk in each study, and the areas of the boxes represent the sample size of each study. The width of the horizontal lines on the dark boxes and within the light boxes represent the 95% confidence intervals for each relative risk; the solid vertical line shows where relative risk is 1, representing no association; and the horizontal center of the diamond and the vertical dotted line represent the combined relative risk, and the horizontal width of the diamond represents the 95% confidence interval of the combined relative risk.
Some studies controlled for smoking status; patients with asthma may represent a heterogeneous group regarding age at onset and avoidance of exposure, which may partially explain the heterogeneity of the findings. Although smoking is a significant risk factor for asthma, some cancers, and cancer mortality, we could not control for smoking in a metaregression because control for smoking status was confounded by other important potential confounders. To our knowledge, age at asthma onset was not a controlled variable in any of the studies. All the European studies had the same design characteristics, which differed across the board from those of US studies. This confounding of key factors made it impossible to distinguish whether individual factors such as location, control for smoking status, or choice of comparator group affected study results. We expect that the methods used, such as how asthma was defined, how patients with asthma were identified, how cancer was identified, and how the comparison group was chosen, may affect individual study results. The use of asthma status or asthma history at one point in time to represent a specific state of the immune system for the long term is fraught with assumptions about the exposure of interest. Eriksson and colleagues23 showed that only 45% of patients with asthma had positive skin prick test reactions at one point in time, and none of these studies accounted for the temporal variability in symptoms. In the studies that also identified patients with allergies, patients with allergy and asthma overlapped, but neither was totally subsumed within the other. The lack of association of cancer incidence in patients with diagnosed allergies, after combining the studies, suggests that there is no strong positive or negative association of cancer incidence with heightened immune system activity.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 4. Results Reported From Studies of Asthma and Cancer Mortality Source 26
Alderson, 1974 Robinette and Fraumeni,25 1978* Markowe et al,27 1987 Vandentorren et al,28 2003
Relative risk (95% CI)
Asthma group, No.
Males
Females
Total sample
1,892 9,550 2,547 940
NR 1.28† 0.70 (0.30–1.40) NR
NR NR 1.20 (0.60–2.50) NR
0.71† NR 0.90 (0.50–1.50) 1.06 (0.81–1.40)
Abbreviations: CI, confidence interval; NR, not reported. *Females are not included in the study population. †P ⬍ .05.
Method of asthma ascertainment was a key study design difference. These studies ascertained asthma based on either clinical diagnosis, hospitalization for asthma, self-report, or referral for skin prick testing. These approaches can result in the inclusion of individuals with varying degrees of asthma severity and may, in some situations (eg, when self-reported), result in misclassification of asthma status. Such misclassification is generally expected to lessen the strength of the observed association. Severity of asthma could have been related to the method used to classify asthma status. The study by Vandentorren28 was the only study that accounted for clinical measures of severity (forced expiratory volume in 1 second); this study focused on mortality. The study by Kallen et al,20 in which patients with asthma were identified as having been hospitalized for asthma, had a substantial effect on the pooled association of cancer incidence and asthma and showed the strongest result in the predicted direction under the immunosurveillance hypothesis. Members of this group may have had more severe asthma, measured as asthma exacerbations, than the patients with asthma in the other cohort studies. This severity could account for the observed protective effect of asthma. However, it is also possible that the association could be biased given that the expected number of cancers was derived from the population data and there was no control for individual risk factors such as smoking. The other 4 studies included in the analysis of asthma and all cancers displayed a small but statistically significant effect in the opposite direction. This result was dominated by the study by Vesterinen et al,21 which was similar in size to the study by Kallen et al20 and was conducted in a neighboring country (Finland).
Except for asthma definition, the Kallen et al20 and Vesterinen et al21 study designs were similar. In the study by Vesterinen et al,21 asthma diagnosis was made by a specialist, and these patients did not seem to be at elevated risk compared with the general population. Studies also differed in period and countries where the studies were conducted. Asthma prevalence varies across time, with increasing prevalence noted across several decades.29 In addition, asthma prevalence varies substantially across various countries.30 The source of this variability is unclear, but it suggests that the asthma populations in these studies may be exposed to different factors across time and across countries, including different treatment approaches. Whether these factors could also affect observed risk for all cancers and confound the meta-analysis is unknown. The results on asthma and cancer mortality did not account for the possibility of competing causes of death. As demonstrated in the study by Robinette and Fraumeni,25 patients with asthma, especially those who have been hospitalized for asthma, may be more likely to experience other causes of mortality. This meta-analysis focused on the incidence of all cancers and did not address whether asthma is associated with the decreased risk of any specific cancer. Unless the excess risk of a specific cancer associated with asthma is very high, an analysis of all cancers would likely fail to detect such an association. One recent study31 of specific cancers evaluated the association of asthma and atopy (as measured by skin prick testing) with prostate cancer, breast cancer, colorectal cancer, lung cancer, melanoma, leukemia, and lymphoma. They found a small significant association of asthma with
Table 5. Results of Cohort Studies Quantifying the Association Between Allergy and All Cancers Source
Allergy patients, No.*
Cancers in allergy patients, No.
Relative risk (95% CI)
Covariates matched or otherwise controlled
1,840 2,397 NR
118 17 NR
1.40 (1.10–1.77) 1.07 (0.63–1.73) Males: 1.13 (0.92–1.39) Females: 1.00 (0.85–1.17)
Race, sex, smoking, age Sex, calendar year Age, sex, smoking history, time since last physician contact, number of allergies
McWhorter, 198822 Eriksson et al, 199523 Mills et al, 199224
Abbreviations: CI, confidence interval; NR, not reported stratified by sex. *Includes patients with asthma.
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prostate cancer only. Although other outcomes were associated with a point estimate suggesting a protective effect of asthma or atopy, the CIs were very wide and covered the null hypothesis of no association. In other words, any increased risk that may exist for a particular cancer is so small that it will be undetectable when all cancers are combined. In conclusion, the meta-analysis did not show a significant association between asthma and cancer incidence or cancer mortality. One large cohort study that showed a significant protective effect on cancer incidence was counterbalanced by 4 studies that, when combined, showed a significant increased risk. Only 2 studies could be included in the metaanalysis of cancer mortality, and no association was detected. The individual cohort study methods varied substantially by type of asthma ascertainment, possible confounding of treatment, and other factors, and the meta-analysis was constrained by the limited data available in the published articles. The ideal study design to test the hypothesis of interest would be a cohort study that measured specific aspects of immune system activity at baseline and at regular intervals throughout a long follow-up period. If one uses patients with asthma as a surrogate for hypersensitive immune systems, the identification of important confounding variables, including treatment, would be essential to understanding whether there is an association between cancer and asthma. REFERENCES 1. Severson R, Davis S, Thomas DB, Stevens RG, Heuser L, Sever LE. Acute myelocytic leukemia and prior allergies. J Clin Epidemiol. 1989;42:995–1001. 2. Smyth M, Godfrey D, Trapani J. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001;2: 293–299. 3. Hallgren R, Arrendal H, Hiesche K, Lundquist G, Nou E, Zetterstrom O. Elevated serum immunoglobulin E in bronchial carcinoma: its relation to the histology and prognosis of the cancer. J Allergy Clin Immunol. 1981;67:398 – 406. 4. Hallgren R, Nou E, Arrendal H, Hiesche K. Smoking and circulating IgE in bronchial carcinoma. Acta Med Scand. 1982; 211:269 –273. 5. Winters W, Heiner D. IgE levels in sera of cancer patients. J Allergy Clin Immunol. 1976;57:181–186. 6. Meers PD. Allergy and cancer. Lancet. 1973;1973:884 – 885. 7. Cockcroft DW, Klein GJ, Donevan RE, Copland GM. Is there a negative correlation between malignancy and respiratory atopy? Ann Allergy. 1979;43:345–347. 8. Cochrane Reviewers’ Handbook 4.1. Oxford, England: The Cochrane Collaboration; 2000. 9. Sharp S, Sterne J. sbe16: meta-analysis. Stata Tech Bull. 1997; 38:9 –14. 10. Sharp S, Sterne J. sbe16.1: new syntax and output for the meta-analysis command. Stata Tech Bull. 1998;42:6 – 8. 11. Sharp S, Sterne J. sbe16.2: corrections to the meta-analysis command. Stata Tech Bull. 1998;43:15. 12. Sharp S. sbe23: meta-analysis regression. Stata Tech Bull. 1998; 42:16 –24.
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