Inhaled Corticosteroids Might Not Protect Against Lung Cancer/From the Authors
By Chang, Kwok Chiu Leung, Chi Chiu; Tam, Cheuk Ming; Au, David H; Chien, Jason W; Bryson, Chris L
To the Editor: We read with interest the cohort study by Dr. Parimon and colleagues (1), which suggested a reduced risk of lung cancer among patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroids (ICS). As lung cancer is the most common cause of death among patients with COPD (2-5), it might be tempting to consider ICS for chemopreven-tion of lung cancer. However, there may be a few concerns.
A major concern was the limited number of ICS users included in the cohort study (1). In using ICS dose as a continuous categorical variable, it is conceivable that a minor decrease in lung cancer events among higher-dose ICS users, either by chance or by virtue of death from other causes, could generate an apparent protection of ICS against lung cancers by its high leverage. Another concern was the lack of a definite dose- response relationship shown by the study (1). A considerable lag period is expected between onset of early precancerous lesions (where ICS is postulated to act) and detection of lung cancer. However, the median time interval for detecting lung cancer was only 1.4 years. If we assume that current usage of ICS indicates chronic usage, it might be better to study ICS usage itself, rather than the much less stable dosage. Based on Parimon and coworkers’ original data, Table 1 shows that lung cancer rates are similar for nonusers and all ICS users combined, with lower-dose ICS users actually demonstrating a higher rate than nonusers.
The investigators emphasized a similar point estimate in the adjusted hazard ratio (around 0.4) for the higher-dose ICS, despite modifying various conditions in their analysis. Again, the small number of ICS users might limit the robustness of multivariable analysis. If the protective effect were indeed so early and strong for ICS doses equivalent to 1,200 [mu]g or more of triamcinolone per day, it would probably have been detected by a recent randomized controlled trial involving more than 3,000 patients receiving fluticasone 1,000 mg (equivalent to 4,000 [mu]g of triamcinolone) daily, with or without salmeterol, followed up for 3 years (6).
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
KWOK CHIU CHANG
CHI CHIU LEUNG
CHEUK MING TAM
Department of Health
Hong Kong, China
References
1. Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:712-719.
2. Miller YE, Keith RL. Inhaled corticosteroids and lung cancer chemo-prevention. Am J Respir Crit Care Med 2007;175:636-637.
3. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902-1909.
4. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297- 1303.
5. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE; Lung Health Study Research Group. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005;142:233-239.
6. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789.
From the Authors:
We appreciate the comments on our article (1) by Dr. Chang and colleagues. We certainly agree that influential data points may distort a true relationship. However, this effect is often less pronounced when continuous exposure variables are transformed into categorical variables. Typically, the amount of information in these transformations is reduced. We analyzed the data using both continuous and categorical classifications and found similar results: individuals receiving higher doses of inhaled corticosteroids were at reduced risk of lung cancer. In addition, we made an a priori decision to analyze our data both continuously and categorically and that our categorical variable cut points would be based on a distribution to give us approximately an equal number of exposed individuals in each stratum.
In regard to the follow-up time, we restricted enrollment to individuals who did not have evidence of lung cancer; however, it remains distinctly possible that some disease was included. We would like to emphasize that even after restricting our analyses to those individuals who had a lung cancer diagnosis after 1 year of enrollment, our principal effect persisted. In addition, our analyses of confounding by indication suggested that individuals who had lung cancer were more likely, not less likely, to receive an inhaled corticosteroid.
We appreciate the reframing of our results in Chang and colleagues’ Table 1. However, the results are identical to those that we presented and we believe readily interpretable in any form. The history of lung cancer prevention studies suggests that all clinicians should be cautious (2, 3) not only when interpreting the results of observational studies, but also should apply equal care in the setting of clinical trials where approximately 40% of the participants not randomized to inhaled corticosteroids may have received this medication after withdrawal (4).
Conflict of Interest Statement: D.H.A. was compensated $1,500 in 2006 from GlaxoSmithKline for participating in the ”Assessing the Impact of Recent Label Updates for ADVAIR and Serevent Special Issues Board.” J.W.C. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.L.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.
DAVID H. AU
VA Puget Sound Health Care System
and
University of Washington
Seattle, Washington
JASON W. CHIEN
Fred Hutchinson Cancer Research Center
and
University of Washington
Seattle, Washington
CHRIS L. BRYSON
VA Puget Sound Health Care System
and
University of Washington
Seattle, Washington
References
1. Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:712-719.
2. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitaminEand beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:s1029-s1035.
3. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.
4. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789.
Copyright American Thoracic Society Jun 1, 2008
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