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NSAIDs and a Lower Risk of Prostate Cancer: Causation or Confounding?
Mayo Clin Proc, March 2002, Vol 77
Editorial
217
March 2002
Mayo Clinic Proceedings
Volume 77 Number 3
Editorial
NSAIDs and a Lower Risk of Prostate Cancer: Causation or Confounding?
T
he well-designed prospective cohort study by Roberts et al1 in this issue of Proceedings found that regular nonsteroidal anti-inflammatory drug (NSAID) use among men between 50 and 79 years old was associated with a lower rate of being diagnosed as having prostate cancer over a median of 51/2 years of follow-up. The cohort, initially assembled in 1990, had a high level of surveillance for prostate cancer for 2 reasons: (1) living in the catchment area of the Mayo Clinic, where the intensity of prostate cancer screening has been high,2 and (2) being in a study focused on prostatic health (a quarter of study subjects were actually screened with digital rectal examinations [DREs] and prostate-specific antigen [PSA] determinations as part of the study protocol). Of 569 NSAID users, 23 (about 4%) were diagnosed as having prostate cancer, while 68 (about 8.5%) of 793 NSAID nonusers were diagnosed with prostate cancer. This association appeared weaker, at least based on the point estimate, for men aged 50 to 59 years, although the broad confidence intervals around this point estimate are still consistent with a substantial preventive effect. The exposure of interest in this study is daily NSAID use, as self-reported by study subjects at baseline and confirmed in some subjects at follow-up toward the end of the study. Of the 569 daily NSAID users, 440 (more than three quarters) were taking aspirin alone as opposed to other NSAIDs or a combination. Although information on dose (or, for that matter, dose response) is not provided in the article, I hypothesize that most of these men were probably taking low-dose aspirin for primary or secondary prevention of coronary heart disease events.
Is the observed association between regular NSAID use and a lower rate of prostate cancer diagnosis real, and if so, does the association reflect causation or confounding? The authors’ multivariable analysis makes it unlikely different distributions of age or self-reported family history of prostate cancer among NSAID users vs nonusers was responsible for the finding. However, other potential confounders deserve consideration. See also page 219. A lower intensity of prostate cancer surveillance among men taking NSAIDs could explain a lower rate of prostate cancer diagnosis in these men, as, in the “PSA era,” screening drives incidence.2 If NSAID use is a proxy for poorer general health, that explanation makes sense, as these men might get less screening. Indeed, Table 1 of the article indicates at least some common comorbidities were represented significantly more often among the men taking NSAIDs (about a third of these men had had a prior myocardial infarction, an absolute indication for low-dose aspirin). However, the intensity of both DREs and PSA tests actually appeared higher among the men taking NSAIDs. Perhaps these men were more “medicalized” and were screened more intensively for prostate cancer as a result. Our own group’s surveys have suggested that primary care physicians, at least, are not very sensitive to patient age or comorbidity in their prostate cancer screening practices, in contrast to the recommendations of their urologic colleagues.3 However, additional adjustment for the number of physician visits in the last year and for a spectrum of urologic and nonurologic comorbidities did not change the main result of the analysis. It would be reassuring to know in addition that distributions of PSA levels and biopsy rates were similar in the NSAID users and nonusers. Nevertheless, with the information at hand, lower levels of prostate
Address reprint requests and correspondence to Michael J. Barry, MD, Medical Practices Evaluation Center, Massachusetts General Hospital, 50 Staniford St, 9th Floor, Boston, MA 02114-2696 (email: [email protected]). Mayo Clin Proc. 2002;77:217-218
217
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
218
Editorial
cancer surveillance among men regularly taking NSAIDs does not seem to be a very plausible explanation for the findings. Another enticing potential explanation is that the type of men who take low-dose prophylactic aspirin have other health behaviors that reduce their risk for prostate cancer. For example, these men may have also reduced their intake of animal fat and red meat, which may also reduce their risk of prostate cancer.4 In retrospective analyses of clinical trials performed for other purposes, vitamin E supplementation reduced the incidence of prostate cancer by 32%,5 and selenium supplementation reduced the incidence of prostate cancer by 63%6; both results were statistically significant. These findings await confirmation in prospective trials specifically designed to address the preventive effect of these micronutrients on prostate cancer.7 However, if either or both truly reduce the incidence of prostate cancer, a potential confounder emerges. Men over the age of 50 years in my Boston, Mass, general internal medicine practice commonly reported taking the combination of vitamin E, selenium, and low-dose aspirin for preventive purposes in the 1990s, even before the formal publication of these studies. If this observation is generalizable, use of these other micronutrients may confound the relationship between aspirin intake and a subsequent prostate cancer diagnosis. Should older men begin aspirin prophylaxis to reduce their risk of prostate cancer given these findings and the findings in some other suggestive nonexperimental studies referenced by Roberts et al? The first question is, why aren’t they taking aspirin already? In the Physicians’ Health Study, male physicians aged 50 to 84 years had a 44% reduction in the number of fatal and nonfatal myocardial infarctions over about 5 years with assignment to take low-dose aspirin at a dose of 325 mg every other day (admittedly, a dose too low for them to have been included as regular NSAID users in the current study).8 On the other hand, this study showed trends toward a greater risk of hemorrhagic strokes, peptic ulcers, and need for transfusions in the aspirin group and no reduction in overall cadiovascular mortality in this trial. Although regular readers of the Proceedings from outside the Rochester, Minn, region may think otherwise, most of the Olmsted County men included in this cohort were not physicians; nevertheless, the benefits of low-dose aspirin should presumably
Mayo Clin Proc, March 2002, Vol 77
generalize to similar populations of older men, including the men represented in this study. For men already taking aspirin for the prevention of myocardial infarction, this study provides no incentive for them to stop and, without a dose-response analysis, probably little incentive for men currently taking aspirin every other day to graduate to daily use. On the other hand, for men who have been undecided about prophylactic aspirin use, perhaps this study, while not an experiment, provides enough additional evidence to tip some of their personal risk-benefit assessments in the direction of starting aspirin. Men considering aspirin prophylaxis for any indication, though, should be aware of the small but probably real risks involved. It’s worth remembering that changes in prostate cancer incidence may not be reflected in changes in prostate cancer mortality that are in the same direction. In fact, currently, the best way to reduce the risk of a prostate cancer diagnosis is probably to avoid prostate cancer screening in general and PSA testing in particular. Whether this method of prostate cancer risk reduction carries a price in terms of a higher long-term risk of prostate cancer mortality remains to be seen. Michael J. Barry, MD Medical Practices Evaluation Center Massachusetts General Hospital Boston 1.
2. 3. 4. 5. 6. 7. 8.
Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. A population-based study of daily nonsteroidal antiinflammatory drug use and prostate cancer. Mayo Clin Proc. 2002; 77:219-225. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA. 1995;274:1445-1449. Fowler FJ Jr, Bin L, Collins MM, et al. Prostate cancer screening and beliefs about treatment efficacy: a national survey of primary care physicians and urologists. Am J Med. 1998;104:526-532. Giovannucci E, Rimm EB, Colditz GA, et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst. 1993; 85:1571-1579. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440-446. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a doubleblind cancer prevention trial. Br J Urol. 1998;81:730-734. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. J Urol. 2001;166:1311-1315. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989;321:129-135.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Editorial
217
March 2002
Mayo Clinic Proceedings
Volume 77 Number 3
Editorial
NSAIDs and a Lower Risk of Prostate Cancer: Causation or Confounding?
T
he well-designed prospective cohort study by Roberts et al1 in this issue of Proceedings found that regular nonsteroidal anti-inflammatory drug (NSAID) use among men between 50 and 79 years old was associated with a lower rate of being diagnosed as having prostate cancer over a median of 51/2 years of follow-up. The cohort, initially assembled in 1990, had a high level of surveillance for prostate cancer for 2 reasons: (1) living in the catchment area of the Mayo Clinic, where the intensity of prostate cancer screening has been high,2 and (2) being in a study focused on prostatic health (a quarter of study subjects were actually screened with digital rectal examinations [DREs] and prostate-specific antigen [PSA] determinations as part of the study protocol). Of 569 NSAID users, 23 (about 4%) were diagnosed as having prostate cancer, while 68 (about 8.5%) of 793 NSAID nonusers were diagnosed with prostate cancer. This association appeared weaker, at least based on the point estimate, for men aged 50 to 59 years, although the broad confidence intervals around this point estimate are still consistent with a substantial preventive effect. The exposure of interest in this study is daily NSAID use, as self-reported by study subjects at baseline and confirmed in some subjects at follow-up toward the end of the study. Of the 569 daily NSAID users, 440 (more than three quarters) were taking aspirin alone as opposed to other NSAIDs or a combination. Although information on dose (or, for that matter, dose response) is not provided in the article, I hypothesize that most of these men were probably taking low-dose aspirin for primary or secondary prevention of coronary heart disease events.
Is the observed association between regular NSAID use and a lower rate of prostate cancer diagnosis real, and if so, does the association reflect causation or confounding? The authors’ multivariable analysis makes it unlikely different distributions of age or self-reported family history of prostate cancer among NSAID users vs nonusers was responsible for the finding. However, other potential confounders deserve consideration. See also page 219. A lower intensity of prostate cancer surveillance among men taking NSAIDs could explain a lower rate of prostate cancer diagnosis in these men, as, in the “PSA era,” screening drives incidence.2 If NSAID use is a proxy for poorer general health, that explanation makes sense, as these men might get less screening. Indeed, Table 1 of the article indicates at least some common comorbidities were represented significantly more often among the men taking NSAIDs (about a third of these men had had a prior myocardial infarction, an absolute indication for low-dose aspirin). However, the intensity of both DREs and PSA tests actually appeared higher among the men taking NSAIDs. Perhaps these men were more “medicalized” and were screened more intensively for prostate cancer as a result. Our own group’s surveys have suggested that primary care physicians, at least, are not very sensitive to patient age or comorbidity in their prostate cancer screening practices, in contrast to the recommendations of their urologic colleagues.3 However, additional adjustment for the number of physician visits in the last year and for a spectrum of urologic and nonurologic comorbidities did not change the main result of the analysis. It would be reassuring to know in addition that distributions of PSA levels and biopsy rates were similar in the NSAID users and nonusers. Nevertheless, with the information at hand, lower levels of prostate
Address reprint requests and correspondence to Michael J. Barry, MD, Medical Practices Evaluation Center, Massachusetts General Hospital, 50 Staniford St, 9th Floor, Boston, MA 02114-2696 (email: [email protected]). Mayo Clin Proc. 2002;77:217-218
217
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
218
Editorial
cancer surveillance among men regularly taking NSAIDs does not seem to be a very plausible explanation for the findings. Another enticing potential explanation is that the type of men who take low-dose prophylactic aspirin have other health behaviors that reduce their risk for prostate cancer. For example, these men may have also reduced their intake of animal fat and red meat, which may also reduce their risk of prostate cancer.4 In retrospective analyses of clinical trials performed for other purposes, vitamin E supplementation reduced the incidence of prostate cancer by 32%,5 and selenium supplementation reduced the incidence of prostate cancer by 63%6; both results were statistically significant. These findings await confirmation in prospective trials specifically designed to address the preventive effect of these micronutrients on prostate cancer.7 However, if either or both truly reduce the incidence of prostate cancer, a potential confounder emerges. Men over the age of 50 years in my Boston, Mass, general internal medicine practice commonly reported taking the combination of vitamin E, selenium, and low-dose aspirin for preventive purposes in the 1990s, even before the formal publication of these studies. If this observation is generalizable, use of these other micronutrients may confound the relationship between aspirin intake and a subsequent prostate cancer diagnosis. Should older men begin aspirin prophylaxis to reduce their risk of prostate cancer given these findings and the findings in some other suggestive nonexperimental studies referenced by Roberts et al? The first question is, why aren’t they taking aspirin already? In the Physicians’ Health Study, male physicians aged 50 to 84 years had a 44% reduction in the number of fatal and nonfatal myocardial infarctions over about 5 years with assignment to take low-dose aspirin at a dose of 325 mg every other day (admittedly, a dose too low for them to have been included as regular NSAID users in the current study).8 On the other hand, this study showed trends toward a greater risk of hemorrhagic strokes, peptic ulcers, and need for transfusions in the aspirin group and no reduction in overall cadiovascular mortality in this trial. Although regular readers of the Proceedings from outside the Rochester, Minn, region may think otherwise, most of the Olmsted County men included in this cohort were not physicians; nevertheless, the benefits of low-dose aspirin should presumably
Mayo Clin Proc, March 2002, Vol 77
generalize to similar populations of older men, including the men represented in this study. For men already taking aspirin for the prevention of myocardial infarction, this study provides no incentive for them to stop and, without a dose-response analysis, probably little incentive for men currently taking aspirin every other day to graduate to daily use. On the other hand, for men who have been undecided about prophylactic aspirin use, perhaps this study, while not an experiment, provides enough additional evidence to tip some of their personal risk-benefit assessments in the direction of starting aspirin. Men considering aspirin prophylaxis for any indication, though, should be aware of the small but probably real risks involved. It’s worth remembering that changes in prostate cancer incidence may not be reflected in changes in prostate cancer mortality that are in the same direction. In fact, currently, the best way to reduce the risk of a prostate cancer diagnosis is probably to avoid prostate cancer screening in general and PSA testing in particular. Whether this method of prostate cancer risk reduction carries a price in terms of a higher long-term risk of prostate cancer mortality remains to be seen. Michael J. Barry, MD Medical Practices Evaluation Center Massachusetts General Hospital Boston 1.
2. 3. 4. 5. 6. 7. 8.
Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. A population-based study of daily nonsteroidal antiinflammatory drug use and prostate cancer. Mayo Clin Proc. 2002; 77:219-225. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA. 1995;274:1445-1449. Fowler FJ Jr, Bin L, Collins MM, et al. Prostate cancer screening and beliefs about treatment efficacy: a national survey of primary care physicians and urologists. Am J Med. 1998;104:526-532. Giovannucci E, Rimm EB, Colditz GA, et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst. 1993; 85:1571-1579. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440-446. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a doubleblind cancer prevention trial. Br J Urol. 1998;81:730-734. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. J Urol. 2001;166:1311-1315. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989;321:129-135.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.