Cholesterol-lowering drugs and advanced prostate cancer incidence in a large U.S. cohort.

BACKGROUND: 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use in the United States. Long-duration statin use was associated with substantially reduced risk of advanced prostate cancer in a recent large prospective study. METHODS: We examined the association between use of cholesterol-lowering drugs and prostate cancer incidence by disease stage and grade among 55,454 men in the Cancer Prevention Study II Nutrition Cohort. Proportional hazards modeling was used to calculate RRs. RESULTS: During follow-up from 1997 to 2003, we identified 3,413 cases of incident prostate cancer, including 317 cases of advanced prostate cancer. After adjustment for age, history of prostate-specific antigen testing, and other potential prostate cancer risk factors, current use of cholesterol-lowering drugs for 5 or more years was not associated with overall prostate cancer incidence (multivariate adjusted rate ratio, 1.06; 95% confidence interval, 0.93-1.20), but was associated with a marginally statistically significant reduction in risk of advanced prostate cancer (rate ratio, 0.60; 95% confidence interval, 0.36-1.00). CONCLUSION: These results provide some support for the hypothesis that long-term statin use is associated with reduced risk of advanced prostate cancer.     

A large cohort study of nonsteroidal anti-inflammatory drug use and melanoma incidence

Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (P(interaction) = .38), tumor thickness (P(trend) = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.     

A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and tumor growth in the rodent colon. We assessed NSAID use in relation to risk of human large-bowel cancer in a hospital-based, case-control study of 1326 patients with colorectal cancer and 4891 control patients. For regular NSAID use that continued into the year before interview, the multivariate relative risk estimate was 0.5 (95% confidence interval, 0.4 to 0.8); the estimate decreased as the duration of use increased, but the trend was not statistically significant. Similar results were obtained whether cancer or non-cancer controls were used, and the inverse association was apparent for both colon cancer and rectal cancer in men and women and in subjects younger and older than 60 years. Regular NSAID use that had been discontinued at least 1 year previously and non-regular use were not associated with risk. Almost all regular NSAID use was of aspirin-containing drugs. The present data suggest that the sustained use of NSAIDs reduces the incidence of human large-bowel cancer.     

Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention

Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds.     

Aspirin and other nonsteroidal antiinflammatory drugs and colorectal neoplasia

The apparent contradiction between the absence of an effect of 325 mg aspirin taken every other day on the incidence of colorectal cancer in a randomized controlled trial and the consistent inverse association between aspirin and other non-steroidal anti-inflammatory drugs and colorectal cancer and polyps in observational epidemiologic studies is discussed. It is noted that the randomized trial of aspirin may have limited external validity. Information is needed on the effects of timing, duration and quantity of dose, and the effects of other non-steroidal anti-inflammatory drugs, particularly in view of the complexity of balancing established and potential risks and benefits of a possible public health intervention. Mechanisms whereby these drugs could influence the development of colorectal neoplasia are considered.     

Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer

Background  

Eighty percent of all breast cancers and almost 90% of breast cancer deaths occur among post-menopausal women. We used a nested case control design to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer occurrence among women over 65 years of age. The cyclooxygenase (COX)-2 enzyme is expressed more in breast cancers than in normal breast tissue. COX-2 inhibition may have a role in breast cancer prevention.     

Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, account for most cholesterol-lowering drug use in the United States. A recent large case-control study reported that use of statins for more than 5 years was associated with a 47% reduction in risk of colorectal cancer. No other large studies have examined this association. We examined the association between use of cholesterol-lowering drugs and colorectal cancer incidence among 132,136 men and women in the Cancer Prevention Study II Nutrition Cohort. We identified 815 incident cases of colorectal cancer among study participants during follow-up from the date of completion of a study questionnaire in 1997 through August 31, 2001. Current use of cholesterol-lowering drugs was not associated with colorectal cancer incidence (multivariable adjusted rate ratio [RR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.26). Current use of cholesterol-lowering drugs for 5 years or more was also not associated with colorectal cancer incidence (multivariable adjusted RR = 1.09, 95% CI = 0.83 to 1.43). Our results do not support the hypothesis that statin use strongly reduces risk of colorectal cancer. However, we cannot rule out a small reduction in risk or an effect associated with only specific types or doses of statins.     

Aspirin and other non-steroidal anti-inflammatory drug use and colorectal cancer survival: a cohort study

Background:

Aspirin has been widely reported to reduce the incidence of colorectal cancer. Recently, a survival benefit after diagnosis has also been suggested. Data regarding such a benefit are to date contradictory. This study examines the effect of non-steroidal anti-inflammatory drug (NSAID) use on mortality in colorectal cancer in a larger patient cohort than previously to further clarify this effect, especially in terms of exposure timing and dosing.

Methods:

A study using the General Practice Research Database assessed whether aspirin or NSAID exposure in the year immediately following diagnosis affected all-cause mortality in a cohort of 13 994 colorectal cancer patients. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index and comorbidity.

Results:

Overall mortality was slightly lower in patients treated with aspirin, (hazard ratio (HR)=0.91; 95% confidence interval (CI)=0.82–1.00). This effect was observed only in patients treated with prophylaxis-dose aspirin (HR=0.89, CI=0.80–0.98) and only in patients taking aspirin before diagnosis (HR=0.86, CI=0.76–0.98). Differential effects were observed depending on the time after diagnosis. Up to 5 years, a reduction in mortality was observed for aspirin users (HR=0.83, CI=0.75–0.92), whereas after 10 years there was an increase in mortality (HR=1.94, CI=1.26–2.99). For NSAID use, no significant effect was observed on overall mortality (HR=1.07, CI=0.98–1.15). High-dose NSAID use was associated with a slight increase in mortality (HR=1.41, CI=1.26–1.56).

Interpretation:

These findings provide further indication that aspirin may be beneficial in reducing mortality in colorectal cancer during the first 5 years. The same cannot be said for other NSAIDs, where a small increase in mortality was observed.     

Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.     

Inverse association between nonsteroidal anti-inflammatory drugs and prostate cancer.

BACKGROUND: Prostate cancer is considered a major health problem in western countries. Promising results from observational studies on cancer at other sites fuelled the publication of several studies assessing the association between nonsteroidal anti-inflammatory drug (NSAID) use and prostate cancer. However, these studies show conflicting results. METHODS: We conducted a cohort study with a nested case-control analysis to further study the association between NSAIDs and prostate cancer. We used data from the General Practice Research Database in United Kingdom. RESULTS: Aspirin use was associated with a reduced risk of prostate cancer [odds ratio (OR) = 0.70, 95% confidence interval (95% CI) = 0.61-0.79]. We also found that paracetamol use with a treatment duration longer than 1 year was associated with a decreased risk (OR = 0.65, 95% CI = 0.54-0.78). Non-aspirin-NSAID (NA-NSAID) and paracetamol short-term use was associated with a small increased risk whereas long-term users of NA-NSAIDs presented an OR of 0.89 (95% CI = 0.73-1.08). DISCUSSION: Our findings support a protective effect of aspirin and paracetamol against prostate cancer. The transient elevated risk observed among newly started users of NA-NSAIDs and paracetamol is most likely explained by prothopathic bias. We found some suggestion of a reduced risk with long-term use of NA-NSAID.     

Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer: a meta-analysis.

BACKGROUND: The association between use of nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, and risk of pancreatic cancer is controversial. We did a meta-analysis to summarize available evidence from epidemiologic studies investigating the relation between use of aspirin or other NSAIDs and the risk of pancreatic cancer. METHODS: We identified potential studies by searching the MEDLINE database (from 1966 to October 2006) and by reviewing the reference lists of pertinent publications. Studies were eligible for inclusion if they met the following criteria: (a) had a case-control or prospective design, (b) examined exposure to aspirin or NSAIDs, (c) the outcome was pancreatic cancer incidence or mortality, and (d) they provided a relative risk (RR) estimate with corresponding confidence interval or sufficient information to permit their calculation. Study-specific RR estimates were pooled using a random effects model. RESULTS: A total of 11 studies (3 case-control studies, 7 cohort studies, and 1 randomized trial), involving 6,386 pancreatic cancer cases, was included in the meta-analysis. The summary RR estimate did not indicate any association between aspirin/NSAID use and risk of pancreatic cancer [any/regular use versus nonregular/never use: RR, 1.01; 95% confidence interval (95% CI), 0.91-1.11; P(heterogeneity) = 0.09]. Neither use of aspirin, nonaspirin NSAIDs, nor overall NSAIDs were associated with pancreatic cancer risk. There was also no overall association with frequent (six or more tablets/times per week versus none: RR, 0.86; 95% CI, 0.61-1.23) or long-term (>or=20 years) use of aspirin (RR, 1.21; 95% CI, 0.74-1.96). CONCLUSIONS: Current epidemiologic evidence does not indicate that use of aspirin or NSAIDs is associated with the risk of pancreatic cancer.     

Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women

Chronic inflammation is associated with increased risk of multiple cancers, including breast cancer. Adipose tissues produce proinflammatory cytokines, and obesity is a risk factor for postmenopausal breast cancer. We evaluated the association of regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk, overall and by body mass index (BMI) and tumor subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We conducted a population-based, case-control study involving 5,078 women aged 25-75 years who were recruited primarily from the Nashville metropolitan area of Tennessee. Multivariate unconditional logistic regression models were used to estimate odds ratios and 95 % confidence intervals for breast cancer risk after adjusting for multiple potential confounding factors. Regular use of any NSAID was associated with significantly reduced breast cancer risk (OR 0.78; 95 % CI 0.69–0.89). This association was observed for regular use of baby aspirin only (OR 0.82, 95 % CI 0.69–0.99), other NSAIDs only (OR 0.81, 95 % CI 0.69–0.95), and both baby aspirin and other NSAIDs (OR 0.52, 95 % CI 0.40–0.69). These significant inverse associations were found among overweight women (BMI ≥25 kg/m²) overall and by subtypes of breast cancer, but not among women with BMI <25 kg/m² (P for interaction = 0.023). Regular use of NSAIDs was inversely associated with breast cancer risk, particularly among overweight women. Overweight women may benefit more from the protective effects of NSAID use than normal-weight women.