Long-Term Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Cutaneous Melanoma: Results of a United States Case–Control Study
Clara Curiel-Lewandrowski1,2, Tamar Nijsten3, Maria L. Gomez1, Loes M. Hollestein4, Michael B. Atkins5 and Robert S. Stern1
Experimental and observational studies continue to demonstrate conflicting results regarding the role of several commonly used drugs as melanoma chemopreventive agents. This case–control study was designed to assess the associations between cutaneous melanoma (CM) and exposure to nonsteroidal anti-inflammatory drugs(NSAIDs) and statins in current users.
A total of 400 CM and 600 eligible age- and gender-matched community based controls were prospectively recruited and interviewed. We assessed participants’ demographic characteristics, CM risk factors, and current and previous use of medications. Multivariable conditional logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between NSAIDs and/or aspirin (ASA), statin exposure, and CM risk. Half of the subjects were men (mean age 60 years). After adjusting for confounders, use of any type of NSAIDs for more than 5 years significantly reduced the risk of melanoma development compared with the low-exposure group adjusted OR¼0.57; 95% CI¼0.43–0.77). Subgroup analyses showed that the observed risk reduction was primarily driven by continuous ASA use (45 years adjusted OR¼0.51, 95% CI¼0.35–0.75). No significant protective effect was observed with statin exposure (OR¼0.97, 95% CI¼0.73–1.29).
Long-term use of NSAIDs, especially ASA, is associated with a significantly decreased risk of CM development. Clinical intervention studies are warranted to further investigate the potential role of ASA and other NSAIDs as chemopreventive agents for CM.
Journal of Investigative Dermatology (2011) 131, 1460–1468; doi:10.1038/jid.2011.58; published online 10 March 2011
Skin Cancer Doctors 
#1 by shaun on June 19, 2011 - 9:33 am
It’s well known today how inflammation is involved in the aetiology of many cancers,
in breast cancer managament aspirin now has a definitive role
so I’m not surprised with this melanoma finding
#2 by skinpathonline on June 19, 2011 - 9:46 am
Was there any hypotheses given as to why NSAIDS resulted in a reduced risk for CM development?
#3 by Dr Ian Katz on June 19, 2011 - 10:23 am
Here we go…
How might nonsteroidal anti-inflammatory drugs inhibit the development of skin cancer?
Inflammatory stimuli result in the production of cutaneous eicosanoids, such as prostaglandins, and they promote tumorigenesis. Cyclooxygenase (COX) is the rate-limiting enzyme for the production of prostaglandins from arachidonic acid. This enzyme exists in two forms: COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act as nonselective inhibitors of COX, inhibiting both the COX-1 and COX-2 isoenzymes. COX-1 is constitutively expressed in normal tissue and plays an important role in tissue homeostasis, whereas COX-2 is an inducible enzyme and is markedly overexpressed at sites of inflammation and neoplasia. Acute UVB exposure activates expression of COX-2 in contrast to a lack of COX-2 expression in normal skin (Buckman et al., 1998). Increased COX-2 expression also occurs in several types of premalignant and malignant epithelial lesions, including actinic keratoses, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) (An et al., 2002). Recently, increased expression of COX-2 has been detected in melanomas compared with benign melanocytic nevi (Minami et al., 2011). Elevated tumor COX-2 is associated with increased angiogenesis, tumor invasion, and promotion of tumor cell resistance to apoptosis (Khan et al., 2011). Additionally, aspirin possesses antioxidant properties, inhibits activation of NF-upregulates tumor suppressor genes, such as P53, CDKN1A, and BAX; and downregulates antiapoptotic genes, such as BCL2 (Elwood et al., 2009).
Evidence indicates that chronic administration of NSAIDs reduces the risk of several cancers. Perhaps the most compelling studies relate to long-term (greater than 5 years) NSAID chemoprevention of colorectal cancer (CRC) (Dubé et al., 2007; Flossmann et al., 2007; Din et al., 2010). Also, use of aspirin and other NSAIDs decreases the incidence of carcinogeninduced colon tumors, and several epidemiological investigations and therapeutic trials have shown up to a 50% reduction in the risk of colorectal adenoma and cancer in individuals taking NSAIDs (Rothwell et al., 2010). Moreover, familial adenomatous polyposis patients who take sulindac or celecoxib experience a reduction in adenoma size and number (Moreira and Castells, 2010). Additionally, a decreased risk of esophageal SCC has been demonstrated with prolonged administration of NSAIDS but not with selective COX-2 inhibition (Szumiło et al., 2009). Although a large cohort study found that aspirin use did not alter the development of dysplasia or adenocarcinoma (Gatenby et al., 2009), long-term exposure to NSAIDs may be associated with a reduction in the risk of pancreatic cancer (Bonifazi et al. 2010). Less definitive data exists for other cancers, and some work suggests that NSAIDs may reduce the risk of breast cancer (García Rodríguez and González-Pérez, 2004). Selective COX-2 inhibitors were shown to be more protective against breast cancer than nonspecific NSAIDs (Ashok et al., 2011). A pooled analysis of studies found that non-aspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer; in particular, this was true for non-smokers (Daugherty et al., 2011). Additionally, a recent case–control study showed that any use of propionates, such as ibuprofen or naproxen, was associated with a modest reduction in prostate cancer risk, whereas use of other NSAIDs offered no protection (Mahmud et al. 2011). More confusing is the evidence for head and neck cancer (HNC). One study found a significant protective association between aspirin use and HNC risk, but another showed a significantly increased risk of oral/oropharyngeal cancer with non-low-dose aspirin use. Other studies were equivocal (Wilson et al., 2011).
For skin cancer, recent NSAID use of short duration offered a better protective effect for SCC and BCC than a longer duration of use (Clouser et al., 2009). A recent randomized placebo-controlled study showed a significantly decreased incidence of nonmelanoma skin cancer in participants taking celecoxib compared with those receiving placebo (Elmets et al., 2010).
#4 by Dr Ian Katz on June 19, 2011 - 11:05 pm
An alternative view:
A large cohort study of nonsteroidal anti-inflammatory drug use and melanoma incidence.
Asgari MM, Maruti SS, White E.
Source
Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA. maryam.m.asgari@kp.org
Abstract
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
#5 by Dr Ian Katz on June 19, 2011 - 11:32 pm
Dr Margaret Oziemski provided the above and writes:
“more studies are needed before using it in clinical practice as a melanoma chemopreventative
however after being at the recent skin cancer conference and listening to Diona Damian talking about vitamin B3 and reduction in skin cancer and solar keratoses I am starting to use 500mg daily in the actinopaths who are growing SCCs between 3 – 6 monthly visits to see if there can be a reduction as expected
regards Marg Oziemski”