In these large prospective studies of women and men, we found that use of non-aspirin NSAIDs was associated with an elevated risk of RCC, especially among those who used them for a long duration. Use of aspirin or acetaminophen was not associated with RCC risk.
Although aspirin has been associated with a reduced risk of several types of cancer, previous epidemiologic data pointed toward an increased risk of RCC in aspirin users 8, 23
. A meta-analysis of 5 case-control studies and 3 cohort studies of RCC reported RRs of 1.21 (95% CI 1.07–1.36) for case-control studies and 1.45 (95% CI 0.87–2.40) for small cohort studies 8
. However, we found no association for aspirin with risk of RCC in our two independent populations. Evaluation of dose and duration of use of aspirin also did not reveal any association with RCC risk.
One prospective study 24
and seven case-control studies 9–11, 23, 25–28
have evaluated acetaminophen in relation to RCC risk; three of the studies found a positive association 9–11
. Acetaminophen is a metabolite of phenacetin, which was banned in 1970s-early 1980s worldwide due to its carcinogenic effect especially in renal pelvis tumors 9, 26
. However, we found little evidence that use of acetaminophen was associated with RCC risk, although a small elevated risk related to remote use cannot be excluded.
The potential explanation for the discrepancy in findings for aspirin and acetaminophen in our studies vs. previous studies may include that most of the previous studies were retrospective, which might be susceptible to biased recall of use of analgesics and reverse causation (i.e., cases might have used analgesics due to symptoms related to RCC).
In terms of non-aspirin NSAIDs, there have been few studies with RCC risk. Although one case-control study found a positive association with RCC risk 9, 12
the study reported a similar positive association with other analgesics including aspirin, acetaminophen, and phenacetin. A retrospective cohort study in Denmark using prescription database found that prescription of non-aspirin NSAIDs was associated with incidence (RR=1.4 [95% CI 0.9–2.1]12
and mortality (RR=1.72 [95% CI 1.4–2.1]) 29
of kidney cancer. In our study, we found a positive association only with non-aspirin NSAIDs, with a strong dose-response relation for duration of use. Because we observed the associations in two independent populations, it is unlikely to be a chance finding. Also, because we found no association with other analgesics and the study period was until 2006, residual confounding by phenacetin may not explain the positive association we found with non-aspirin NSAIDs. Contrary to our findings on RCC, meta-analyses reported that use of non-aspirin NSAIDs was associated with reduced risk of breast 30
, prostate 31
, and colorectal cancers 7
with the magnitude of association similar to that of aspirin. Analgesics in general have been associated with elevated risk of high blood pressure 32
, a risk factor for RCC. However, our results did not differ by presence of hypertension. NSAIDs are also associated with elevated risks of both acute and chronic renal diseases by inhibiting the synthesis of renal prostaglandins 33, 34
, which can result in chronic subacute renal injuries, such as tubular necrosis, papillary necrosis and interstitial nephritis 35, 36
. This has the potential for an injury-related DNA damage and subsequent uncontrolled cell proliferation, leading to carcinogenesis 37
. The mechanism may be mediated by the inhibition of COX-1-derived renal prostaglandins which are important for renal homeostasis 38
and NSAIDs are known to inhibit both COX-1 and 2. Selective COX-2 inhibitors, another NSAIDs class, were recently added to the cohorts’ questionnaires, so we were not able to study their relation to RCC risk due to a short follow up time. Still, this does not provide an explanation why non-aspirin NSAIDs, but not aspirin was positively associated with RCC, since both are considered NSAIDs and the renal injuries aforementioned have been described with both classes 35, 39
. Since the actual doses of aspirin and non-aspirin NSAIDs are different, the delivered target renal tissue dose could also be different between these 2 classes and may lead to a different threshold for neoplastic transformation.
These analgesics are frequently and often heavily used by individuals with rheumatoid arthritis (RA). Studies among RA patients which evaluated cancer incidence have not found increased risk for RCC, although the analgesic exposure history in the study was somewhat limited 40
Our study carries limitations. First, although we had extensive information on risk factors for RCC and adjusted for them in multivariable analysis, residual confounding can remain a concern. The results on non-aspirin NSAIDs were somewhat attenuated after adjustment for multiple covariates. However, given the strength of the association, especially for long duration of use, residual confounding may not entirely explain the association. Second, confounding by indication (e.g., RCC patients started to use analgesics due to symptoms before diagnosis) may have been an issue for these widely used analgesics. However, the strongest association we found among those who used the longest duration argues against the possibility. Third, because phenacetin was still available in the U.S. up to the mid-1980s, our results with follow-up started in 1986 and 1990 might have been still confounded by past use of phenacetin. However, differential association between non-aspirin NSAIDs and other analgesics and strong duration effect for non-aspirin NSAIDs are not explained by the possibility. Fourth, we have only recently started to collect more detailed information on dose of use of NSAIDs, with inadequate follow-up to evaluate this issue. With longer follow-up, we will be able to evaluate more detailed dose-response relation between non-aspirin NSAIDs and RCC risk in the future.
This study has strengths. To our knowledge, it is the first prospective study of non-aspirin NSAIDs and the largest prospective study of analgesics in relation to RCC risk. The prospective design minimizes biases that can affect case-control studies. Our study was unique to have information on use of analgesics ascertained multiple times during follow-up, which enabled us to calculate duration of usage, a much stronger predictor of RCC risk for non-aspirin NSAIDs than usage at baseline.
Risks and benefits should be considered in deciding whether to use analgesics; if our findings are confirmed, an increased risk of RCC should also be considered.