By Robert L. Coleman, MD
Professor, University of Texas; M.D. Anderson Cancer Center, Houston
Dr. Coleman reports no financial relationships relevant to this field of study.
This article originally appeared in the January 2014 issue of OB/GYN Clinical Alert.
SYNOPSIS: In this pooled analysis of more than 7700 ovarian cancer patients and nearly 12,000 controls, low dose aspirin and high dose non-aspirin NSAID use was associated with a risk reduction for invasive epithelial ovarian cancer of 20 to 34% relative to non-users. Acetaminophen use was not associated with a risk reduction, irrespective of dose or frequency.
SOURCE: Trabert B, Ness RB, Lo-Cigani WH, et al., Aspirin, nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: A pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 2014;106:djt431.
Increasing evidence is emerging linking regular aspirin use and reduced risks of several malignancies. However, the association to invasive ovarian cancer has been inconclusive, largely attributed to low prevalence and small sample sizes. To better understand this relationship, Trabert and colleagues collected individual case data from 12 population-based case–control studies of ovarian cancer. The study sample consisted of 7776 case patients and 11843 control subjects who were accrued between 1992 and 2007. Exposure data were collected regarding use, dose, duration, and frequency. Outcomes were limited to invasive epithelial ovarian, fallopian tube, and primary peritoneal cancer. Patients with low malignant potential and non-epithelial tumors were excluded. In addition, while all histologies were analyzed, a sensitivity analysis of type of serous cancer (high vs. low-grade) was conducted due to the underlying biology of these two lesions. Adjustments were made for important confounding factors affecting ovarian cancer risk such as family history, steroidal contraception use, parity, body mass index, race and age, as well as history of endometriosis, tubal ligation, hysterectomy, and estrogen replacement use. Further sensitivity analyses were conducted removing potential factors that were incompletely reported or collected between the various studies. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. The authors reported that aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for non-aspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily (regular) aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low-dose (< 100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for non-aspirin NSAIDs, the reduced risk was strongest for high-dose (≥500mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). The authors concluded that aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin.
The relationship between aspirin use and disease has been demonstrated in both retrospective studies and in prospective, randomized clinical trials. The benefits have long been known for cardiovascular risk, and recently the beneficial effects have extended to several solid tumors, including colorectal cancer, esophageal cancer, bladder cancer, endometrial cancer, liver and lung cancer, and female breast cancer.1 The risk reduction in ovarian cancer is not surprising, as there is a biological/pharmacological link: inflammation.2 Aspirin and non-aspirin NSAIDs are potent inhibitors of COX, particularly COX-1. Aspirin is an irreversible inhibitor of COX-1, and NSAIDs reversibly inhibit both COX-1 and COX-2 and are distinguished from acetaminophen, which is a more effective inhibitor of COX-2. The observations from the current study would suggest COX-1 is more important to cancer risk reduction. In addition, it is becoming clear that macrophage infiltration is an important survival mechanism for cancer cell support and subsequent angiogenesis.3 The impact on local microenvironment effects by many pharmacological agents is aggressively being investigated as options for tumor control and, as in the current case, for cancer prevention.
Large population-based studies such as this, in which data are dependent on recall and personal estimation of use over time, is very difficult to interpret. One confounding variable is recall, in which cancer patients are more likely to link exposure to outcome relative to controls. However, other factors are more difficult to tease out such as intermittent regular use or the development of a condition, which might increase the risk for ovarian cancer but is mitigated by increased and episodic use of pharmacological agents to treat the effects of that disorder (e.g. endometriosis). The authors admit they could not clearly evaluate this aspect in the study. However, multiple sensitivity analyses were performed to judge the robustness of the finding and suggest the link is consistent.
It is somewhat curious that low-dose, regular use of aspirin is more efficacious than high-dose aspirin, yet high-dose non-aspirin NSAIDs are more efficacious than low-dose NSAIDs, particularly since the mechanism of action is directed to COX inhibition. In addition, the use of regular high-dose NSAIDs, particularly COX-2 inhibitors, has been associated with increased cardiovascular risks, making it a poor choice for chemoprevention.4 Nevertheless, low-dose regular aspirin use appears to clear a safety margin that also provides extensive protection against a variety of ailments. This is an extremely important consideration because institution of a chemoprevention strategy risks exposure of large numbers of unaffected individuals who will never attain a benefit from treatment. Ovarian cancer, which has a low annual incidence and overall lifetime risk, is very difficult to study in the general population. Targeting high-risk populations (such as BRCA mutation carriers or Lynch syndrome patients) may improve the therapeutic index and make prospective trials to document its efficacy a feasible adventure.
- Rothwell PM, Price JF, Fowkes FG, et al: Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602-1612.
- Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst. 2002;94:252-266.
- Altinoz MA, Korkmaz R: NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer. Neoplasma 2004;51:239-247.
- Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.