Christina M. Nagle

Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer

Chronic inflammation has been proposed as the possible causal mechanism that explains the observed association between certain risk factors, such as the use of talcum powder (talc) in the pelvic region and epithelial ovarian cancer. To address this issue we evaluated the potential role of chronic local ovarian inflammation in the development of the major subtypes of epithelial ovarian cancer. Factors potentially linked to ovarian inflammation were examined in an Australia‐wide case–control study comprising 1,576 women with invasive and low malignant potential (LMP) ovarian tumours and 1,509 population‐based controls. We confirmed a statistically significant increase in ovarian cancer risk associated with use of talc in the pelvic region (adjusted odds ratio 1.17, 95% CI: 1.01–1.36) that was strongest for the serous and endometrioid subtypes although the latter was not statistically significant (adjusted odds ratios 1.21, 95% CI 1.03–1.44 and 1.18, 95% CI 0.81–1.70, respectively). Other factors potentially associated with ovarian inflammation (pelvic inflammatory disease, human papilloma virus infection and mumps) were not associated with risk but, like others, we found an increased risk of endometrioid and clear cell ovarian cancer only among women with a history of endometriosis. Regular use of aspirin and other nonsteroidal anti‐inflammatory drugs was inversely associated with risk of LMP mucinous ovarian tumours only. We conclude that on balance chronic inflammation does not play a major role in the development of ovarian cancer.

Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium

BACKGROUND Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. 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. RESULTS 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 nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily 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 nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). CONCLUSIONS Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Recreational physical activity and epithelial ovarian cancer: A case-control study, systematic review, and meta-analysis

It remains unclear whether physical activity is associated with epithelial ovarian cancer risk. We therefore examined the association between recreational physical activity and risk of ovarian cancer in a national population-based case-control study in Australia. We also systematically reviewed all the available evidence linking physical activity with ovarian cancer to provide the best summary estimate of the association. The case-control study included women ages 18 to 79 years with a new diagnosis of invasive (n = 1,269) or borderline (n = 311) epithelial ovarian cancer identified through a network of clinics, physicians, and state cancer registries throughout Australia. Controls (n = 1,509) were randomly selected from the national electoral roll and were frequency matched to cases by age and state. For the systematic review, we identified eligible studies using Medline, the ISI Science Citation Index, and manual review of retrieved references, and included all case-control or cohort studies that permitted assessment of an association between physical activity (recreational/occupational/sedentary behavior) and histologically confirmed ovarian cancer. Meta-analysis was restricted to the subset of these studies that reported on recreational physical activity. In our case-control study, we observed weakly inverse or null associations between recreational physical activity and risk of epithelial ovarian cancer overall. There was no evidence that the effects varied by tumor behavior or histologic subtype. Twelve studies were included in the meta-analysis, which gave summary estimates of 0.79 (95% confidence interval, 0.70-0.85) for case-control studies and 0.81 (95% confidence interval, 0.57-1.17) for cohort studies for the risk of ovarian cancer associated with highest versus lowest levels of recreational physical activity. Thus, pooled results from observational studies suggest that a modest inverse association exists between level of recreational physical activity and the risk of ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2321–30)

Dietary influences on survival after ovarian cancer.

We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population‐based case‐control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The womens usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state‐based cancer registries and the Australian National Death Index (NDI). Crude 5‐year survival probabilities were estimated using the Kaplan‐Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57–0.99, p‐value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57–0.98, p‐value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58–1.01, p‐value trend 0.04). Inverse associations were also seen with protein (p‐value trend 0.09), red meat (p‐value trend 0.06) and white meat (p‐value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p‐value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival.

Endometrioid and clear cell ovarian cancers: a comparative analysis of risk factors

Endometrioid and clear cell subtypes of ovarian cancer are both known to be closely associated with endometriosis and endometrial pathology, and so have often been combined in studies of causation. We have examined these ovarian cancers separately for potentially distinct risk factors in our population-based, Australia-wide case control study of 142 women with incident invasive endometrioid, 90 with clear cell ovarian cancers and 1508 population controls. Multivariate logistic regression was used to calculated odds ratios (ORs) and 95% confidence intervals (CIs). Increasing parity, and hormonal contraceptive use for > or = 5 years, strongly decreased the risks of both subtypes. Breast feeding and tubal ligation were also inversely associated, but significantly so only for the endometrioid subtype. As expected endometriosis increased the risk of both subtypes (OR 2.2, 95% CI 1.2-3.9 for endometrioid and OR 3.0, 95% CI 1.5-5.9 for clear cell). Obesity was associated only with clear cell cancers, where we observed a two-fold increased risk (OR 2.2, 95% CI 1.2-4.1). Also a significant trend of decreasing risk with increasing intensity of smoking (p trend 0.02) and education beyond high school was associated with decreased development of clear cell cancers only. Endometrioid and clear cell ovarian cancers have some shared as well as some distinct risk factors, and therefore should be considered separately in studies of ovarian cancer.

Early menstrual characteristics associated with subsequent diagnosis of endometriosis

OBJECTIVE The aim of this study was to investigate the association between early menstrual characteristics, before symptom onset, and later diagnosis of endometriosis. STUDY DESIGN This was a case-control study of 268 Australian women with surgically confirmed moderate-to-severe endometriosis (cases) and 244 women without endometriosis (controls). Early menstrual cycle characteristics, before age at symptom onset, were analyzed. RESULTS Menarche after age 14 years was strongly and inversely associated with endometriosis (odds ratio, 0.3; 95% confidence interval, 0.1-0.6). A history of dysmenorrhea was associated with subsequent endometriosis (odds ratio, 2.6; 95% confidence interval, 1.1-6.2). Despite a suggestive trend, shorter menstrual cycle length was not associated with endometriosis. Duration of natural menstruation and heaviness of flow were not associated with subsequent risk of endometriosis; neither was the reported type of sanitary protection used nor history of sexual intercourse during menstruation. CONCLUSION There is a decreased risk of endometriosis with late age at menarche and an increased risk in women who report an early history of dysmenorrhea.

The influence of prediagnostic demographic and lifestyle factors on esophageal squamous cell carcinoma survival

Demographic and lifestyle factors, in particular tobacco smoking and alcohol, are well established causes of esophageal squamous cell carcinoma (ESCC); however, little is known about the effect of these factors on survival. We included all 301 patients with incident ESCC, recruited into a population‐based case–control study of esophageal cancer in Australia. Detailed information about demographic and lifestyle factors was obtained at diagnosis, and deaths were identified using the National Death Index. Median follow‐up for all‐cause mortality was 6.4 years. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated from Cox proportional hazards models, adjusted for age, sex, pretreatment AJCC tumor stage, treatment and presence of comorbidities. Two hundred and thirteen patients (71%) died during follow‐up. High lifetime alcohol consumption was independently associated with poor survival. Relative to life‐long nondrinkers and those consuming <1 drink/week, the HRs for those with average consumption of 7–20 drinks/week or ≥21 drinks/week were 2.21 (95% CI = 1.27–3.84) and 2.08 (95% CI = 1.18–3.69), respectively. There was a suggestion of worse survival among current smokers (HR = 1.42, 95% CI = 0.89–2.28); however, the risk of early death was greatest among current smokers who reported regularly (≥7 drinks/week) consuming alcohol (HR = 3.84, 95% CI = 2.02–7.32). Other lifestyle factors putatively associated with risk of developing ESCC were not associated with survival. In addition to increasing disease risk, heavy alcohol consumption may be independently associated with worse survival among patients with ESCC. Future clinical follow‐up studies should consider alcohol as a potential prognosticator, in addition to known clinicopathologic factors.

Epithelial ovarian cancer: Testing the 'androgens hypothesis'

In 1998, Risch proposed a hypothesis for the pathogenesis of ovarian cancer relating to the role of androgens in stimulating epithelial cell proliferation. Although this hypothesis has been widely discussed, direct evidence to support it is scant. To address this issue, we have conducted a detailed analysis of factors possibly associated with high circulating levels of androgens, including polycystic ovary syndrome (PCOS), hirsutism and acne (all clinically associated with hyperandrogenism) using the data collected in an Australia-wide, population-based case-control study. Cases aged 18-79 years with a new diagnosis of invasive epithelial ovarian cancer (n=1276) or borderline malignant tumour (n=315) were identified through a network of clinics and cancer registries throughout Australia. Controls (n=1508) were selected from the National Electoral Roll. Women self-reported a history of PCOS, acne, hirsutism and also use of testosterone supplements or the androgenic medication Danazol. We found no evidence that a history of PCOS, acne or hirsutism was associated with ovarian cancer overall, or with specific subtypes, with the exception of serous borderline tumours that were positively associated with a history of PCOS (OR 2.6; 95% CI 1.0-6.1). Women who had ever used testosterone supplements had an increased risk of ovarian cancer (OR 3.7; 95% CI 1.1-12.0); however, use of the androgenic medication Danazol did not increase risk (OR 1.0; 95% CI 0.4-2.9). Overall, our results do not support the hypothesis that androgen-related disorders increase the risk of ovarian cancer.

Body size and risk of epithelial ovarian and related cancers: a population-based case-control study.

Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body‐mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case‐control study in Australia. Cases aged 18–79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self‐administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2–4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7–1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7–4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1–2.8) but not mucinous tumors (1.1; 0.7–1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a womans risk of developing distinct histological subtypes of ovarian cancer.

Aspirin, nonsteroidal anti-inflammatory drugs, paracetamol and risk of endometrial cancer: a case-control study, systematic review and meta-analysis

Aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) have been associated with reduced risk of a number of cancer types, however, previous studies of endometrial cancer have yielded inconclusive results. We analyzed data from the Australian National Endometrial Cancer Study (ANECS), a population‐based case–control study (1,398 cases, 740 controls). We systematically reviewed all the evidence linking aspirin/NSAIDs use with endometrial cancer and conducted a meta‐analysis. For ANECS, unconditional logistic regression was used to estimate odds ratios (OR) adjusting for potential confounders. For the systematic review, we searched Pubmed, Embase, Web of Science and conducted a review of citations from retrieved articles. The meta‐analysis risk estimates were pooled using a random‐effects model. In our case–control study, women who had ever used aspirin in the last 5 years had a significantly lower risk of endometrial cancer OR = 0.78 [95% confidence interval (CI): 0.63‐0.97]. There was a significant inverse dose–response (p‐trend <0.001) such that women who reported using ≥2 aspirin/week had almost half the risk OR = 0.54 (0.38–0.78). No significant associations were observed between use of half‐aspirin/day, non‐aspirin NSAIDs or paracetamol and endometrial cancer risk. The results were similar when examined by cancer subtype. Nine studies were included in the meta‐analysis. The overall pooled risk estimate for any versus no use of aspirin was 0.87 (0.79–0.96) with no evidence of heterogeneity. The pooled risk estimate for obese women (BMI ≥ 30 kg/m2) was 0.72 (0.58–0.90) but there was no association for non‐obese women. Overall these results suggest that aspirin may reduce the risk of endometrial cancer, particularly among obese women.