Study Links NSAIDs to Increased Mortality in Endometrial Cancer

Theodore Brasky, PhD

An association was found between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and endometrial cancer risk, according to the results of a recent study led by The Ohio State University Comprehensive Cancer Center ­— Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC ­– James) and published in the Journal of the National Cancer Institute.

Compared with NSAID nonusers, NSAID use was associated with a 66% (HR, 1.66; 95% CI, 1.21-2.30) increased risk of endometrial carcinoma­—specific mortality among patients diagnosed with type I tumors. This increased risk held true for both former and current users of NSAIDs, with the strongest association found among women who formerly used NSAIDs for 10 or more years (HR, 2.23; 95% CI, 1.19-4.18; P_trend = .01). There was no clear association found between the use of NSAIDs and endometrial carcinoma­—specific mortality among women with type II tumors.

"There is increasing evidence that chronic inflammation is involved in endometrial cancer and progression and recent data suggests that inhibition of inflammation through NSAID use plays a role," Theodore Brasky, PhD, co-lead author of the study and a cancer epidemiologist with the OSUCCC ­— James, said in a press release.

Brasky was surprised by these findings, given that they contrast the results of previous studies that suggest NSAIDs can be used to reduce inflammation and reduce the risk of developing or dying from certain cancers, such as colorectal cancer.

The authors of the study evaluated 4374 patients with endometrial carcinoma from the NRG Oncology/Gynecology Oncology Group 210 Study (GOG-210 Study). These patients had completed a presurgical questionnaire that assessed their history of prediagnostic NSAID use as well as endometrial cancer risk factors. Of 6124 women enrolled, 5492 (89.7%) completed the questionnaires. Medical records and cancer registries provided the researchers with patient information on recurrences, vital status, and causes of death.

Endometrial tumors were characterized as low-grade (grades 1 and 2) endometrioid carcinoma (n = 2657), high-grade (grade 3) endometrioid carcinoma (n = 582), serous carcinoma (n = 663), carcinosarcoma (n = 309), or clear cell carcinoma (n = 163). The researchers further classified low- and high-grade tumors as type I (n = 3239) and serous, clear cell, and carcinosarcomas as type II (n = 1135).

Of the 4374 patients enrolled in the GOG-210 Study, the median follow-up was 60 months after diagnosis. Five hundred fifty carcinoma-specific deaths and 737 recurrences were recorded in total.

The presurgical questionnaire included an assessment of patients’ “regular” use, which the researchers defined as 1 or more NSAID per week for 1 or more years (or more than 50 pills during any 1-year period) of aspirin, nonaspirin NSAIDs (including ibuprofen, naproxen, indomethacin, piroxicam, and sulindac), and cyclooxygenase-2 (COX-2) inhibitors.

For each NSAID type, information was also collected on duration of regular use (<1, 1-4.99, 5-9.99, and ≥10 years) and recency of regular use (former or current) relative to the date that patients completed the questionnaire. Combination exposure variables represented recency and duration based on cross-tabulations. A summary variable, referred to as “any NSAIDs,” represented patients who claimed to be regular users of aspirin, nonaspirin NSAIDs, or COX-2 inhibitors.

According to the results of this study, NSAID use was not clearly associated with any tumor characteristic, including stage, histology, myometrial invasion, lymph node involvement, peritoneal cytology, or peritoneal biopsy result.

The researchers specifically looked at the relationship between NSAID use and endometrial carcinoma&shy;—specific mortality stratified by cancer subtypes (types I and II), given the strong association between subtype and prognosis. Relative to nonuse, any use of these anti-inflammatory drugs was associated with a 66% increased risk of endometrial carcinoma&shy;–specific mortality among women with type I tumors. The risk was similar for both former and current NSAIDs users and was found to be statistically significant with 10 or more years of use. There was no association identified between NSAID use and endometrial carcinoma-specific mortality for women diagnosed with type II tumors.

However, women who formerly used NSAIDs for 10 or more years saw an approximate doubling of increased risk (HR,1.92; 95% CI, 1.20-3.08; P_trend = .004) of endometrial carcinoma&shy;—specific mortality.

When the authors of the study stratified the cancers by individual histologies, they found an association between NSAID use and higher endometrial carcinoma&shy;—specific mortality for patients diagnosed with low-grade (HR, 2.18; 95% CI, 1.33-3.58) and high-grade endometrioid tumors (HR, 1.65; 95% CI, 1.03-2.62), as well as carcinosarcomas (HR, 1.54; 95% CI, 1.00-2.38). These associations were more pronounced in former and current users, but they only increased with longer duration of use for carcinosarcomas. Among patients with serous or clear cell histologies, there were no associations between NSAID use and mortality.

On the other hand, unlike mortality, any NSAID use was not associated with recurrence from type I endometrial carcinoma (HR, 1.16; 95% CI, 0.92-1.47).

When recurrence models were stratified by individual tumor histologies, any NSAID use was associated with a 54% (HR, 1.54; 95% CI, 1.03- 2.32) increased risk of recurrence among women with high-grade endometrioid tumors. A statistically nonsignificant 47% (HR, 1.47; 95% CI, 0.97-2.23) increased risk of recurrence was found among patients with carcinosarcomas. For each of these correlations, neither was strengthened by an increased duration of NSAID use.

"This study identifies a clear association that merits additional research to help us fully understand the biologic mechanisms behind this phenomenon,” said Brasky.

David Cohn, MD, gynecologic oncology division director at the OSUCCC &shy;— James and co-author of the study, said it is important to remember that these types of patients are more likely to die of cardiovascular disease than their actual cancer. Thus, women who take NSAIDs to reduce their risk of heart attack should continue to do so.

“While these data are interesting, there is not yet enough data to make a public recommendation for or against taking NSAIDS to reduce the risk of cancer-related death,” he said in a statement.

Brasky TM, Felix AS, Cohn DE, et al. Nonsteroidal anti-inflammatory drugs and endometrial carcinoma mortality and recurrence [published online December 16, 2016]. J Natl Cancer Inst. doi:10.1093/jnci/djw251.