Association of Nonsteroidal Anti-inflammatory Drug Use With Survival in Patients With Squamous Cell Carcinoma of the Head and Neck Treated With Chemoradiation Therapy

This cohort study investigates the association between nonsteroidal anti-inflammatory drug (NSAID) use and survival in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy (CRT) at a single institution between 2005 and 2017.


Introduction
Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer death in the United States. There is an increasing incidence of human papillomavirus (HPV)-associated tumors with 53 000 new cases in 2019. 1,2 HPV-associated tumors more frequently have phosphoinositide 3-kinase (PI3K) gene variations independent of tobacco exposure. 3,4 By exploiting this oncogenic addiction phenotype, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been identified as potential chemotherapeutic agents owing to the effect they have on cyclooxygenase inhibition, which is required for prostaglandin synthesis. 5 Concurrent use of NSAIDs has been shown to be associated with a survival advantage for colorectal cancer and a wide range of cancer histologies. 6 Whether NSAID use protects against the development of HNSCC remains controversial, as results have been mixed or inconclusive. [7][8][9][10][11] Recently, however, Hedberg et al found that regular NSAID use at any time improves disease-specific survival (DSS) and overall survival (OS) in patients with PI3K-altered HNSCC. 12 Less explored is the association of NSAID use with definitive chemoradiation therapy (CRT). This cohort study was performed using a large single institution HNSCC database to further examine the survival outcomes associated with NSAID use during CRT.

Methods
The Roswell Park Comprehensive Cancer Center institutional review board approved this retrospective cohort study of patients with HNSCC diagnosed and treated at a single institution with CRT between January 1, 2005, and August 1, 2017. An approved waiver of consent was obtained from the Roswell Park Comprehensive Cancer Center because the research met the criteria for minimal risk to the study participants. This study did not follow the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Eligibility
To be included in this study, patients had to have the following criteria: (1) a first-time diagnosis of cancer, (2) an invasive squamous cell carcinoma limited to the head and neck, (3) treatment with CRT, and (4) successful completion of the treatment. Our complete patient selection criteria are shown in   Analyses for the association between clinical outcomes and each particular variable were conducted.
Only variables that were considered potential confounding factors were included before backward selection. All related factors that were significant at level α = .20 in the backward selection analyses were included in the final multivariate analysis. Survival estimates for OS and DSS were calculated using Kaplan-Meier survival curves. All tests were 2-sided, and P < .05 was considered statistically significant. SAS, version 9.4 (SAS Institute, Inc) was used for statistical analyses. Few studies have previously examined the association between NSAID use during HNSCC treatment and patient survival. In a retrospective analysis examining 329 veterans, Lumley et al Although we were unable to test for PI3K, our results suggest an OS advantage but not a DSS advantage. Hedberg et al suggest that PIK3CA variations may be a clinically useful marker to identify which patients with HNSCC will benefit from NSAID use 12 ; however, until such testing is routine, the   The exact mechanism by which NSAIDs are associated with survival in HNSCC remains unclear.

Results
Our study did not find a reduction in distant metastasis among patients taking NSAIDs, which is a potential explanation for the improved survival proposed by prior meta-analyses. 15,16 There was also no DSS advantage for patients taking NSAIDs observed in our study. This suggests the observed survival advantage may be associated with the cardiovascular benefits of NSAIDs rather than any chemoprotective properties they may have, particularly because there was a higher proportion of patients with diabetes and coronary artery disease in the group taking NSAIDs. This is increasingly important because the risk of noncancer death now surpasses that of cancer death, with heart disease being the leading cause of noncancer mortality. 19 The fact that anticoagulants were not associated with improved OS while NSAIDs were suggests that the cyclooxygenase mechanism may be a contributing factor to survival. This mechanism may be a combination of local recurrence reduction through cyclooxygenase inhibition and treatment of underlying cardiovascular disease.

Limitations
This study is limited by several factors. Because of the nature of a retrospective review, the results are prone to information bias from miscoding of patient data and medication entry errors. In regard to NSAIDs, we had access to patient comorbidity data but did not have the reason why patients were prescribed regular NSAID use; nor did we have the duration of use. The vast majority of patients noted to be taking NSAIDs at the time of consultation were taking a "baby" (81-mg) aspirin, which was continued during CRT. Another limitation is the imbalance of primary tumor sites between the cohorts, with a small increase of patients with larynx and hypopharynx primary tumor sites and current smokers in the group not taking NSAIDs. This is adjusted for using multivariate analysis and does not alter the significance of the results. Despite these limitations, this review provides a large cohort of patients treated for HNSCC with CRT and concurrently taking NSAIDS.

Conclusions
The results of this study suggest that there may be an OS advantage for patients taking NSAIDs during chemoradiation for HNSCC. Further studies examining this association are warranted.