Long-term use of NSAID reduces the risk of oral cancer

Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2004

Presenter: J. Sudbo
Presenter's Affiliation: Norwegian Radium Hosptial, Oslo, Norway
Type of Session: Scientific


  • Oral cavity cancers are often associated with high rates of morbidity and mortality
  • COX-2 may play a role in the development of squamous cell carcinomas (SCCA) of the head and neck
  • Cycloxegenase-2 (COX-2) has been found to be increased in head and neck cancers but virtually absent in normal head and neck tissue
  • Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2
  • The current study explores the possible protective role NSAIDs may play in the development of oral cavity SCCA

Materials and Methods

  • The Norwegian National Health Survey (NNHS) contains health information on over 300,000 individuals.  This database was queried to find individuals at high risk for oral cavity cancers defined as individuals with >15 pack-year history of smoking
  • These high-risk patients were cross-linked to the Norwegian Cancer Registry (a national cancer registry containing around 40,000 individuals) to find high-risk patients who have been diagnosed with oral cavity cancers
  • These patients were then tightly matched to controls by age (+/- 5 years), gender, and tobacco and alcohol history from the remaining high-risk patients to perform a population-based nested case-control study
  • Additional information including smoking history, medications, age, gender, and other comorbidities was obtained into the Norwegian Cancer Registry


  • Patients were accrued to the NNHS between 1975 and 1990, and a total of 3275 persons at high risk for oral cancer were identified
  • 454 of the 3275 people identified as being high risk were found to have a history of oral cavity SCCA
  • 454 matched controls were selected from the remaining 2779 patients at high risk who did not have oral cavity cancer
  • 90/454 (20%) patients with oral cavity SCCA and 187/454 (41%) controls had a history of NSAID use
  • Hazard ratio (HR) for developing oral cancer with use of NSAIDs = 0.35 (95% CI 0.26-0.48)
  • HR based on time of use of NSAIDs was as follows:
    • 0.5-10 years: HR = 0.39 (95% CI 0.22-0.64)
    • 10-15 years: HR = 0.30 (95% CI 0.18-0.50)
    • 15-20 years: HR = 0.31 (95% CI 0.18-0.53)
    • 20-35 years: HR = 0.45 (95% CI 0.25-0.83)
  • There was no difference in the risk reduction with the type of NSAID used including aspirin, ibuprofen, naproxen, indomethacin, piroxicam, and ketoprofen.
  • No difference was seen in overall survival with use of NSAIDs (p=0.201)
  • Time varying covariate analysis was performed to determine the effects of NSAIDs only while patients were taking NSAIDs.  In this analysis, if a patient was taking NSAIDs and then stopped (or vice versa), that patient would cross between groups at the time that their medication status changed
    • For patient ages <60, absolute risk of oral cavity CA was increased, but not significantly
    • For patient ages >60, absolute risk of oral cavity CA was significantly decreased (p-value not reported)
    • Overall, by time-variate analysis, HR = 0.71 (p=0.01)

Author's Conclusions

  • An absolute decrease in the risk of oral cavity SCCA of 65% was seen with NSAID use
  • All types of NSAIDs were protective
  • There was no association between duration of NSAID use and the decrease in risk of oracl carity SCCA

Clinical/Scientific Implications

The current study shows a protective effect with long-term use of NSAIDs for the development of SCCA of the oral cavity.  While the results of this study are promising, it must be noted that the study was conducted in a retrospective manner, and potential biases between the study groups may be present.  However, it appears that the patient populations in this study are well-matched and possible imbalances between groups are not readily evident from the information that has been presented.  This study adds to the body of evidence that NSAIDs may play a protective role in the development of SCCA, particularly in high-risk populations.  Future prospective, randomized trials should be conducted to evaluate this possibility.

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