NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND PANCREATIC CANCER RISK: A NESTED CASE-CONTROL STUDY

1. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND PANCREATIC CANCER RISK: A NESTED CASE-CONTROL STUDY Marie Bradley, Carmel Hughes, Marie Cantwell and Liam Murray Cancer Epidemiology and Prevention Research Group, & School of Pharmacy, Queen’s University Belfast

2. Pancreatic cancer Chemoprevention of cancer with NSAIDs GPRD Nested case-control study examining the effect of NSAIDs on pancreatic cancer risk using GPRD Overview

3. Pancreatic Cancer • In the United Kingdom (UK) in 2006 there were around 7,600 cases of pancreatic cancer diagnosed. • Rapidly fatal • Presents at an advanced stage • 5th leading cause of cancer mortality, in the western world • Five year survival rate of 1%. • As incidence and mortality increase with age, the pancreatic cancer burden will rise in the future, due to population ageing and increased life expectancy.

4. Smoking 4. Age 2. Genetic factors/ 5. Obesity Family history 3. Chronic pancreatitis Important to identify other aetiological factors for pancreatic cancer in order to improve prospects for primary prevention. Known risk factors for pancreatic cancer

5. Large body of epidemiological and experimental evidence suggesting that exposure to aspirin and NSAIDs is associated with a reduced risk of colorectal cancer through inhibition of COX-2. COX-2 expression is increased in inflammation and carcinogenesis. COX- 2 blockade has been shown in experimental studies to induce apoptosis, inhibit endothelial cell migration, neovascularisation and the invasive potential of pancreatic cancer cells. However evidence is limited. Chemoprevention of cancer using cyclooxygenase (COX) inhibitors

6. Primary Aim: “Investigation of the role of NSAIDs and aspirin in the aetiology/prevention of pancreatic cancer using the General Practice Research Database (GPRD)” Aims

7. GPRD is the world’s largest computerised database of anonymised longitudinal patient records from primary care. Started up in 1987. 3.7 million (up to standard) UTS patients. 434 UTS practices across the UK. 5.5% of the UK population. Representative of UK population in terms of age, sex, and geographic distribution. The general practice research database (GPRD)

8. Case-control study. Source population from (GPRD). Patients <85years old and had ≥5 years of follow-up, prior to the diagnosis date. Cases had a diagnosis of primary malignant neoplasia of the exocrine pancreas between 01/1995 and 06/2006. Up to 7 controls matched with each case on general practice site, sex and year of birth. Primary exposure of interest was exposure to NSAIDs/aspirin in the five years prior to the diagnosis date One year lag time. Methods

9. Total dose of NSAIDS per patient (the average daily dose in units of Defined Daily Dose [DDD]). Total duration of NSAID use per patient. The dose (DDDs) and duration (days) of NSAID use per patient were divided into quartiles. The effect of dose (DDDs) and duration (years) combined. Effect of different NSAID groups. Methods

10. Conditional logistic regression analyses were used to generate odds ratios (OR) and 95% confidence intervals (95% CI) associated with NSAID use compared to non-use. All estimates of OR were adjusted for smoking status, Body Mass Index (BMI), alcohol use, and history of chronic pancreatitis, prior cancer, diabetes. Also adjusted for use of steroids, PPIs, H2RAs and hormone replacement therapy (HRT). Analyses

11. 1141 cases and 7954 controls were identified. Analysis examined: Effect of any use Effect of dose Effect of duration of use Effect of dose and duration Effect of different groups of NSAIDs Results

12. 1.Dose of NSAIDs used

13. 2.Duration of NSAID use

14. 3.Dose and Duration of NSAID use combined since entry into GPRD

15. 4.NSAID groups

16. Results • No significant reductions in risk of pancreatic cancer for ever use compared with never use of a NSAID. • No overall association between pancreatic cancer risk and the total dose of NSAIDs prescribed and no risk reduction was seen among subjects who used the highest doses of NSAIDs. • A 20% reduction in risk was seen among subjects who had been prescribed a NSAID for approximately 2 years or longer in the 5 years before diagnosis. • A 30% reduction in pancreatic cancer risk was also seen in subjects who had used lower than average doses of NSAIDs for 5 years or more since entry into the GPRD.

17. Results • Ever use versus never use of COX-2 inhibitors and oxicams in the five years before the index date, was associated with modest reductions in pancreatic cancer risk (20% and 30% respectively) but statistical significance was not achieved and too few subjects were exposed to these preparations to allow a more detailed analysis of use of these drugs.

18. Study strengths: NSAID exposure was determined by prospectively collected prescription data, avoiding self-reported exposure and its associated disadvantages Study size Representative sample Discussion

19. It therefore appears that long-term use (>2 years) of NSAIDs may protect against pancreatic cancer and that duration of use may be more important than dose. As there was no further reduction in risk with use of more than one DDD per day, which represents a standard anti-inflammatory dose, it does not appear that doses which exceed those that are routinely used for the main indications of these drugs are required for prevention. Conclusion