NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND PANCREATIC CANCER RISK: A NESTED CASECONTROL STUDY

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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, Queens University
  Belfast

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Overview

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

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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.

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Known risk factors
for
pancreatic cancer

• 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.

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Chemoprevention of
cancer using
cyclooxygenase (COX) inhibitors

• 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.

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Aims

• Primary Aim
• Investigation of the role of NSAIDs and
  aspirin in the aetiology/prevention of pancreatic
  cancer using the General Practice Research
  Database (GPRD)

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The general
practice research database (GPRD)

• GPRD is the worlds 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.

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Methods

• Case-control study.
• Source population from (GPRD).
• Patients lt85years 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.

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Methods

• 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.

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Analyses

• 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).

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Results

• 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

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1.Dose of NSAIDs used
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2.Duration of NSAID use
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3.Dose and Duration of
NSAID use
combined since entry
into GPRD
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4.NSAID groups
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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.

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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.

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Discussion

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

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Conclusion

• It therefore appears that long-term use (gt2
  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.