Studying the Risk of Cancer with Topical Calcineurin Inhibitor Use in Children: Design Issues

1
Studying the Risk of Cancer with Topical
Calcineurin Inhibitor Use in Children Design
Issues

• Lois La Grenade MD MPH
• Center for Drug Evaluation Research
• Office of Drug Safety

2
Outline

• Observational studies - general methods
• Methods for risk of cancer with long term use of
  calcineurin inhibitors (CI) in children with
  atopic dermatitis (AD)

3
Epidemiologic Methods

• Observational Studies
• Case Control
• Cohort
• Registries

4
Case Control Studies

• Retrospective
• Start with disease of interest (cases)
• Compare with people without disease (controls)
• Compare frequency of the exposure of interest
  between cases controls

5
Case Control Studies - Advantages

• Less expensive
• Relatively quick
• Generally useful for studying most rare events
  with common exposures

6
Case Control Studies - Disadvantages

• Subject to several biases
• Recall
• Selection
• Unsuitable for studying diseases with very long
  latency periods e.g. cancer
• Difficult for rare exposures

7
Cohort Studies

• Compare exposed vs. non-exposed persons
• Start with a defined group of people (defined by
  exposure disease place of residence etc.)
• Followed through time for occurrence of
  disease(s) of interest
• Prospective

8
Cohort Studies - Advantages

• Cases exposure determined prospectively so
  recall bias minimized
• All cases can potentially be captured so
  selection bias reduced
• Can study several outcomes or diseases
• Most closely resemble experimental design toxin
  administered then follow for outcome
• Consequent high acceptance by scientific community

9
Cohort Studies - Disadvantages

• More expensive
• Large sample sizes for rare diseases
• Long
• Problems from losses to follow-up

10
Retrospective Cohort Studies

• Can be used to overcome disadvantages of
  prospective cohorts viz. length
• Use a preexisting cohort e.g. occupational
  cohort cohort exposed to a drug of interest
• Instead of comparison controls can compare
  disease with population incidence rates
  (Standardized Incidence Ratio - SIR)

11
Registries

• Exposure based occupational drug exposures
• Disease based State National Cancer
  Registries
• Complete (usually mandatory) all subjects with
  exposure/disease captured
• Incomplete (usually voluntary) only some
  cases/exposed persons captured

12
Uses of Registries in Epidemiology

• Exposure registries cases ascertained in
  exposure cohort e.g. cohort of drug exposed
  people
• Case based registries as source of cases for
  case control study
• Complete registries generally far more useful
• Can be used to determine incidence rates when
  based in defined population
• Incidence of rare events with rare exposures

13
Topical Calcineurins atopic dermatitis in
children
14
Cancer Risk with Calcineurin Inhibitor (CI) Use
in Children with AD

• Special problems with cancer studies
• Rare events particularly in the young
• Very long latency i.e. many years between
  exposure clinically apparent cancer
• Prospective method (cohort or registry) ideal

15
Cohort Design

• Prospective
• Exposure assessment accurate standardized
• Dose duration of topical CI can be assessed
• Case ascertainment complete accurate
• Data on confounding/risk factors

16
Cohort Study - Indication

• There is good evidence of an association between
  a disease an exposure
• Clinical studies
• Case control studies
• Other studies e.g. animal studies
• Introduction of a new agent that requires
  monitoring for its possible association with
  several diseases

Gordis Epidemiology 1996 Kelsey et al
Methods in Observational Epidemiology1996
17
International Monitoring of Adverse Drug
Reactions of Long Latency

• Fletcher AP Griffin JP
• Adverse Drug React. Toxicol. Rev. 1991 10 (4)
  209 230
• for adverse reactions of long latency to be
  detected methods have to be used that permit
  observation of the patient to be followed for
  many months or years..An essential requirement
  is the identification of a cohort of patients
  exposed to a particular drug .who may be
  accessed at specified intervals of time.

18
Cohort Study Design - Cancer Risk with
Calcineurin Inhibitor (CI) Use in Children with
AD

• Background
• Objectives
• Population
• Sample Size/Power
• Exposure definition assessment
• Endpoint (cancers) definition ascertainment
• Measures to reduce bias losses to follow-up
• Analysis Plan

19
Background

• Enhanced photocarcinogenicity with both topical
  CI vehicles
• Carcinogenicity studies signal for lymphoma
  other systemic malignancies
• Oral CI use associated with risk of lymphoma
  cutaneous other malignancies

20
Objective

• To investigate the risk of developing cutaneous
  systemic malignancies in children with atopic
  dermatitis (AD) who have long term intermittent
  treatment with topical CIs

21
Outcomes of Interest

• Cutaneous malignancies
• Melanoma
• Non-melanoma (basal squamous)
• Systemic
• Lymphoma (Hodgkins NHL)
• Others
• Additional cutaneous end points e.g. actinic
  keratoses

22
Population

• Traditional study
• Cohort of children (aged 2 - 16 years) with AD
• Follow for 10 15 years
• Document treatment type response confounding
  factors e.g. sunlight exposure skin type
  disease severity
• Document occurrence of malignancies as they occur
• At end of follow up compare incidence in CI
  treated vs. non-CI treated group

23
Cohort - Population

• Traditional study - difficulties
• Very long
• Very large sample size
• May find that most patients have used both CI and
  non-CI treatment regimens (or vice versa) and
  comparison may be difficult

24
Cohort Population (Alternate method)

• Cohort of CI users (aged 2 16 years) with AD
• Follow subjects for minimum 10 year period
• Use age specific population incidence rates for
  cancer as comparator
• (Standardized Incidence Ratio SIR)
• Similar to occupational epidemiology methods

25
SIR Approach - Difficulties

• No US national incidence rates for most cutaneous
  malignancies
• May have to extrapolate from data from other
  countries e.g. Finland or from US local data
  e.g. Southeastern Arizona

26
US Age Specific Incidence of all Malignancies
per 100000 by gender
Surveillance Epidemiology and End Results
(SEER) Program (www.seer.cancer.gov) SEERStat
Database Incidence - SEER 9 Regs Public-Use Nov
2002 Sub (1973-2000) National Cancer Institute
DCCPS Surveillance Research Program Cancer
Statistics Branch released April 2003 based on
the November 2002 submission.  
27
Age Specific Incidence of SCC per 100000 by
gender Southeastern Arizona
Males
Females
Harris RB et al 2001 JAAD (43)4 528-536
28
Age Specific Incidence of BCC per 100000 by
gender Southeastern Arizona
Males
Females
Harris RB et al 2001 JAAD (43)4 528-536
29
Power/Sample Size Calculations
Background rate 6/10000 represents annual
incidence rate for all cancers in 25 - 29 age
group SEER Cancer Statistics Review
1973-1999 Power 80 0.05
30
Power Sample Size Calculations
Annual incidence rate for all cancers in 15 - 19
age group SEER Cancer Statistics Review
1975-2000 Power 80 0.05
31
Power Sample Size Calculations
Annual incidence rate for lymphoma in 0 - 19 age
group SEER Cancer Statistics Review
1973-1999 Power 80 0.05
32
Probability of finding no event with defined
sample sizes Lymphoma
Incidence 24.1/million Age 0-19 years SEER
Cancer Statistics Review 1973-1999
33
Probability of finding no event with defined
sample sizes
N10000
N20000
Lymphoma incidence 24.1/million Age 0-19 years
34
Sample Size/Power

• Multicenter multinational cohort would boost
  sample size and power considerably
• Use of additional end points e.g. AK might also
  increase power

35
AK as additional End Point

• Actinic Keratoses (AK)
• precancerous skin lesions proliferation of
  abnormal keratinocytes within epidermis
• SCC in situ
• may become SCC (60 of all SCC may start as AK)
• Very rare in young people

Fu W Cockerell C 2003 Arch Dermatol13966-70
36
Exposure Definition

• Need to define long term intermittent exposure
  to CIs
• At enrollment
• Suggestions
• 6 weeks/3 months continuous or intermittent use
• 30 GM over 6 weeks

37
Exposure Assessment (Enrollment During Study)

• Possibilities
• Prescription Self report by care giver
• Return unused portions of tubes
• Weigh unused tubes/portions
• Consider additional burden on participants
  (losses to follow-up) vs. more accurate
  information

38
Ascertainment of Malignancies

• Pathologic/histologic definitions
• ICD codes
• Systemic malignancies could be ascertained by
  linkage with state/national cancer registries
  once a unique identifier was obtained for each
  subject at baseline
• But not true for most cutaneous malignancies
• Self reporting of cutaneous malignancies
  unreliable

39
Ascertainment of Cutaneous Malignancies

• Most state national cancer registries collect
  limited data on skin malignancies (usually data
  on invasive melanomas only)
• Non-melanoma skin cancers (basal squamous cell
  cancers) often treated in office procedure
• Basal cell cancers (BCC) AK may be treated with
  cryotherapy or electrocautery without even
  histology

40
Ascertainment of Cutaneous Malignancies

• Best done by periodic (annual) physical
  examination (PE) of the skin by physician
  preferably a dermatologist
• PE particularly important for good capture of all
  cutaneous outcomes hence early accurate
  assessment of the risk

41
Follow-up

• Duration
• Minimum 10 years for each subject in keeping
  with long latent period for cancers

42
Minimizing Losses to Follow-up

• Losses to follow-up
• Important source of bias in cohort studies of
  long duration
• So vigorous methods will have to be used to
  reduce losses to follow-up
• Statistical methods to handle losses to follow-up

43
Statistical Analysis Plan

• Crude adjusted incidence rate
• SIR
• Methods for handling losses to follow-up

44
Registry - Cancer Risk with Calcineurin Inhibitor
(CI) Use in Children with AD

• Ideal
• Exposure registry
• Registration of all users of CIs (probably
  mandatory) prospective collection of unique
  identifier (e.g. SSN)
• Link to state/national cancer registries for
  detecting systemic malignancies
• Would still need periodic examination by
  physician to ascertain skin cancers

45
Mandatory Registry - Advantages

• All users registered
• Minimal survivor bias minimal losses to
  follow-up
• If ascertainment of malignancies were also
  complete registry would provide fastest
  incidence results

46
Mandatory Registry - Disadvantages

• Poor acceptance by physicians patients
• Expensive
• No accurate exposure assessment
• No data on confounding factors
• Not possible to ascertain most skin cancers

47
Summary
48
Practical Issues

• Duration of follow-up
• Sample Size/Power
• Endpoint (cancers) ascertainment
• How often by whom
• Measures to reduce bias
• losses to follow-up
• What level of uncertainty

49
Acknowledgements

• Yi Tsong PhD. Actg. Deputy Director QMR OB
• David Graham MD MPH Associate Director for
  Science ODS