According to the British Association of Dermatologists, 15% to 25% of actinic keratosis (AK) lesions spontaneously resolve during a one-year period.¹ However, AK lesions may develop into invasive squamous cell carcinoma (SCC) if left untreated.² The rate of progression from AK to SCC is unknown. Mathematical models derived from a study predicted that for an individual with an average of 7.7 AKs, the probability of developing an SCC at the same or nearby site within a 10-year period is approximately 10.³ The risk of malignant transformation is higher in patients who are immunocompromised. In Canada, 74,100 new cases of non-melanoma skin cancers (NMSCs) and 270 deaths due to these cancers were predicted for 2011.²

AK typically manifests as 2 mm to 6 mm scaly macules, papules, or plaques that are skin to reddish-brown in colour, and may be flat or thickened (hyperkeratotic).^4,5 Patients with AK are usually referred to dermatologists and diagnosis is frequently made on clinical appearance alone.¹ A skin biopsy may be required when there is clinical doubt or suspicion of invasive malignancy.^1,5 Detectable AK may be associated with a field change where the surrounding skin is also altered and subclinical lesions may be present.² Patient input to the CADTH Common Drug Review (CDR) suggests that cosmetic issues are a major concern for patients, and this can have a negative impact on self-confidence.

The submitted product is a combination of two topical therapies, 5-fluorouracil 0.5% (5-FU) and salicylic acid 10% (SA). 5-FU is an antimetabolite that is already approved as monotherapy for treatment of AK, although at a concentration of 5%. SA is a keratolytic, and the theory behind its use is to improve penetration of the combination in hyperkeratotic AK. The 5-FU/SA combination under review is administered once daily to affected lesions, until lesions have cleared or for a maximum of 12 weeks. It is indicated for the management of grade I/II hyperkeratotic AK.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of 5-FU (0.5%) combined with SA 10% applied topically once daily for the topical treatment of slightly palpable and/or moderately thick hyperkeratotic actinic keratosis (grade I/II) of the face, forehead, and balding scalp in immunocompetent adult patients.

Contents

• Clinical Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Introduction
    • Results and Interpretation
    • Potential Place in Therapy
    • Conclusions
  • 1. INTRODUCTION
    • 1.1. Disease Prevalence and Incidence
    • 1.2. Standards of Therapy
    • 1.3. Drug
  • 2. OBJECTIVES AND METHODS
    • 2.1. Objectives
    • 2.2. Methods
  • 3. RESULTS
    • 3.1. Findings from the Literature
    • 3.2. Included Studies
    • 3.3. Patient Disposition
    • 3.4. Exposure to Study Treatments
    • 3.5. Critical Appraisal
    • 3.6. Efficacy
    • 3.7. Harms
  • 4. DISCUSSION
    • 4.1. Summary of Available Evidence
    • 4.2. Interpretation of Results
    • 4.3. Potential Place in Therapy
  • 5. CONCLUSIONS
  • APPENDIX 1. PATIENT INPUT SUMMARY
    • 1. Brief Description of Patient Groups Supplying Input
    • 2. Condition and Current Therapy Related Information
    • 3. Related Information About the Drug Being Reviewed
  • APPENDIX 2. LITERATURE SEARCH STRATEGY
  • APPENDIX 3. EXCLUDED STUDIES
  • APPENDIX 4. DETAILED OUTCOME DATA
  • APPENDIX 5. SUMMARY OF OTHER STUDIES
  • REFERENCES
• Pharmacoeconomic Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Background
    • Summary of Identified Limitations and Key Results
    • Conclusions
  • INFORMATION ON THE PHARMACOECONOMIC SUBMISSION
    • 1. SUMMARY OF THE MANUFACTURER’S PHARMACOECONOMIC SUBMISSION
    • 2. MANUFACTURER’S BASE CASE
    • 3. SUMMARY OF MANUFACTURER’S SENSITIVITY ANALYSES
    • 4. LIMITATIONS OF MANUFACTURER’S SUBMISSION
      • Uncertain internal validity of the Simon et al. trial
      • Uncertain external validity of the Simon et al. trial
      • Assumptions related to resource use
      • Exclusion of relevant comparators
      • Uncertain assumptions regarding patient adherence and persistence
      • Uncertainty in calculated QALYs
    • 5. CADTH COMMON DRUG REVIEW REANALYSES
    • 6. ISSUES FOR CONSIDERATION
      • Expected use below the neck
      • Unclear place in therapy
    • 7. PATIENT INPUT
    • 8. CONCLUSIONS
  • APPENDIX 1. Cost Comparison
  • APPENDIX 2. Summary of Key Outcomes
  • APPENDIX 3. ADDITIONAL INFORMATION
  • APPENDIX 4. SUMMARY OF OTHER HEALTH TECHNOLOGY ASSESSMENT REVIEWS OF DRUG
  • APPENDIX 5. REVIEWER WORKSHEETS
    • Manufacturer’s Model Structure
    • Manufacturer’s Results
    • CADTH Common Drug Review Reanalyses
  • REFERENCES
• CDEC FINAL RECOMMENDATION
  • Recommendation
  • Reasons for the Recommendation
  • Background
  • Summary of CDEC Considerations

The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

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