Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

J Clin Invest. 2017 Jan 3;127(1):106-116. doi: 10.1172/JCI89820. Epub 2016 Nov 21.


Background: Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis.

Methods: The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed.

Results: Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration.

Conclusion: Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.

Trial registration: ClinicalTrials.gov NCT02019355.

Funding: Not applicable (investigator-initiated clinical trial).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Topical
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Calcitriol / administration & dosage
  • Calcitriol / analogs & derivatives
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / pathology
  • Cytokines / genetics
  • Cytokines / immunology
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / genetics
  • Keratosis, Actinic / drug therapy*
  • Keratosis, Actinic / genetics
  • Keratosis, Actinic / immunology
  • Keratosis, Actinic / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Precancerous Conditions / drug therapy*
  • Precancerous Conditions / genetics
  • Precancerous Conditions / immunology
  • Precancerous Conditions / pathology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology


  • Cytokines
  • calcipotriene
  • Calcitriol
  • thymic stromal lymphopoietin
  • Fluorouracil

Associated data

  • ClinicalTrials.gov/NCT02019355