Continuing medical educationTopical pharmacotherapy for skin cancer: Part I. Pharmacology
Introduction
Since the introduction of 5-fluorouracil in the 1960s,1 a number of topical drugs have been used for the treatment of skin tumors. Some of these topical drugs have been approved by the US Food and Drug Administration for selected indications; others are used off-label or are under investigation.
The purpose of this review is to provide an in-depth analysis of the available topical treatments for primary skin cancers (Table I), including their mechanism of action, formulations, indications, side effects, and contraindications. The effectiveness of these drugs in the treatment of skin cancer, according to evidence-based medicine guidelines, is evaluated in part II of this continuing medical education article.
Section snippets
5-Fluoruracil
Key points 5-Fluorouracil acts as an antimetabolite, interfering with DNA synthesis Topical 0.5%, 1%, 2%, and 5% 5-fluorouracil are approved by the US Food and Drug Administration for the treatment of actinic keratoses The 5% formulation is also approved by the US Food and Drug Administration for the treatment of superficial basal cell carcinomas The most common local skin reactions observed during treatment with 5-fluorouracil include erythema, blistering, necrosis, and erosions, accompanied by pruritus and
Imiquimod
Key points Imiquimod is a synthetic immune response modifier Imiquimod 5%, 3.75%, and 2.5% cream are approved by the US Food and Drug Administration for face and scalp actinic keratoses Imiquimod 5% is also approved by the US Food and Drug Administration for the treatment of superficial basal cell carcinomas Patients treated with imiquimod may experience moderate to severe local skin reactions, occasionally extending beyond the application site, including pruritus, burning, erythema, vesicles, erosions,
Diclofenac
Key points Diclofenac acts by downregulating cyclooxygenase enzymes and increasing apoptosis A unique topical formulation containing diclofenac 3% gel in 2.5% hyaluronic acid is approved by the US Food and Drug Administration for the treatment of actinic keratoses Diclofenac 3% gel in 2.5% hyaluronic acid is considered a well-tolerated treatment, with mild irritant side effects at application sites
Diclofenac is a potent nonsteroidal antiinflammatory drug (NSAID).
Ingenol mebutate
Key points Ingenol mebutate has a dual mechanism of action: the induction of rapid cellular death (within a few hours) followed by an inflammatory response (within days) Two formulations of ingenol mebutate are available and approved by the US Food and Drug Administration for the treatment of actinic keratoses: a 0.015% gel for the face and scalp lesions once daily for 3 days and a 0.05% gel for the trunk and extremities once daily for 2 days The most common local skin reactions related to the use of
Retinoids
Key points Retinoids interfere with cell proliferation and differentiation through their interaction with specific cellular and nuclear receptors Topical retinoids used off-label in the treatment of skin cancer include tretinoin, isotretinoin, adapalene, and tazarotene Topical retinoids may be responsible for mild to moderate local side effects, including erythema, peeling, dryness, burning, and pruritus
Retinoids include a variety of vitamin A (retinol) derivatives that are commercially available for the
Emerging therapies
Key points Resiquimod is an immune response modifier investigated for the topical treatment of actinic keratoses Piroxicam, a NSAID that inhibits the activity of COX-1 and COX-2, is being evaluated as a possible agent in the treatment of actinic keratoses Topical experimental formulations containing calcium dobesilate 2.5% and potassium dobesilate 5% have been utilized for the treatment of basal cell carcinomas and actinic keratoses Betulinic acid is a natural compound that exerts cytotoxic,
Conclusions
Several topical drugs are now available for the treatment of superficial forms of skin cancer. New molecules are under development, as are new formulations, new dosages and simpler therapeutic schedule of existing agents, which may ensure greater patient compliance.
References (65)
- et al.
Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis
Clin Ther
(2002) - et al.
Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease): a randomized, double blind, placebo-controlled trial
J Am Acad Dermatol
(2006) - et al.
Erythroplasia of Queyrat treated with imiquimod 5% cream
J Am Acad Dermatol
(2006) - et al.
Successful treatment of recurrent extramammary Paget’s disease of the penis and scrotum with imiquimod 5% cream
Presse Med
(2011) - et al.
Topical imiquimod treatment of a cutaneous melanoma metastasis
J Am Acad Dermatol
(2000) - et al.
Safety studies of topical imiquimod 5% cream on normal skin exposed to ultraviolet radiation
Toxicology
(2002) - et al.
Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response
J Am Acad Dermatol
(2012) - et al.
Clinical findings using ingenol mebutate gel to treat actinic keratoses
J Am Acad Dermatol
(2013) - et al.
Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses
J Am Acad Dermatol
(1994) - et al.
Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial
J Am Acad Dermatol
(2003)
Treatment of lentigo maligna with tazarotene 0.1% gel
J Am Acad Dermatol
Tumors of the skin: effects of local use of cytostatic agents
Skin (Los Angeles)
The effects of 5-fluorouracil (5-FU) ointment in the treatment of neoplastic dermatoses
Dermatologica
Tumors of the skin. XII. Topical 5-fluorouracil for epidermal neoplasms
J Surg Oncol
Topical treatment strategies for non-melanoma skin cancer and precursor lesions
Semin Cutan Med Surg
Topical therapy for actinic keratoses: current and evolving therapies
Rev Recent Clin Trials
Effectiveness of 5-fluorouracil treatment for actinic keratosis - a systematic review of randomized controlled trials
Int J Dermatol
Treating skin cancer with topical cream
Expert Opin Pharmacother
Basic pharmacology of topical imiquimod, 5-fluorouracil, and diclofenac for the dermatologic surgeon
Dermatol Surg
Therapeutic strategies for actinic keratoses—a systematic review
Eur J Dermatol
Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results
Br J Dermatol
Topical treatment of Bowen’s disease with 5-fluorouracil
J Cutan Med Surg
Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen's disease
Br J Dermatol
Temporary ectropion due to topical fluorouracil
Cutis
Cicatricial ectropion: a complication of topical 5-fluorouracil
J Plast Reconstr Aesthet Surg
Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil
Clin Cancer Res
Advances in the use of topical imiquimod to treat dermatologic disorders
Ther Clin Risk Manag
The antitumoral mode of action of imiquimod and other imidazoquinolines
Curr Med Chem
Imiquimod as an antiangiogenic agent
J Drugs Dermatol
Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle
Br J Dermatol
Imiquimod and lymphatic field clearance: a new hypothesis based on a remote immune action on skin cancer
Acta Derm Venereol
Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: a case series and review
J Dermatolog Treat
Cited by (75)
Local immunotherapy of cancer and metastasis
2021, Systemic Drug Delivery Strategies: Volume 2 of Delivery Strategies and Engineering Technologies in Cancer ImmunotherapyExtramammary Paget disease of the vulva
2021, Seminars in Diagnostic PathologyNanoparticles for topical drug delivery: Potential for skin cancer treatment
2020, Advanced Drug Delivery ReviewsQbD guided early pharmaceutical development study: Production of lipid nanoparticles by high pressure homogenization for skin cancer treatment
2019, International Journal of PharmaceuticsCitation Excerpt :Although the mortality rate is low, skin cancer is one of the most frequent type of cancers among Caucasians. Cream and solution forms of 5-FU at a concentration of 0.5–5% in the global pharmaceutical market for topical treatment of skin cancer (Micali et al., 2014). These conventional systems provide a short contact time with the administration site.
Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives
2023, Clinical, Cosmetic and Investigational Dermatology
Funding sources: None.
Conflicts of interest: None declared.