Non-melanoma skin cancers: Photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies

doi:10.1016/j.clindermatol.2013.08.020

Clinics in Dermatology

Volume 31, Issue 6, November–December 2013, Pages 792-798

https://doi.org/10.1016/j.clindermatol.2013.08.020 Get rights and content

Abstract

Surgical modalities–excision, Mohs micrographic surgery, and electrodesiccation with curettage–are the preferred treatments for nonmelanoma skin cancer (NMSC). When used within guidelines, they have cure rates greater than 90%. Despite this, many other treatments have been studied and utilized for NMSC. We present a comprehensive review of the literature on these topical treatments. Photodynamic therapy (PDT) is administered under numerous and significantly varied regimens, and there are a wide range of cure rates reported. Even with aggressive regimens, PDT is not as effective as surgery is, and it is not a first-line therapy for NMSC. The cryotherapy regimen aggressive enough to adequately treat NMSC carries adverse effects and cosmetic outcomes poor enough to negate its usefulness. Topical 5-fluorouracil and imiquimod are efficacious and safe for the treatment of superficial basal cell carcinoma (BCC) but not other BCC subtypes or squamous cell carcinoma. They are self-administered twice daily for several weeks; therefore, patient and tumor selection are vital to ensuring adherence. There are currently insufficient data to support the use of topical diclofenac and ingenol mebutate for NMSC.

Introduction

Nonmelanoma skin cancers (NMSC) are the most common malignancies in the United States with an annual incidence of greater than 3 million. The vast majority are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with a BCC:SCC incidence ratio in immunocompetent persons of 4:1.¹ Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement. Cutaneous SCC is associated with a substantial risk of metastasis, and over 3000 people were expected to die from NMSC in 2012.¹

The goal of NMSC treatment is complete eradication of the tumor while preserving aesthetically- with functionally-important structures. Surgical modalities–excision, Mohs micrographic surgery, and electrodesiccation with curettage (EDC)–are the preferred treatments for NMSC. Each of these has specific indications based on characteristics of both the tumor (e.g. location, histologic subtype, diameter, depth) and the patient (e.g. immunosuppression) and, when used within these guidelines,² has a cure rate of greater than 90%.³ Despite the favorable efficacy of surgical treatment methods, many other treatment modalities have been studied and utilized for nonmelanoma skin cancer.

Section snippets

Overview

Topical PDT is a non-surgical treatment widely used for actinic keratoses and some thin nonmelanoma skin cancers. The components of photodynamic therapy are photoactivating light from either a coherent (laser) or noncoherent source and an exogenous photosensitizer, such as aminolevulinic acid (ALA) or methyl-aminolevulinic acid (MAL).⁴ The light source and method of exposure varies greatly between studies, as do the methods of assessing response to PDT.

Efficacy

Among NMSC, superficial BCC is most

Overview

Cryotherapy is a simple, rapid, and inexpensive method of tissue destruction by the application of liquid nitrogen. Malignant cells have a high water content, high metabolism, and microcirculation and are thus very sensitive to cryotherapy. Practical requirements are rapid freezing at a rate greater than 100 °C per minute, tissue temperature less than − 25 °C, slow thawing at a rate of 10 °C per minute or less, and at least 2 freeze-thaw cycles. The optimum duration of freezing is not known;

5-fluorouracil

5-fluorouracil is a pyrimidine analogue whose cytotoxic metabolites are incorporated into DNA and RNA, inducing cell cycle arrest and apoptosis. Topical 5-FU is used in the treatment of actinic keratosis and superficial basal cell carcinoma via twice-daily application for two or more weeks.

Overview

Imiquimod stimulates the innate immune response by inducing, synthesizing, and releasing cytokines, thereby inducing secretion of interferon-gamma by naïve T cells. Imiquimod 5% cream is applied between twice and five times a week for 6 to 16 weeks, depending on whether it is being used for condyloma acuminata, actinic keratosis, or superficial basal cell carcinoma.

Efficacy

Topical imiquimod is most efficacious for superficial BCC (sBCC). Studies of varied regimens ranging from twice weekly to twice

Overview

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) that reduces the production of prostaglandins by inhibiting inducible cyclooxygenase 2 (COX-2). Its approved treatment regimen for actinic keratosis consists of twice-daily application for 60 to 90 days.

Efficacy

Although there exists evidence to support the use of topical diclofenac for actinic keratosis,⁸⁶ including in solid organ transplant recipients, there are no data regarding its efficacy for basal cell or invasive squamous cell

Overview

Ingenol mebutate is an agent extracted from the sap of Euphorbia peplus, a plant which has long been used in the home therapy of skin diseases including verruca and actinic keratosis.93., 94., 95. Ingenol mebutate appears to have multiple mechanisms of action, including direct cell death and a complex inflammatory response mediated in part by protein kinase C activation.⁹⁶ It was FDA-approved for the treatment of actinic keratosis in January 2012.

Efficacy

One phase IIa trial has evaluated ingenol

Conclusions

Surgical treatment of NMSC continues to be superior to non-surgical interventions. Perhaps, in time, topical therapies will gain further support and favor however, based on the current data, surgery remains the gold standard, save for the elderly or infirmed patient who is adverse to surgical internvention.

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Non-melanoma skin cancers: Photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies

Abstract

Introduction

Section snippets

Overview

Efficacy

Overview

5-fluorouracil

Overview

Efficacy

Overview

Efficacy

Overview

Efficacy

Conclusions

J Am Acad Dermatol

Facial Plast Surg Clin North Am

J Invest Dermatol

J Photochem Photobiol B

J Photochem Photobiol B

J Photochem Photobiol B

J Am Acad Dermatol

J Am Acad Dermatol

Ophthalmology

J Am Acad Dermatol

J Invest Dermatol

Br J Plast Surg

J Am Acad Dermatol

Clinics

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Photodynamic therapy with violet light and topical 6-aminolaevulinic acid in the treatment of actinic keratosis, Bowen's disease and basal cell carcinoma

J Eur Acad Dermatol Venereol

Photodynamic therapy of superficial basal cell carcinoma with 5-aminolevulinic acid with dimethylsulfoxide and ethylendiaminetetraacetic acid: a comparison of two light sources

Photochem Photobiol

A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8–20 mm), with a 12-month follow-up

J Eur Acad Dermatol Venereol

Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial

Eur J Dermatol

Photodynamic therapy for basal cell carcinoma: clinical and pathological determinants of response

J Eur Acad Dermatol Venereol

Treatment of superficial basal cell carcinomas using topically applied delta-aminolaevulinic acid and a filtered xenon lamp

Arch Dermatol Res

Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma

Br J Dermatol

Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment

Br J Dermatol

Photodynamic therapy with 5-aminolaevulinic acid, dimethylsulfoxide and curettage in basal cell carcinoma: a 6-year clinical and histological follow-up

J Eur Acad Dermatol Venereol

Topical 5-aminolevulinic acid mediated photodynamic therapy of superficial basal cell carcinoma using two light fractions with a two-hour interval: long-term follow-up

Acta Derm Venereol

Long-term follow-up and histological changes of superficial nonmelanoma skin cancers treated with topical delta-aminolevulinic acid photodynamic therapy

Arch Dermatol

A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage

Br J Dermatol

Evaluation of recurrence after photodynamic therapy with topical methylaminolaevulinate for 157 basal cell carcinomas in 90 patients

Acta Derm Venereol

Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial

Br J Dermatol

Photodynamic therapy using topical 5-aminolaevulinic acid vs. surgery for basal cell carcinoma

J Eur Acad Dermatol Venereol

Our PDT experience in the treatment of non-melanoma skin cancer over the last 7 years

J Eur Acad Dermatol Venereol

Photodynamic therapy and imiquimod immunotherapy for basal cell carcinomas

Acta Clin Belg

Recurrence rate of basal cell carcinoma after topical aminolevulinic acid-based photodynamic therapy

Acta Dermatovenerol Croat

Routine double treatments of superficial basal cell carcinomas using aminolaevulinic acid-based photodynamic therapy

Br J Dermatol

Photodynamic therapy of superficial basal cell carcinomas using topical 5-aminolevulinic acid in a nanocolloid lotion

Dermatology

Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer

Br J Cancer

High and sustained efficacy after two sessions of topical 5-aminolaevulinic acid photodynamic therapy for basal cell carcinoma: a prospective, clinical and histological 10-year follow-up study

Br J Dermatol

MAL-PDT for difficult to treat nonmelanoma skin cancer

Dermatol Ther

Fractionated 5-aminolaevulinic acid-photodynamic therapy vs. surgical excision in the treatment of nodular basal cell carcinoma: results of a randomized controlled trial

Br J Dermatol