Mechanism of Action and Formulations

Topical 5-fluorouracil (5-FU) has been used in clinical practice since the 1960s. It is a structural analogue of thymine that blocks DNA synthesis by inhibiting thymidylate synthetase (Table 220-1). Topical 5-FU is commercially available as a 0.5% cream carried in a microsphere vehicle, as a 1% solution or 1% cream, as a 2% or 5% solution, and as a 5% cream. The solution can also be used for intralesional injection.

Indications

5-FU 5% cream has been approved by the US Food and Drug Administration (FDA) since 1970 for the treatment of actinic keratoses in any location and superficial basal cell carcinomas; 5-FU 0.5% cream is FDA approved for treatment of actinic keratoses of the face and anterior scalp. 5-FU is used twice daily until an inflammatory response is seen, usually 2–4 weeks. The 0.5% cream can be used once daily. 5-FU may also be a useful adjunct before cryosurgery of actinic keratoses.1 Pretreatment with a keratolytic agent, prolonged therapy, more frequent applications, or the use of occlusive dressings may increase therapeutic response.

Treatment Considerations

Irritation during treatment sometimes requires reduction or interruption of treatment and the addition of emollients or topical corticosteroids to help quell brisk inflammation. A number of approaches to decrease irritation have been devised; whether or not efficacy is preserved is disputed.2 Weekly pulse dosing involves applying the medication for 1–2 days per week for 6–7 weeks. Use of the 0.5% 5-FU cream with microsphere vehicle may allow for a more tolerable irritation profile.3

During 5-FU treatment, previously subclinical actinic keratoses, basal cell carcinomas, and squamous cell carcinomas may become apparent and respond to treatment. A systematic review of 13 randomized controlled trials on the effectiveness of 5-FU for the treatment of actinic keratoses demonstrated that about 50% of patients obtain complete clearance after treatment and an overall reduction of 80% in lesion count can be expected.1 However, about two-thirds of patients will require retreatment after 1 year. Histological cure rates for superficial basal cell carcinomas after 5-FU treatment are between 90% to 93%; however, it is not recommended in nodular and high-risk, basal cell carcinomas since the drug does not seem to control deeper tumor growth,4 and there is a possibility that treatment can mask the persistence or recurrence of basal cell cancer.

Verrucae vulgaris, verrucae plana, plantar warts, and condylomata acuminata have been treated with varying response rates with topical and intralesional 5-FU. Additionally, actinic cheilitis, mucosal leukoplakia, radiodermatitis, Bowen disease, Bowenoid papulosis, and erythroplasia of Queyrat have all been reported to respond to treatment with topical 5-FU. Further, there are reports of the successful treatment of both psoriasis and keratoacanthomas with topical and intralesional 5-FU,4 and of infantile digital fibromatosis treated with intralesional 5-FU.5 Combined use of ablative Er:Yag laser and topical 5-FU is an effective treatment option for giant keratoacanthomas if surgery is contraindicated.4 Intralesional 5-FU has also been reported to be effective in the treatment of keloids and hypertrophic scars.6,7 Controversial results have been observed with treatment of nail psoriasis with 5-FU: one trial demonstrated a 25% reduction in pitting and hyperkeratosis in twenty patients with nail psoriasis treated with 1% 5-FU solution for 6 months,4 while a second randomized, double-blind study failed to demonstrate difference between the treatment group and placebo.4 Vitiligo patients may benefit from the combination of dermabrasion and 5% 5-FU cream, or 5-FU alone under occlusive dressings.4

The systemic absorption of topically applied 5-FU is limited, with absorption selectively greater from abnormal skin than from surrounding normal skin. Microsphere-based formulations may retain 5-FU at the target site, with less drug reaching the systemic circulation.8 Rarely, systemic effects of 5-FU include nausea and anorexia, stomatitis, diarrhea, myelosuppression, alopecia, and cardiac and neurologic toxicity. Side effects of the topical preparation include local irritation, erythema, pain, swelling, pruritus, dyspigmentation, allergic contact dermatitis, and photosensitivity. Unusual reactions may include onycholysis, onychodystrophy, and the appearance of telangiectasias. The use of injectable preparations may be complicated by pain, local ulceration, erosion, desquamation, and dyspigmentation.6

Mechanism of Action and Formulations

Mechlorethamine [methyl-bis (2-chloroethyl) amine hydrochloride] was the first nitrogen mustard (NM) to be used in clinical medicine. Mechlorethamine acts as an alkylating agent and is not cell-cycle specific; however, its greatest effect is on cells in the late G1 or S phases. The primary target of mustard is the 7-nitrogen atom of guanine. The main role of topical NM in dermatology is in the treatment of the patches and plaques of cutaneous T-cell lymphoma (CTCL). The utility of NM in treating mycosis fungoides (MF), the most common type of CTCL, was first described in 1959. The topical activity of NM has been attributed not only to its alkylating activity, but also to its potential for immune stimulation. The delayed-type hypersensitivity reaction induced by nitrogen mustard is mediated by Th1-type response, while the malignant T-cells in MF express Th2-type cytokines. The contact hypersensitivity reaction can potentially stimulate malignant T-cells to shift from Th2 to Th1-type cytokine expression and activity leading to apoptosis of the malignant T-cells and tumor regression.9

Mechlorethamine hydrochloride (Mustargen) is available in powder form, 10-mg per glass vial. Topical NM is prepared as either an aqueous solution or an ointment preparation. A variety of ointment bases can be used, including Aquabase®, Aquaphor®, hydrophilic petrolatum, a 50/50 mixture of liquid paraffin-white soft paraffin, and white soft paraffin.10 Aqueous solutions can be made to desired concentrations by dissolving the NM powder in tap water (one vial of 10-mg powder dissolved in 100-mL water yields a 10 mg% concentration). The solution is unstable and should be applied immediately to the skin using a sponge or cloth. Ointment preparations can be compounded by pharmacists.9 Nitrogen mustard compounded in Aquaphor® formulations showed higher stability than in Transcutol®, Labrasol®, and Aquaphilic® ointments. However, a significant increase in stability can be obtained when the free radical inhibitor BHT (butylated hydroxytoluene) is added to Transcutol® or Labrasol® formulations.10

With either preparation, concentrations of 10–20 mg% are generally used and are applied daily, with increases in concentration and frequency of application pending clinical response. One approach is to apply the preparation to the entire body (sparingly to intertriginous sites, and excluding the genitalia) initially to avoid missing areas of subclinical involvement and thus theoretically increase the potential for cure.10 Alternatively, treatment may be limited to only clinically affected areas. Treatment should be continued daily until complete response is attained. The benefit of a prolonged maintenance period in preventing disease relapse has not been shown.9 With proper application, there is minimal contamination of the surrounding environment, but those assisting in the application of the drug should limit their exposure and wear protective gloves. Effort should be made to dispose of empty vials or unused solution in accordance with Environmental Protection Agency guidelines.

Indications

Many large retrospective series support the use of topical NM in MF. NM has been reported to produce complete response rates of 67%–80% for MF patients with limited patch/plaque disease (stage IA) and 35%–68% for patients with generalized patch/plaque (stage IB) disease.9 Relapses are common even with the continuation of therapy.11 The efficacy of aqueous and ointment-based preparations is similar.9 Topical NM as primary monotherapy has limited use in patients with tumor stage or erythrodermic disease.9 Topical NM has also been used in the treatment of psoriasis,12 alopecia areata,13 and histiocytosis X.14

Treatment Considerations

Unlike the systemic preparation, there are no reports of systemic side effects following topical NM application. Furthermore, topical NM has been used safely in pediatric patients.9 Local side effects include irritant or allergic contact dermatitis, immediate-type hypersensitivity, secondary cutaneous malignancies, and dyspigmentation. Irritant contact dermatitis is generally mild and resolves with reduction in concentration and/or frequency, or with topical steroid treatment. Allergic contact dermatitis has been reported to develop in up to 35%–66% of patients on long-term treatment with aqueous NM and in fewer than 10% of those using the ointment preparation.9 If hypersensitivity occurs, patients may be treated with dilutions below the threshold for clinically observable contact dermatitis. However, delayed-type hypersensitivity may be of therapeutic benefit. Twice-weekly dosing of topical NM in combination with betamethasone cream may offer a balance of tolerability and efficacy.15 Up to 8% of patients may develop an urticarial immediate-type hypersensitivity to topical NM, often necessitating treatment discontinuation. Changes in pigmentation may also occur secondary to use of topical mechlorethamine. Hyper- and hypopigmentation are prone to develop in areas of previous CTCL and tend to resolve spontaneously, although slowly.

There have been reports of secondary cutaneous malignancies developing in patients treated with NM, including basal and squamous cell carcinomas, keratoacanthomas, and isolated reports of lentigo maligna and primary melanoma.9 It is difficult to determine causality in these cases, as many of these patients were treated with multiple therapies, including known carcinogenic therapies such as psoralen and ultraviolet A phototherapy and radiation.

Mechanism of Action and Formulations

Carmustine [bischloroethylnitrosourea (BCNU)] is a nitrosourea that acts by alkylation to inhibit DNA, RNA, and protein synthesis. The topical formulation, introduced in 1971, is used primarily in the treatment of CTCL.