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An Overview of Skin-Directed Therapies
Marianne C. Tawa RN, MSN, ANP
Nurse Practitioner, Dermatology and Oncology, Dana Farber Cancer Institute

Article previously published in the Cutaneous Lymphoma Foundation's Forum Winter 2012 newsletter.

In most clinical situations, treatment of cutaneous T-cell lymphoma (CTCL) is tailored to the stage and particular features of the disease, general health concerns, and lifestyle considerations. Patients with disease limited to the skin (stages 1 and II) can often achieve clinical response with one of the readily available skin-directed therapies.

This approach to treatment is supported by the understanding that the malignant T-cells spend the majority of their time in the skin because of the homing tendencies to antigens and are dependent on the skin for survival. Thus, therapies can be delivered efficiently to the target organ, namely the skin.

Topical Corticosteroids
Topical corticosteroids are the cornerstone of treatment for a myriad of skin disorders, both acute and chronic in their origins. These agents are employed first line in the treatment of CTCL because of ease of administration and product accessibility.

Topical corticosteroids possess multiple immunomodulatory and anti-inflammatory effects. In early-stage disease, topical corticosteroid therapy has proven to be a mainstay for both induction and maintenance of clinical remissions. Topical corticosteroids are packaged in a variety of vehicle systems including creams, ointments, lotions, foams, gels and solutions.

Clinicians may recommend alternating a stronger potency (class I) agent with a lesser potent (class III or IV) agent over time in efforts to diminish side effect profiles as well as provide opportunity for longer duration of treatment. Local side effects from topical corticosteroids include skin atrophy (thinning), striae (stretch marks), bruising, acne and dilated blood vessels. Suppression of the adrenal gland is a very rare consequence of prolonged topical corticosteroid application.

Topical Chemotherapy: Nitrogen Mustard and Carmustine
The alkylating agents nitrogen mustard (NM) (also known as mechlorethamine) and carmustine (also known as bichloronitrosourea or BCNU) are cytotoxic chemotherapeutic agents employed for topical management of CTCL. During the past four decades, they have been used widely for the treatment of early stages (1A, IB, and IIA) CTCL.

Topical Nitrogen Mustard (NM) therapy requires thoughtful collaboration among the patient, clinician, and compounding pharmacist. A 10mg formulation of NM is dissolved in water, ointment or gel base. Typically, patients apply a thin film at bedtime to all skin surfaces excluding eyelids, lips, and genital region. They should be advised to wash their hands with soap and water after the application process. The most frequent complication associated with NM therapy is the development of an irritant reaction characterized by skin redness and itching. This reaction can be addressed with product dilution and subsequent desensitization. Drug cessation is warranted if a true allergic reaction with hive-like response occurs. Patients with CTCL who demonstrate clinical clearing of patch and plaque lesions for the duration of NM therapy for 6-12 months may taper the frequency of treatments over time to a less cumbersome schedule. Less frequently encountered toxicities of NM therapy include potential for bone marrow suppression and secondary skin cancers.

Carmustine is available in powder and ointment forms. Local application site redness can develop, although irritant and contact reactions occur less often. In current practice, carmustine is rarely, if ever, selected as an alternative to NM.

Topical Retinoid: Bexarotene Gel
The synthetic retinoid (vitamin A derived chemical) agent bexarotene (Targretin®, Eisai Pharmaceuticals) selectively binds and activates retinoid X receptors (RXRs). These receptors function as transcription factors that regulate expression of genes that control cellular differentiation and proliferation. The precise mechanism of action for RXRs in the management of CTCL remains unclear. Redness, itching, and pain at the application site may occur in the initial weeks of therapy.

For some patients the solution to this problem may be titration of bexarotene with careful and conservative drug application ranging from less frequent every other day to more frequent twice to four times daily over time. In clinical practice, the topical retinoid class of drugs is considered second line therapy for patients who have demonstrated persistent disease after treatment with topical corticosteroids or other conservative skin directed therapies.

Phototherapy: Broadband Ultraviolet B (290-320nm), Narrowband UVB (311nm) and Psoralen with UVA (320-400nm)
Ultraviolet light therapy is one of the most widely used skin-directed therapies for early stage CTCL. Radiation within the ultraviolet B (290- 320 nm) and UVA (320-400nm) spectrums is prescribed for a host of T-cell mediated skin diseases including psoriasis, vitiligo and cutaneous graft-versus-host-disease.

In early stage CTCL, phototherapy is typically selected when skin involvement is diffuse and/or topical treatments have proven to be impractical. The benefits of UVA and UVB have been described for decades as the correlation between CTCL manifestations in covered areas of the body (e.g.,. bather’s trunk, flanks and folds) and sparing in sun-exposed skin was observed.

Patients often share subjective reports of improvement in their skin during the summer months or following a tropical vacation. The mechanism of action for ultraviolet light therapy is broad with effects produced on cell surface membrane proteins causing apoptosis (cell death). In general, UVB reaches the more superficial skin layer of the epidermis, while UVA penetrates deeper into the dermis.

Both broad and narrow band UVB therapies are carried out in dermatology practices equipped with specially calibrated “light boxes.” UVB therapy does not require administration of an oral sensitizing agent in order to produce beneficial effects in the skin. It is a reasonable choice for therapy when the lesions are thin and do not involve the hair follicle (folliculotropic mycosis fungoides). Patients are exposed to the UVB spectrum in a graduated fashion at increased doses with treatments taking place two to three days per week. The goal of therapy is clinical response with an eventual taper to a more manageable schedule of one day per week. One of the major hindrances to phototherapy is the time requirements for patient visits, which may disrupt work or home life. In addition, access to a treatment center may be geographically challenging for patients who reside in rural or remote areas. Redness and burning can be problematic in certain fair complexioned individuals; therefore, patients should be assessed prior to each treatment.

Psoralen and UVA (PUVA) phototherapy involves the combination of the photosensitizing agent 8-methoxypsoralen with UVA light. UVA radiation has a longer wave length than UVB and can penetrate window glass and, likewise, can penetrate the larger and thicker lesions of CTCL. Patients ingest the psoralen 1 ½ to 2 hours before exposure to an escalating dose of UVA light. Treatments are delivered three days per week initially until a maximal response is achieved. Over time, patients will reduce the frequency of treatments to a less cumbersome maintenance schedule. Toxicities of PUVA include burning, nausea related to psoralen administration, and increased risk of skin cancers. Patients are expected to wear UVA eye protection up to 24 hours following treatment because of the small but theoretical risk of cataract formation.

Radiation
Radiation therapy shares a long history in the management of lymphomas with CTCL as the first variant to be treated dating back to the early 20th century. Photons initially were employed, but by the 1940’s Trump and colleagues replaced photon-based radiation with radiation from accelerated electrons in efforts to more effectively deliver treatment to a wide field, such as the skin surface, while ensuring patient safety.

Over the past fifty years, total skin electron beam therapy (TSEBT) has undergone multiple modifications with the goal of delivering a sufficient dose to the target tissue while minimizing radiation damage to normal skin. The premise for electron therapy in CTCL is to produce direct toxicity to tumor cells within the target volume.

Candidates for TSEBT are those patients who have extensive skin involvement of their CTCL lesions or have exhausted other conventional skin-directed therapies such as topicals and phototherapy. The depth of penetration for electrons is quite minimal, approximating only 5mm; therefore, radiation effects are produced only as deep as the dermal skin layer.

TSEBT is typically administered over a 9-10-week period. Patients receiving TSEBT assume six standing positions during the course of therapy. Contact lenses, goggles, and shields for the finger and toe nail plates are placed prior to radiation exposure to ensure protection to these important structures. Patients are assessed at weekly intervals for findings of redness, swelling, blisters and infection. In some instances, treatment schedules may be interrupted for short recovery periods. The side effect profile for TSEBT includes itching, dry skin, fissuring, dilated blood vessels, fatigue, temperature dysregulation, sun sensitivity, rash, skin infections, brittle nails, hair loss, and skin cancers. Patients are instructed throughout the course of TSEBT, and for a period of time thereafter, to keep the skin well-hydrated with moisturizers, apply UVA/UVB blocking sun screens, wear sunglasses, and consider photo-protective garments for outdoor exposures. 


Marianne Tawa is a nurse practitioner with the Dermatology and Cutaneous Oncology Department at the Dana Farber Cancer Institute in Boston, MA.

An Overview of Skin-Directed Therapies