ABSTRACT: Mycosis fungoides is a low-grade lymphoproliferative disorder of skin-homing CD4+ lymphocytes that may produce patches, plaques, tumors, erythroderma, and, ultimately, systemic dissemination. Treatment selection is generally guided by institutional experience, patient preference, and toxicity profile, as data from phase III clinical trials are limited. Effective topical treatments currently include mechlorethamine (Mustargen), carmustine(Drug information on carmustine) (BCNU, BiCNU), corticosteroids, bexarotene (Targretin, a novel rexinoid), psoralen plus ultraviolet A, ultraviolet B, and total-skin electron-beam radiotherapy. Effective systemic treatments include interferon, retinoids, bexarotene, denileukin diftitox (Ontak), extracorporeal photopheresis, chemotherapy, and high-dose chemotherapy with allogeneic bone marrow transplant. Each of these treatments is discussed in detail, followed by specific recommendations for each stage of mycosis fungoides.
Mycosis fungoides is a lowgrade lymphoproliferative disorder of skin-homing CD4+ lymphocytes that may produce patches, plaques, tumors, erythroderma, and, ultimately, result in systemic dissemination. Details regarding epidemiology, clinical presentation, histopathology, molecular profile, staging, and prognosis were discussed in the last issue of ONCOLOGY. This part of the article will focus on the treatment of mycosis fungoides, providing an overview of major topical and systemic therapies followed by a discussion of specific treatment recommendations for each stage of mycosis fungoides.
Topical mechlorethamine hydrochloride (Mustargen), also known as nitrogen mustard, is an alkylating agent with proven activity in the treatment of mycosis fungoides patches and plaques. Typically, a 10 to 20 mg percent solution of mechlorethamine is applied once daily to all skin surfaces if diffuse skin involvement is present, and only to involved sites if skin disease is limited. For patients with slow response, the frequency of application may be increased to twice daily or the concentration may be increased to 30 to 40 mg percent. Therapy is typically continued for at least 6 months after complete skin clearance.
Cutaneous intolerance, manifested by erythema and pruritus, occurs in roughly 50% of patients treated with aqueous mechlorethamine but is reduced to less than 10% in patients treated with mechlorethamine dissolved in an ointment such as Aquaphor. Options for patients with cutaneous intolerance include changing from an aqueous to an ointment-based preparation, reducing the concentration of topical mechlorethamine to 1 mg percent followed by gradual dose titration, applying concomitant topical steroids, and attempting systemic desensitization. Other cutaneous side effects of mechlorethamine may include xerosis, hyperpigmentation, and, rarely, bullous reactions, urticaria, and Stevens-Johnson syndrome.
Bone marrow suppression is not observed due to minimal systemic absorption. Mechlorethamine monotherapy has not been associated with an appreciable risk of secondary skin cancers,[ 2] but use of the drug in combination with other topical therapies such as total-skin irradiation or psoralen plus ultraviolet A (PUVA) may increase the risk of cutaneous basal and squamous cell carcinomas.
Topical carmustine (BCNU, BiCNU), another alkylating agent with activity similar to mechlorethamine, is typically applied to all skin surfaces once daily at doses of 10 to 20 mg/d for 4 to 8 weeks. Due to systemic absorption that results in bone marrow suppression, the maximum duration of treatment is limited. Cutaneous hypersensitivity is uncommon (7% in one series) but chronic skin telangiectasis may occur.
Glucocorticoids are an important component in the treatment of hematologic malignancies, likely due to their ability to induce apoptosis of neoplastic lymphoid cells. Class I (most potent) topical steroids, such as 0.05% clobetastol propionate, 0.05% diflorasone diacetate(Drug information on diflorasone diacetate), and 0.05% halobetasol propionate (Ultravate), effectively treat most mycosis fungoides patches and plaques. These agents are applied twice daily to involved skin for 2 to 3 months before treatment efficacy is assessed. Patients with steroid-responsive disease typically continue maintenance therapy for at least 1 month after clearing. Toxicity includes reversible depression of serum cortisol (in 10% to 15% of patients) and skin atrophy.
Bexarotene (Targretin) belongs to a new class of agents called rexinoids that bind to the retinoid X receptor, resulting in transcription of various genes that control cellular differentiation and proliferation. Promising phase I/II data suggest that 1.0% topical bexarotene gel applied twice daily is well-tolerated and effective in patients with stage IA-IIA mycosis fungoides. Toxicity appears limited to skin irritation. As with systemic retinoids, bexarotene in both its topical and systemic forms should be avoided in pregnant women because of possible teratogenic effects.
PUVA and Ultraviolet B
Ultraviolet radiation effectively treats a variety of skin disorders, although the exact mechanism of action remains unclear. Ultraviolet light is divided into three classes-UVA, UVB, UVC, in order of increasing energy. UVA has a wavelength of 320 to 400 nm and activates the oral photochemotherapeutic agent 8- methoxypsoralen (8-MOP, Oxsoralen), resulting in DNA crosslinking and apoptotic cell death. In contrast, UVB has a wavelength from 290 to 320 nm and effectively treats patches without the addition of an oral agent.
Contraindications to therapy with UVR include systemic lupus erythematosus, previous or current nonmelanoma skin cancer, pregnancy, porphyria, and genetic syndromes due to DNA repair defects. In addition, ingestion of oral 8-methoxypsoralen should be avoided in patients with preexisting liver dysfunction, as liver toxicity is possible in this subgroup.
Patients treated with PUVA ingest 0.6 mg/kg of 8-methoxypsoralen 1.5 to 3 hours prior to receiving UVA irradiation. The initial UVA dose may be as low as 0.5 J/cm2 and is increased by 0.5 to 1.0 J/cm2 every treatment session until complete response or tolerance dose is achieved. Treatments are given two to three times per week until skin clearing and are then gradually tapered to once every 2 to 4 weeks for no more than 1 year.
Mycosis fungoides patches can be effectively treated by broadband UVB or narrowband UVB (wavelength: 311-312 nm)[12,13] without psoralen ingestion. Therapy is typically initiated at doses that are 50% to 70% of the dose required to induce minimal skin erythema. Patients receive treatment 3 days per week with gradual increases in dose until patient tolerance and/or clinical response is achieved. Following maximal response, treatments continue for several months, but the frequency is gradually tapered to once every 2 weeks. When selecting patients for UVB therapy, it is important to consider skin type, as UVB radiation may be less effective in people with darkly pigmented skin, given the ability of melanin to absorb ultraviolet radiation.
Acute side effects of PUVA and UVB include skin erythema (which may be painful), hyperpigmentation, xerosis, pruritus, and blistering. Eye goggles are used to decrease the risk of cataract formation. PUVA may cause nausea and vomiting after ingestion of 8-methoxypsoralen, but this may be avoided by the substitution of 5-methoxypsoralen, which is currently available in Europe. Long-term toxicity includes photoaging (PUVA ≈ UVB) and cutaneous carcinogenesis (PUVA > UVB).
Total-Skin Electron Radiotherapy
Total-skin electron-beam radiotherapy (TSEBT) is a technically challenging modality used for the treatment of T1-4 skin disease. Guidelines for TSEBT developed by the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group are presented in Table 1.
At our institution, these objectives are achieved with a mounted linear accelerator that emits 6-MeV electrons. The patient stands 3.8 meters from the gantry, and just behind a 3.2-mm thick Lexan polycarbonate screen that serves to attenuate and scatter the electron beam, resulting in an electron energy of 3.9 MeV at the skin surface. A total of six treatment positions are designated: anteroposterior, right and left anterior oblique, posteroanterior, and right and left posterior oblique (Figure 1). These positions maximize skin unfolding, thereby improving dose homogeneity in the lateral dimension. Each position is treated with two fields-upper and lower-to maximize dose homogeneity in the vertical dimension.
On treatment day 1, the anteroposterior, right posterior oblique, and left posterior oblique positions are treated. On treatment day 2, the posterior, right anterior oblique, and left anterior oblique positions are treated with the same dose. Over the course of a 48-hour treatment cycle, a patient will receive 2 Gy to the entire skin surface. This pattern continues, with patients receiving treatment 4 days a week for a total of 9 weeks, thereby delivering a total dose of 36 Gy to the skin surface. The depth-dose curves for both a single beam and all six beams are presented in Figure 2, which illustrates how this treatment arrangement satisfies the guidelines for skin dose and soft-tissue dose established by the Cutaneous Lymphoma Project Group.
A complex regimen of patch and boost treatments is utilized to ensure adequate dose delivery to all sites of cutaneous disease. For example, our institution uses 120-kV orthovoltage photons to deliver patch treatments to the soles of feet (14 Gy in 14 fractions, treatment days 1-7 and 30-36) and perineum (18 Gy in 18 fractions, treatment days 1-9 and 28-36). In addition, an electron reflector mounted above the patient's head increases the dose to the scalp. Patients with plaques or tumors that are bleeding, weeping, or painful also receive an upfront boost (2 Gy in 5 fractions) with either electrons or orthovoltage photons. Asymptomatic plaques and tumors that persist at the end of treatment receive a similar boost.
Acute and chronic morbidity is minimized by using small daily fractions and a complicated shielding regimen that protects the eyes, ears, lips, hands, and feet. Common acute toxicities from TSEBT include mild skin erythema, whole-body alopecia, possible loss of fingernails and toenails, hand and foot edema, and hypohidrosis. In general, TSEBT does not cause serious long-term complications, although permanent nail dystrophy, xerosis, partial scalp alopecia, and fingertip dysesthesias have been described.