Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.
From the perspective of a medical oncologist, mycosis fungoides (MF, a subset of cutaneous T-cell lymphoma [CTCL]) is often regarded as a low-grade lymphoma that shows several similarities to low-grade B-cell lymphomas. For example, MF is disseminated at diagnosis; that is, by the time lymphoma is seen in the skin, there is already blood and bone marrow involvement, although this may be subclinical. In addition, MF is responsive to treatment but resistant to cure. Thus, patients can expect long-term survival, at least by stage-adjusted or prognostic-feature-adjusted disease, but will require control of symptoms.
When MF is divided by stage, patients with patch- and plaque-stage disease (stages IA, IB, and IIA) have an excellent duration of survival. Those who have Sézary syndrome have a median survival of about 30 months, whereas the duration for stage IV disease is much shorter than this. Therefore, the oncologist's therapeutic approach should be tailored to disease stage and to the patient's expected duration of survival. Patients with early-stage disease may survive for many years, thus irreversible treatment-related toxicities should be avoided; for those patients with more aggressive forms of the disease, a more toxic, less well-tolerated treatment may be acceptable.
Mycosis Fungoides: Responsive to Treatment But Resistant to Cure
One of the few randomized, controlled trials in MF was conducted by Kaye et al. Patients were randomized to receive either conservative therapy with topical nitrogen mustard or combined-modality systemic and skin-directed therapy consisting of electron beam therapy plus cyclophosphamide, doxorubicin, etoposide, and vincristine. This produced the somewhat disappointing result in that there was really no difference in outcomes for these two approaches, thus demonstrating that the use of early aggressive therapy appears to provide no overall survival benefit over sequential topical therapies. Therefore, the approach of sequential, palliative single-agent therapies, similar to the approach adopted for patients with low-grade B-cell lymphomas, might be a useful one.
However, there are certain critical differences that distinguish MF from follicular B-cell lymphomas. First (due to skin lesions), CTCL is almost invariably symptomatic at onset, and the presence of these skin lesions means that a "watch and wait" approach is not feasible. Second, the loss of the integument as a host defense is an important feature of this disease. If patients are left untreated, they are likely to suffer not only from the neoplastic process but also from infections, which can have lethal consequences. Third, the histopathologic diagnosis of CTCL may be difficult and consequently often delayed. Finally, CTCL is amenable to more treatment modalities, such as phototherapy, cytokines, and immunotherapy, than low-grade B-cell lymphomas.
The focus of this manuscript will primarily be on drug therapies for CTCL. The reader is referred elsewhere for further information on the use of radiotherapy.[3-7]
One of the major concerns in treating patients with antineoplastic agents is acute toxicity, commonly myelosuppression by non-stem-cell-toxic therapies, and immunosuppression. In addition, there are side effects such as hyperlipidemia and hyperthyroidism, which are common with retinoids. Other chronic toxicities with MF treatments include photodamage to the skin (such as premature ageing), telangectasia, skin ulcerations, the induction of secondary malignancies, the induction of stem-cell injury by certain chemotherapeutic agents, and prolonged T-cell anergy, which can be produced by some chemotherapies as well as some recently available biologic agents.
As shown in Figure 1, the available skin-directed therapies are generally effective in producing good, long-term responses in patients at early disease stages, providing complete response rates of about 60%.[8-11] In particular, psoralen plus ultraviolet A (PUVA) plus retinoids or interferon (IFN) can achieve very high overall response rates in these patients. However, all of these agents have associated side effects. The most common toxicity of nitrogen mustard is hypersensitivity. In addition, myelosuppression and the induction of secondary malignancies are both possible toxicities, though these are not usually seen in clinical practice.
Topical carmustine (BCNU), on the other hand, is more often associated with myelosuppression. For PUVA, the principal toxicities are skin erythema and secondary malignancies including melanoma. During treatment with topical corticosteroids, skin atrophy is seen, along with systemic effects from absorption of high-potency steroids. Electron beam radiotherapy can result in anhydrosis, telangiectasia, and induction of secondary malignancies. Treatment decisions must therefore take into account both the benefits and possible drawbacks of therapy.
Dr. Hymes is a consultant for Ligand Pharmaceuticals and a member of the speakers' bureaus for GlaxoSmithKline, Merck, and Celgene.
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