Cutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages, but survival rates decrease dramatically as the disease progresses. As no curative therapies are currently available, the goal of therapy is preventing or delaying progression from early disease stages while minimizing long-term toxicity. No single agent, including psoralen plus ultraviolet A (PUVA), can control disease progression fully, so combination therapy is needed to improve response rates. In addition, low-dose combination therapy may improve treatment safety and tolerability. A combination of PUVA and interferon (IFN)α in early disease has been shown to be effective and well tolerated. Likewise, small studies of PUVA and bexarotene (Targretin) indicate good efficacy for this combination. Reduced doses of these combinations may also be effective as maintenance therapies following complete remission. Other treatment combinations shown to be effective in early disease stages include bexarotene with IFNα, and bexarotene with denileukin diftitox (Ontak). In advanced stages of CTCL, liposomal-encapsulated doxorubicin or extracorporeal photopheresis may be combined with bexarotene or IFNα.
The class of cutaneous lymphomas comprises a variety of diseases. By the new World Health Organization/European Organisation for Research and Treatment of Cancer classification, the largest single disorder is mycosis fungoides (MF), which makes up 50% of cases. The next largest proportion of cases (20%) consists of the so-called CD30 lymphoproliferative diseases. Some of the genetic mechanisms of the disease process in cutaneous T-cell lymphoma (CTCL) have now been well characterized (see the article by Sterry in this supplement), and it is known that there is a clear shift in patients' cytokine profiles during disease progression—from Th1- to Th2-dominating.
In the management of CTCL, there is therefore a rationale for using retinoids and rexinoids, which increase Th1 cytokines,[3,4] and interferon (IFN)α, which can rectify the imbalance between Th1 and Th2 cytokines. Furthermore, resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of CTCL. However, bexarotene (Targretin) has been shown to induce apoptosis as a mechanism of therapy in CTCL. In addition, psoralen plus ultraviolet A (PUVA) acts as deep as the middermis, and plays a key role in the reduction of Langerhans cells and the presentation of antigens in the skin.
In its early stages, CTCL is a relatively benign disease, but once it progresses to stage IIb and to lymph-node involvement there is a dramatic reduction in patients' 5-year survival. At present, there are no curative therapies available for CTCL, and early aggressive therapy does not appear to increase patients' response rates or survival time. The therapeutic goal is therefore to prevent progression from early disease, in which survival rates are good, to advanced-stage disease, which has a poor prognosis. In addition, therapy should aim to minimize cytotoxic effects against normal lymphocytes and to maintain good long-term treatment tolerability. This is best achieved using stage-adapted therapy. As no curative therapies for CTCL are available, long-term treatment with meaningful combinations is mandatory to maintain recurrence-free survival.
Many different therapies are available for the treatment of CTCL—both skin-directed and systemic. This review will focus mainly on combination therapy with PUVA, IFNα, and bexarotene.
Rationale for Combination Therapy for CTCL
There is currently no single agent available that is potent enough to control CTCL; overall response rates to monotherapies are about 50% to 60%. For example, among 104 patients with MF given PUVA monotherapy, 63% (66/104) initially responded to this therapy and experienced complete remission. Over a median follow-up of 94 months, the recurrence rate was 32% (33/104). Thus, the main conclusion of this study was that PUVA, though effective, was not sufficient to control the disease. PUVA has, however, been shown to play a critical role in maintaining response following a complete response to total-skin electron beam therapy.
Combinations of agents with different modes of action may increase patients' response rates and, if the therapies are given at low doses, this may minimize the toxicity of each individual treatment. Moreover, there are some indications that combining drugs may prevent the progression of disease to extracutaneous T-cell lymphoma involvement. Thus, the combination of topical and systemic treatment may consolidate remission and allow continuous therapy with an acceptable side-effect profile.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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