Retinoids are analogs of vitamin A. Vitamin A acid (tretinoin) was discovered in 1946 and came into clinical use in 1969 (32). The first generation of synthetic vitamin A analogues (retinoids) were tretinoin (all-trans-retinoic acid) and isotretinoin (13-cis-tretinoin) (33,34), followed by etretinate and acitretin. Bexarotene represents the third and novel generation of retinoids, the first rexinoid or arotinoid that is selective for the retinoid X receptors (RXRs).
Retinoids belong to the group of biologic response modifiers. They have antiproli-ferative, antiangiogenic, immunomodulating effects and modulate cellular differentiation (35,36). Retinoids exhibit their effect through binding to the retinoid A receptor (RAR) or the retinoid X receptor (RXR) in the nuclei of cells either directly or indirectly via nuclear transcription factors (NTFs), regulating the expression of a wide range of target genes. Depending on their action, panagonists binding to both receptors can be distinguished from selective RAR or RXR agonists. They modulate cell growth and differentiation in a variety of human tumor cell types. Retinoids inhibit cell growth by arresting cells in the Gl-phase or inducing apoptosis, in particularly in T-cell and Hodgkin lymphoma cell lines (37-39). In addition, retinoids exhibit immunomodulatory effects. They enhance IFN-a production, which is partially mediated via IL-12 induction and is synergistic with interleukin 2 (40,41). This produces an up-regulation of MHC complexes and a shift from T-helper 2 (TH2) cells, which are increased in CTCL (42), to TH1 cells. In addition, RA enhances cytotoxic activity of natural killer (NK) cells mimicking some of the biologic effects of IFN (43).
Retinoids alone or in combination with other agents play an important role in the treatment of cutaneous T-cell lymphomas, especially MF and SS. There are only a few reports on the use of retinoids in CL other than MF.
Most retinoids of the first and second generation were usually used orally with dosages of 1-2mg/kg/day. The most commonly reported side effects of these agents are dryness of the skin and mucous membranes, pruritus, increased levels of liver enzymes, hypertriglyceridemia, hypercholesterolemia, axial osteoarthropathy with bone pain, arthralgias, myalgias, and hair loss. Most of these side effects are reversible except for axial osteoarthropathy resulting in stiffness of spine and decreased axial mobility.
Isotretinoin and etretinate have subsequently been replaced by acitretin and the third generation of retinoids, bexarotene, for the treatment of CTCL. An optimal dose of bexarotene of 300 mg/m2/day is recommended. Although higher doses (500-600 mg/m2/day) may be more effective, dose-limiting hypertriglyceridemia with pancreatitis is more common. The most significant side effects of bexarotene are hypertriglyceridemia, hypercholesterolemia, leukopenia, central hypothyroidism, and headache. Hypertriglyceridemia occurs in 82% of the patients and requires additional treatment with lipid-lowering agents such as fenofibrate, HMG-CoA reduc-tase inhibitors or statins. Gemfibrozil is not recommended since it increases bexarotene-induced hypertriglyceridemia (44).
Topical retinoid treatment of MF is usually well tolerated although local irritation occurs in up to 80% of the patients independent of the type of topically applied retinoid (44). This irritation can usually easily be managed by dose reduction or by adding topical steroids.
First studies using isotretinoin as single agent in CTCL were reported 20 years ago (45). Isotretinoin showed an overall response rate (ORR) between 43% and up to 100%. Symptomatic relief of pruritus and fading of skin lesions occurred within few weeks and lasted for several months in most of the studied patients (46). Combined therapy with isotretinoin (1 mg/kg/day) and low dose IFN-a 2b (2 Mio U three times per week subcutaneously.) was shown to be effective with responses maintained for up to 15 months under maintenance therapy (47). Etretinate was one of the most widely used retinoids in CTCL and showed response rates similar to isotretinoin, but it is no longer available. More than 70 patients with MF and SS have been followed in studies using a combined therapy with etretinate and IFN-a (48-52) with ORR of at least 50% (50). Combined therapy with etretinate and IFN-2a was able to induce remission in patients with MF, especially in early stages. The combination of retinoids (etretinate, acitretin) with chemotherapy was effective in patients with advanced stage of MF (53-55).
In a large prospective randomized multicenter trial of 98 patients with MF stage I and II, Stadler et al. (28) compared the use of IFN-a plus acitretin vs. IFN-a plus PUVA. Also, IFN-a was administered at 9 MU three times weekly, sub-cutaneously. Acitretin was used at an initial dosage of 25 mg per day during first week, and 50 mg from weeks 2 to 48. The complete remission rate (CRR) in the group treated with IFN-a plus PUVA was 70% compared to 38.1% in the group with IFN-a and acitretin (28). In addition, time to response in the IFN-a plus PUVA group was significantly shorter than in the other group at 18.6 vs. 21.8 weeks, respectively. Side effects did not differ in the two groups. Based on these data, the authors concluded that a combined treatment of MF stage I and II with IFN-a plus PUVA is more effective than with IFN-a and acitretin.
Oral bexarotene, a RXR-selective retinoid, was approved by the FDA in 1999 for the cutaneous manifestations of CTCL in both early and advanced stages to other therapies (56,57). The efficacy of bexarotene has been well documented in early-stage MF as well as advanced stages of CTCL (58,59). The median duration of response was 10 months (299 days). The recurrence rate after response was 36%. Remarkably, bexarotene was effective also in cases of transformation of MF and erythrodermic MF as well as in patients with SS. A rapid improvement of erythroderma and pruritus occurred within 2 weeks in all four patients with erythrodermic CTCL (60).
Topical retinoids have also been employed in the treatment of early stages of CTCL (stage I and II). Bexarotene (Targretin®) as a topical gel achieved an Overall response rate (ORR) of 58% of the treated lesions (44). Lesions with no previous treatment responded at a higher rate (75% vs. 67%) than lesions that had received previous topical therapy (61). The topical therapy with bexarotene gel could be continued for more than 12 months in one-third of the patients. After long-term use, higher response rates (86% ORR and 28% CRR) were observed than after short-term use (60). A 30% response rate to topical alitreti-noin gel 0.1% (Panretin®), the only topical retinoid possessing both RAR and RXR activity, was seen in the phase I study conducted in MF patients with stage IA disease.
Retinoids can be combined with photochemotherapy (so called Re-PUVA), IFN-a, and chemotherapy. Bexarotene may be combined with topical steroids, phototherapy or with DAB 8389/IL-2 (denileukin diftitox, Ontak®) (62).
Clinical response after retinoid therapy does not necessarily imply histological clearing of skin lesions.(46). The persisting lymphoid infiltrates are most probably the source of recurrences. Nevertheless, retinoids as monotherapy or in combination with other nonaggressive treatment modalities represent a low-risk treatment alternative that is especially suitable for controlling early stages of MF and other CTCL. Combined modality therapies may be more effective in controlling CTCL as it was shown for combination of IFN-a together with retinoids and recently with bexarotene and other modalities.
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