Abstract: The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only. Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis. Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs. Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments, and here in particular a combined therapeutic regimen of chemotherapy and electron beam, bexarotene, or denileukin diftitox, showed more adverse effects than topical or skin-directed treatments. In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.

Plain-language summary: We found 14 studies with a total of 30 publications with 675 participants. Most of the studies (8) had fewer than 50 participants and lasted less than 12 months. None of these studies compared the quality of life of participants with regard to different treatments. Also, no study compared a particular therapy to a "wait and see" strategy. Most of the studies described adverse effects, from mild symptoms to severe life-threatening or even lethal complications depending upon the type of treatment. More aggressive treatment options like systemic chemotherapy showed more adverse effects than topical therapies that are applied directly to the skin. None of the trials reported a long-term benefit (i.e. clearance of all symptoms of disease lasting at least two years). Therefore, the conclusions from these studies should be treated with caution. Treatment of mycosis fungoides should be based on the stage of progression of the disease with a focus on the limitations of severe adverse effects. There is a great need for extensive and well planned research to find effective ways to manage this disease and to evaluate treatment strategies that might be curative. People with mycosis fungoides are encouraged to participate in such trials.