Authors: Tompkins C., Kean Y., Yocum R., and the Panretin® Gel North American Study Group.

Over the past ten years, a number of compounds similar to vitamin A (also known as retinoids) have been studied for use in patients with Kaposi's sarcoma (KS) based on laboratory information suggesting efficacy. Some have been given orally and some have been applied topically to the skin. However, many have had poor efficacy and significant side effects, rendering them of limited use for the treatment of KS. A few years ago, alitretinoin as a topical gel (trade name Panretin®) has become the clear leader in terms of its relative efficacy and lack of side effects. This led to its approval by the Food and Drug Administration (FDA) as a licensed drug for the treatment of KS.

Despite this, it showed somewhat limited efficacy in the initial North American, as well as international, clinical trials. The chance of responding after 12 weeks of therapy was 35% in the North American and 37% in the international trials. This showed that only 1 out of every 3 patients that used the medication would have a significant reduction in KS lesions. In general, this level of effectiveness does not compare favorably with many other treatments, such as the newer chemotherapy regimens such as Doxil (liposomal doxorubicin) or Taxol (paclitaxel). The side effect profile is better, though, with most patients experiencing only a slight to moderate reddening of the skin over and around the lesion.

The data described in this poster is from a continuation of the North American trial mentioned above. After the initial 12-week treatment period on the placebo-controlled trial, the patients were entered on an open-label follow-up period with all patients using the active drug. The measure of effect in this trial was the time to a 50% decrease in lesion measurements by the AIDS Clinical Trial Group (ACTG) criteria, a cumbersome, but well validated measure of KS response to therapy. At the term of entry of patients onto this longer follow-up period, 28% of them already had a response but this rose over further treatment to 48%. The median time to achieving 50% reduction in lesions was 14 weeks. These responses to therapy were also quite persistent with median time to relapse of KS being approximately 65 weeks from the time of initiation of therapy, better than with Doxil. However, it only works on lesions to which it has been directly applied. Side-effects remained limited to a rash, with reddening over the area where the gel was applied.

Therefore, with a longer follow-up time alitretinoin gel seems to be effective in over half of the patients that receive it. The response to treatment is also fairly persistent and lasts well over a year. The drug is safe and well-tolerated. However, it is of limited use in patients that have many or large lesions, severe swelling, rapid growth with many new lesions appearing quickly, or if they have internal disease such as lung, intestinal, or mouth involvement. Clearly, a small but significant number of patients could benefit from this therapy.

As an aside, the issue of antiretroviral therapy and immune reconstitution was not addressed in this study. This is an important consideration, since it is clear that a large number of people with KS will experience improvement just with effective HIV therapy. In the previous North American study, it was investigated in a limited way and the conclusion was made that there was no association with alitretinoin response and changes in response to antiretroviral therapy. However, this was a somewhat flawed analysis and the question of the known therapeutic effect of antiretroviral therapy on KS and its relationship to alitretinoin response remains somewhat unclear.