The drug thalidomide, used in the 1950s and 1960s as a sedative which led to birth defects in newborns of mothers who took the drug, has now been shown to have clinical activity against Kaposi's sarcoma (KS), an AIDS-related cancer.

Researchers at the National Cancer Institute (NCI) have shown in a Phase II study that oral administration of thalidomide induced partial responses to cancerous lesions in 40 percent of the 20 patients treated. The results are published in the July 2000 issue of the Journal of Clinical Oncology.* This study was sponsored by the NCI under a clinical trials agreement with Celgene Corporation.

Robert Yarchoan, M.D., chief of the HIV and AIDS Malignancy Branch at NCI and senior author of the paper, said, "These results look promising and show that thalidomide may prove to be a useful drug in patients with Kaposi's sarcoma." Yarchoan also noted that additional studies are warranted to further explore the use of thalidomide in Kaposi's sarcoma and to define the best dose to use.

The most common birth defects that were seen with thalidomide when it was used as a sedative in the 1950s and 1960s were shortened arms and legs. Robert D'Amato, M.D., Judah Folkman, M.D., and colleagues at Harvard University proposed that these defects might have been due to thalidomide's effect on blood vessels. They subsequently showed that thalidomide was an inhibitor of angiogenesis, the process by which new blood vessels grow to help supply a tumor or tissue with nutrients for its growth and metastasis. Because of this, and the fact that KS is a highly vascular disease, the NCI scientists postulated that the drug might be effective against KS.

Investigators enrolled 20 patients ages 29 to 49 who were HIV-positive and had biopsy-confirmed KS that had progressed for two months prior to enrollment in the study. At the time the trial was started, there was no information on which dose would give the best biologic response.

Phase I trials are usually done to determine maximum tolerable dose of a drug being tested; Phase II trials, such as this, try to determine the most efficacious dose of a drug. To this end, the patients received doses of thalidomide that ranged from 200 milligrams to 1,000 milligrams daily for a median treatment time of about six months. Doses were adjusted for each patient in order to minimize adverse events. There was no clear optimal dose level, indicating that lower dose levels may be sufficient. Smaller studies of thalidomide and KS have shown that doses as low as 100 milligrams a day may be effective.

Of the 20 patients enrolled in this study, none achieved a complete remission of the disease. Eight patients showed a partial response, which was a 50 percent decrease in the number of nodular lesions seen on their skin. Two patients had stable disease, or no change in their lesions, and seven patients had progressive disease. Of the 17 patients who were assessable for response, 14 were on different combinations of anti-retroviral therapy for other HIV-related conditions. Because the patients' disease was progressing on stable anti-retroviral therapy prior to entering the trial, it is unlikely that their anti-retroviral therapy was responsible for the improvement in KS lesions.

The main side effect of thalidomide in this trial was drowsiness. Interestingly, seven patients developed depression, although each had a prior history of depression. Richard Little, M.D., senior oncologist at NCI and lead author of the paper, noted that this is a side effect that future investigators should be alert to, as depression can sometimes be difficult to detect. Both authors noted, however, that the adverse events could usually be managed by lowering the dose. The scientists also found that thalidomide had activity at generally well-tolerated dosage levels.

According to Yarchoan, "Thalidomide is an oral drug that patients can easily take and has shown as good a tumor response in Kaposi's sarcoma as some conventional cytotoxic agents." Yarchoan also notes that other anti-angiogenesis agents now in various phases of development could prove as potent or even more so than thalidomide.

Thalidomide has also been shown, in early clinical trials, to be active against multiple myeloma, a bone marrow disease. Researchers do caution that use of thalidomide may lead to fetal defects if a patient becomes pregnant and that appropriate contraceptive measures must be taken.

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