BETHESDA, Md--Thalidomide, paclitaxel(Drug information on paclitaxel) (Taxol), and vinorelbine (Navelbine) have all shown promise in phase II trials as treatment for Kaposi's sarcoma in AIDS, researchers reported at the National AIDS Malignancy Conference. Although progress has come in treating KS, more effective drugs are needed, especially in light of the lengthening life span emerging for AIDS patients from the use of drug combinations.
"We now have the apparent luxury to manage Kaposi's sarcoma over years rather than months," said Susan E. Krown, MD, of Memorial Sloan-Kettering.
The rationale for testing thalidomide(Drug information on thalidomide) stems from its three possible mechanisms of action against KS, said Mark Bower, MD, PhD, of Chelsea & Westminster and Charing Cross Hospitals, London.
The drug selectively inhibits the synthesis of TNF-alpha, an autocrine growth factor in KS; it has antiangiogenic activity in vivo; and it reduces HIV-1 activation in peripheral blood mononuclear cells in vitro. Moreover, two case reports indicate beneficial effects from thalidomide in people with KS.
Dr. Bower and his colleagues carried out a phase II study in 17 HIV-positive males (median age, 40) with histologically documented Kaposi's sarcoma. Patients had a median CD4 count of 34. All were taking antiretroviral therapy, but none were on protease inhibitors.
The researchers collected a peripheral blood sample before treatment and at four weeks into the therapy, and evaluated each patient's DNA burden of human herpesvirus-8 (HHV-8), thought to be the cause of KS in AIDS patients.
Study participants received 100 mg of thalidomide administered orally each night for eight weeks, a dosage the researchers had used in a previous trial.
Nine patients completed the study. Eight dropped out: one because of poor compliance, one due to progressive disease, and six because of toxicity. Four of the toxicity dropouts suffered a rash that spontaneously resolved within 24 hours of stopping thalidomide; one developed Raynaud's syndrome, the other nausea.
Six of the nine remaining patients had a partial response, Dr. Bower said. Five of the six had detectable HHV-8 at enrollment; and four of these five showed a decline when tested in the midst of the trial, including three who had no detectable HHV-8. "We've shown that thalidomide has biological activity in this disease and that response is associated with a decline in HHV-8," he said.
Similar promising results emerged from a phase II study of low-dose paclitaxel reported by Parkash S. Gill, MD, of the University of Southern California. Paclitaxel had shown preliminary evidence of antitumor efficacy in a previous study in which 13 of 20 patients with AIDS-related Kaposi's sarcoma experienced a partial response.
KS Cell Lines Sensitive to Taxol
Dr. Gill and his colleagues conducted preclinical studies of the drug and found that KS cell lines were very sensitive to paclitaxel, "as sensitive as any cell line that has been studied so far," he said.
The team treated 54 male and two female AIDS-KS patients (median age, 36), most with advanced disease. The median CD4 count was 20. Forty patients had undergone chemotherapy or biological response modifier treatment; 16 had received no prior systemic therapy. Twenty-five patients (45%) had visceral disease--16 involving the lung and GI tract. Lymphedema affected 39 (70%).
The patients received 100 mg/m² of paclitaxel administered over three hours every two weeks. The median number of cycles completed was 10, with a maximum of 22. Side effects included hair loss, neutropenia, and anemia.
Responses were seen in 59% of patients, including one complete response; 25% had stable disease; 16% progressed. The median time to response was 1.5 months, but one patient did not respond until 9 months.
The median response duration was 10.4 months, "which is the longest duration of response that I'm aware of in any trial conducted so far," Dr. Gill said. "The survival curve is also unprecedented. The median survival is 23.8 months." These findings, Dr. Gill concluded, warrant a randomized trial of paclitaxel in AIDS-Kaposi's sarcoma patients.
Vinorelbine (Navelbine), a semisynthetic vinca alkaloid, also showed potency against KS in a phase II trial involving 29 male patients (median age, 36), said Michele Spina, MD, for the Italian Cooperative Group on AIDS and Tumors.
Patients in the study had advanced KS and CD4 counts ranging from 1 to 351 (median, 16). All had either relapsed after previous chemotherapy or progressed during previous cytotoxic therapy. They received 30 mg/m² of vinorelbine given IV every two weeks. Two patients were lost to follow-up. The median number of cycles completed was four.
Three CRs With Vinorelbine
Of the 27 patients evaluated, three had complete remissions, with durations of 5, 8, and 15 months Dr. Spina said. Another nine, had partial remissions that lasted one to six months (median duration, three months). All 12 responders had previously failed vinca alkaloid therapy. Nine other patients had stable disease, and six had progressive disease.
Thirteen patients suffered grade 3 or 4 leukopenia; two had anemia; one experienced thombocytopenia. No neurotoxicity was observed, Dr. Spina said.
Seventeen have now died; median survival is seven months, eight months for responders versus five months for nonre-sponders. "We think vinorelbine is active and well tolerated," Dr. Spina said. "And we think it should be considered also for studies as a first-line single agent or as a component of combination chemotherapy regimens for KS patients."
