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ANTITUMOR ACTIVITY OF 9-CIS RETINOIC ACID: AIDS-RELATED KAPOSI'S SARCOMA
S.A. Miles, University of California-Los Angeles CARE Center, presented interim data on 66 patients treated openly with 9-cis retinoic acid (9-CRA). All of the AIDS Kaposi's sarcoma (AKS) patients entered free of opportunistic infections. Daily oral doses of 9-CRA at 60 to 100 mg led to an overall response rate (RR) of 37%. Adverse drug events (ADEs) included headache (26%), elevated triglycerides (18%), and decreased neutrophils (16%). HIV ribonucleic acid (RNA) levels did not change significantly using 9-CRA with antiviral drugs.
Introduction to open Phase II study Retinoids block in vitro multiplication of cells derived from AKS. Both 9-CRA and all-trans retinoic acid (ATRA) selectively inhibit AKS cells; however, topical and oral studies show 9-CRA to have better profiles for bioavailability and pharmacodynamics compared with ATRA.
Methodology Fourteen US clinical centers enrolled 66 AKS patients free of secondary opportunistic infections. Baseline history included prior local therapy by 47% and various systemic chemotherapies or immunotherapy by 48% of the patients, respectively. The most frequently used concurrent antiviral drug was 3TC (82%) followed by D4T (48%) and AZT (40%).

Oral dosing with 9-CRA began at 60 mg/msq each afternoon. If tolerated, the dose could be increased to 100 mg/msq. Patients reported biweekly to the clinic for CD4 T lymphocyte counts, HIV RNA estimation, and ADEs. Evaluation of the tumor response took place after 16 weeks' 9-CRA therapy in 52 patients.

Therapeutic effects with 9-CRA Fifty-two patients, treated for at least 16 weeks, showed the following responses:
Response No. Patients
Complete 1
Clinical 1
Partial 21
Stable 21
Progressive 8
Ten other nonevaluable patients received 9-CRA for less than 16 weeks.

At baseline, HIV RNA averaged 190,000 copies/mL even though 76% of the patients had been receiving 3 or 4 antiviral drug regimens. HIV RNA levels did not change significantly during added 9-CRA treatment (p>0.05).

Adverse drug events (ADEs) Twenty-two of 66 (33%) patients discontinued taking 9-CRA because of headache (11), dry skin (5), alopecia (4), or fatigue (3). One patient stopped after the diagnosis of a brain lesion, unrelated to test drug. Tolerated ADEs included headache (15), elevated triglycerides (7), and at lower frequency (<7%), desquamation/rash, neutropenia, pneumonia, fever, fatigue, edema, and elevated liver function tests.
Presenter conclusions The test drug, 9-CRA, shows efficacy in AKS patients. Efficacy occurs in the absence of antiviral activity and confounding by antiviral agents. Future studies ought to use lower doses of 9-CRA because of the ADEs induced with once daily dosing at 60 to 100 mg/msq.
For professional correspondence, please contact Dr. Miles by Fax at: (310) 206-3311 or by E-mail at: smiles@medl.medsch.ucla.edu

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
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