Human Chorionic Gonadotropin for AIDS- Associated Kaposi’s Sarcoma

ABSTRACT & COMMENTARY

Synopsis: One-third of men with mucocutaneous AIDS-associated Kaposi’s sarcoma responded to subcutaneously delivered human chorionic gonadotropin.

Source: Gill PS, et al. J Natl Cancer Inst 1997;89: 1797-1802.

Kaposi’s sarcoma is the most common aids-associated malignancy. About 30% of male homosexuals with AIDS develop Kaposi’s sarcoma. Only 3% of women with AIDS develop this complication. This dramatic difference in demographics was the first clue to the influence of the hormonal milieu on the tumor. Subsequently, Lunardi-Iskandar and colleagues demonstrated that the growth of Kaposi’s sarcoma cell lines was blocked in vivo during the early stage of pregnancy. They found that sera from pregnant women and commercial human chorionic gonadotropin preparations exerted growth inhibitory effects on Kaposi’s sarcoma cells in vitro.1 However, purified or recombinant human chorionic gonadotropin did not show antitumor effects. It turns out that some poorly defined factor associated with human chorionic gonadotropin is required to see antitumor effects.

Gill and colleagues examined the efficacy of a number of distinct commercial preparations of the hormone and found that a Wyeth-Ayerst product called APL had the greatest in vitro antitumor effect. They discovered it was capable of inducing regressions in Kaposi’s sarcoma lesions into which it was directly injected.2 Based on the preliminary positive clinical results, Gill et al performed a phase I clinical trial in which APL was administered in different doses and schedules to men with early stage mucocutaneous AIDS-associated Kaposi’s sarcoma.

Patients were entered consecutively, with six patients per group; group I received 5000 IU daily, group II received 10,000 IU three times a week, and group III received 10,000 IU daily. No further dose escalations were planned because of formulation problems. Treatment was continued until tumor progressed. In the absence of progressive disease, patients were kept on treatment indefinitely. No dose-limiting toxicities were noted in any patient; thus, no maximum tolerated dose was defined. However, six of 18 patients had major responses, including two of six at each dose level. The two responders at the highest dose level were complete. Five of the six responses continued for 207-515+ days. An additional nine patients had at least 10 weeks of stable disease.

Side effects of treatment were mainly positive: 15 patients gained weight, nine had increased libido, eight reported increased energy, and seven had increased appetite. No hematologic toxicity was seen. Testosterone levels increased in nearly all patients. Follicle-stimulating hormone and luteinizing hormone levels decreased in 80-90% of patients. Hormonal changes were seen at all dose levels. Gynecomastia was observed in a single patient.

COMMENTARY

APL appears to have considerable potential as a therapy for AIDS in general and AIDS-related Kaposi’s sarcoma in particular. The side effects of therapy were largely salutary, one-third of patients had tumor response, and another half had stable disease. The preparation has direct antitumor effects, but in addition, the increase in testosterone levels and the decrease in FSH and LH levels influence a variety of physiologic functions. Responses were seen in people with CD4+ T cell counts below 200/mm3 and above, people taking and not taking protease inhibitors, and in patients with decreasing and stable or increasing viral loads. Some patients had evidence of an antiviral effect mediated chiefly by APL, but this occurred in only a minority of patients.

Clearly, it is important to determine the active component of the commercial preparation. However, in the meantime, it is difficult to see a major risk associated with the use of APL in patients with Kaposi’s sarcoma. The spectrum of side effects appears to be far more tolerable (actually some are beneficial) than those experienced with other Kaposi’s sarcoma treatments. APL is already FDA approved for other indications. It is an agent that may be worth considering for use even before phase III studies lead the FDA to approve it for this indication.

References

1. Lunardi-Iskandar Y, et al. Nature 1995;375:64-68.

2. Gill PS, et al. N Engl J Med 1996;335:1261-1269.

The human chorionic gonadotropin preparation APL:

a. decreases serum testosterone level in most treated patients.

b. produces responses in about one-third of patients with mucocutaneous AIDS-associated Kaposi’s sarcoma.

c. increases viral load.

d. interferes with the activity of protease inhibitors.

e. induces gynecomastia in 40% of patients.