Correspondence
Intralesional Human Chorionic Gonadotropin for Kaposi's Sarcoma
N Engl J Med 1997; 336:1187-1189April 17, 1997
- Article
To the Editor:
Gill et al. (Oct. 24 issue)1 reported that they induced apoptosis of two nodular cutaneous Kaposi's sarcoma lesions in each of 36 patients by administering human chorionic gonadotropin (hCG) intralesionally three times a week for two weeks; they noted that the efficiency of treatment was dose-dependent, with superior tumor responses in patients receiving 2000 IU per lesion as compared with those receiving 250, 500, or 1000 IU per lesion. As Krown stated in her editorial,2 this treatment had a “limited and primarily cosmetic role,” and there is no “evidence that uninjected lesions benefit.”
Over the past several years, my colleagues and I have administered hCG systemically (intramuscularly) at doses ranging from 150,000 IU to 700,000 IU three times a week to patients with life-threatening cutaneous Kaposi's sarcoma lesions or a combination of cutaneous and visceral lesions. This therapy, which was remarkably well tolerated, resulted in the remission of all lesions.3,4
I do not see the rationale for giving local therapy for a systemic disease; it is now widely accepted that Kaposi's sarcoma is caused by a systemic infection with a unique herpeslike virus.5 The administration of hCG to patients with Kaposi's sarcoma does indeed hold promise, but as with all pharmacologic interventions, the therapeutic benefit depends on the appropriate dosage and route of administration.
5 ReferencesPamela Jo Harris, M.D.
AIDS Clinical Research Center of Washington, D.C., Washington, DC 200091
Gill PS ,Lunardi-Iskandar Y ,Louie S , et al. The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma. N Engl J Med 1996;335:1261-1269
Full Text | Web of Science | Medline2
Krown SE . Kaposi's sarcoma -- what's human chorionic gonadotropin got to do with it? N Engl J Med 1996;335:1309-1310
Full Text | Web of Science | Medline3
Harris PJ . Treatment of Kaposi's sarcoma and other manifestations of AIDS with human chorionic gonadotropin. Lancet 1995;346:118-119
CrossRef | Web of Science | Medline4
Harris PJ . Intramuscular administration of human chorionic gonadotropin to treat Kaposi's sarcoma. AIDS Patient Care STDs 1996;10:154-161
CrossRef | Web of Science | Medline5
Moore PS ,Chang Y . Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection. N Engl J Med 1995;332:1181-1185
Full Text | Web of Science | Medline
To the Editor:
The findings reported by Gill et al. confirm the tumoristatic effect of hCG that we have reported in cultures of both rat mammary carcinomas and human breast epithelial cells.1,2 Their findings add a new dimension to the understanding of the tumoristatic effect of this hormone, in a different model and in tumors with a different cause.
I understand that Kaposi's sarcoma is far removed from breast cancer and chemically induced carcinogenesis, but the tumoristatic effect of hCG on mammary epithelial cancers may open new avenues in our understanding of the role of this hormone in seemingly unrelated organs.
2 ReferencesIrma H. Russo, M.D.
Fox Chase Cancer Center, Philadelphia, PA 191111
Russo J . Basis of cellular autonomy in the susceptibility to carcinogenesis. Toxicol Pathol 1983;11:149-166
CrossRef | Medline2
Russo IH ,Russo J . Role of hCG and inhibin in breast cancer. Int J Oncol 1994;4:297-306
Web of Science | Medline
To the Editor:
In her editorial, Krown speculates on possible indirect antitumor activities of hCG that may explain the relative infrequency of Kaposi's sarcoma in women. However, the excess of Kaposi's sarcoma among men in Western countries can be explained by the high rates of Kaposi's sarcoma in homosexual men with AIDS; epidemiologic data do not support Krown's clinical observation of a higher incidence of Kaposi's sarcoma among men with “all forms of Kaposi's sarcoma.”
In the United States1 and Europe,2 among injection-drug users, African-born heterosexuals, and those infected with the human immunodeficiency virus (HIV) through transfusions, equal proportions of men and women present with Kaposi's sarcoma as their first AIDS-defining illness. In the United States,1 the only other group with high rates of Kaposi's sarcoma was men recorded as having acquired HIV through “other heterosexual” contact, some of whom may not have acknowledged homosexual contact. The people with AIDS who have the lowest risk of Kaposi's sarcoma are those infected with HIV through blood products, and they are overwhelmingly male (hemophilia being a male disorder). In Africa, the male-to-female ratio of AIDS-associated Kaposi's sarcoma has fallen dramatically since the beginning of the AIDS epidemic and is now thought to be around 2:1.3 Kaposi's sarcoma that is associated with chemical immunosuppression after transplantation appears to be no more common in men than in women, with the published sex ratios ranging from 0.5 to 2.7. 2
In contrast, before the AIDS epidemic Kaposi's sarcoma was more frequent in men than in women. Population-based series gave male-to-female ratios ranging from 1 to 6 in Western countries.2 In Africa, Kaposi's sarcoma appears to have been much more common in men than in women before the AIDS epidemic, with a male-to-female ratio of about 10.2
Population-based data therefore do not support the frequent claim that Kaposi's sarcoma is always more common in men than in women. Before the AIDS epidemic, it was clearly more common in men in both Africa and the West. Among people with AIDS, the higher incidence of the sarcoma in men seems to be related to male homosexuality rather than sex in itself. We believe that a factor associated with male homosexual contact is more likely than female sex hormones to explain the excess of AIDS-associated Kaposi's sarcoma among men. Recent work suggests that this factor may be infection with human herpesvirus 8, the epidemiology of which is consistent with transmission by male homosexuals.4 Although a potential role of sex hormones in treating AIDS-associated Kaposi's sarcoma should not be dismissed, epidemiologic data on the occurrence of Kaposi's sarcoma do not provide consistent support for their use.
4 ReferencesAndrew E. Grulich, M.B., B.S.
John M. Kaldor, Ph.D.
National Centre in HIV Epidemiology and Clinical Research, Darlinghurst, NSW 2010, Australia1
Beral V . Epidemiology of Kaposi's sarcoma. Cancer Surv 1991;10:5-22[Erratum, Cancer Surv 1992;12:225.]
Medline2
Grulich A, Kaldor J. The sex ratio of AIDS-associated Kaposi's sarcoma does not provide evidence that sex hormones play a role in pathogenesis. AIDS (in press).
3
Brettle RP ,Leen CL . The natural history of HIV and AIDS in women. AIDS 1991;5:1283-1292
CrossRef | Web of Science | Medline4
Kedes DH ,Operskalski E ,Busch M ,Kohn R ,Flood J ,Ganem D . The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med 1996;2:918-924
CrossRef | Web of Science | Medline
Author/Editor Response
The authors and a colleague reply:
To the Editor: We are aware of the work by Harris,1 who treated six patients with high doses of hCG (up to 700,000 IU) — amounts derived from doses we used in mice given human Kaposi's sarcoma cells in transplantation.2 Harris used various preparations of hCG but failed to define the relative activity of each. This is critical, since we have evidence that the active moiety is not the native hCG heterodimer. She suggests that since Kaposi's sarcoma–related herpesvirus (KSHV) has been described, local therapy has no place in the treatment of patients with Kaposi's sarcoma. This logic is flawed. If a tumor is caused by a virus, there is no reason the tumor cannot be treated locally. Harris's claim that KSHV causes Kaposi's sarcoma is inappropriate. Although correlative data suggest that KSHV is associated with Kaposi's sarcoma, no cause-and-effect relation has been established.
We are aware of the important work of Russo and associates.3 But their experiments were limited to rodents and cell lines, whereas ours were in humans. Their studies were limited to the effects of a preparation of hCG on the mammary gland and mammary tumors, whereas ours was on a sarcoma. Russo and her colleagues limited their investigation to the prevention of mammary-tumor carcinogenesis, whereas we showed direct antitumor effects. They showed that hCG induces the differentiation of human breast epithelium and rat mammary tissue; the effects we showed are not of the induction of differentiation but of cell killing. Most important, our findings show that only certain preparations of hCG have anti–Kaposi's sarcoma activity and that highly purified and recombinant hCG has little or no activity; the active moiety against Kaposi's sarcoma tumor cells in commercial preparations of hCG is not hCG itself.
3 ReferencesParkash S. Gill, M.D.
University of Southern California School of Medicine, Los Angeles, CA 90033Yanto Lunardi-Iskandar, M.D., Ph.D.
Robert C. Gallo, M.D.
University of Maryland, Baltimore, MD 212011
Harris PJ . Treatment of Kaposi's sarcoma and other manifestations of AIDS with human chorionic gonadotropin. Lancet 1995;346:118-119
CrossRef | Web of Science | Medline2
Lunardi-Iskandar Y ,Bryant JL ,Zeman RA , et al. Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature 1995;375:64-68[Erratum, Nature 1995;376:447.]
CrossRef | Web of Science | Medline3
Russo IH ,Koszalka M ,Russo J . Human chorionic gonadotropin and rat mammary cancer prevention. J Natl Cancer Inst 1990;82:1286-1289
CrossRef | Web of Science | Medline
Author/Editor Response
Lunardi-Iskandar et al.1 cited a higher frequency of Kaposi's sarcoma in men than in women as a rationale for investigating the antineoplastic potential of hormones in this tumor. Their subsequent observations — that Kaposi's sarcoma tumors failed to grow in pregnant mice and that tumor growth was inhibited by hCG — led directly to the clinical trials that were the subject of the editorial in question. The reference in the editorial to an excess of Kaposi's sarcoma among men was intended, therefore, to explain the investigators' own rationale for conducting these studies. It constituted neither an endorsement of a hormone-based therapeutic strategy nor a comment on the role of hormones or other factors in the development of this tumor.
That said, there is substantial evidence among immunosuppressed patients that the higher risk of Kaposi's sarcoma among men is not restricted to HIV-infected homosexual men. Among 730 Saudi kidney-transplant recipients, for example, Kaposi's sarcoma developed in 6.1 percent of the men and 3.1 percent of the women.2 Among 7923 French organ recipients, only 1 of 41 patients in whom Kaposi's sarcoma developed was a woman.3 In U.S. AIDS cases reported through December 1994, Kaposi's sarcoma was more frequently a presenting diagnosis of men than of women among injection-drug users (by a factor of 1.7), heterosexuals (by a factor of 2.6), and transfusion recipients other than persons with hemophilia (by a factor of 2.5).4 In Kampala, Uganda, where over 90 percent of cases of Kaposi's sarcoma are AIDS-related, the age-standardized incidence rates of the sarcoma were 30.1 in men and 11 in women,5 despite a male-to-female ratio of AIDS cases that is close to 1. These data do not prove that hormones have a role in the development of Kaposi's sarcoma among the immunosuppressed, or in protecting them from it, but they do not rule out a hormonal contribution. Hormones are not the only feature that distinguishes women from men, however, and environmental or genetic differences could also account for the unequal frequencies of Kaposi's sarcoma in the two sexes. We would note that Grulich and Kaldor base their argument on the frequency with which Kaposi's sarcoma appears as the initial AIDS-defining illness, but this is not a surrogate for the overall incidence, which includes both initial and secondary presentations.
Although human herpesvirus 8 is present in all forms of Kaposi's sarcoma, including its classic and African endemic forms, homosexually acquired infection is unlikely to account for the consistent excess among men in these varied populations. This suggests that multiple factors contribute, in varying degrees, to the development and progression of different forms of Kaposi's sarcoma. Evidence of the involvement of any one factor (such as infectious agents, cytokines, or hormones) does not rule out a role for others.
5 ReferencesSusan E. Krown, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021Charles S. Rabkin, M.D.
National Cancer Institute, Bethesda, MD 208921
Lunardi-Iskandar Y ,Bryant JL ,Zeman RA , et al. Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature 1995;375:64-68[Erratum, Nature 1995;376:447.]
CrossRef | Web of Science | Medline2
al-Sulaiman MH ,al-Khader AA . Kaposi's sarcoma in renal transplant recipients. Transplant Sci 1994;4:46-60
Medline3
Farge D . Kaposi's sarcoma in organ transplant recipients. Eur J Med 1993;2:339-343
Medline4
AIDS public information data set. (Data through December 1994.) Atlanta: Centers for Disease Control and Prevention, 1994.
5
Wabinga HR ,Parkin DM ,Wabwire-Mangen F ,Mugerwa JW . Cancer in Kampala, Uganda, in 1989-91: changes in incidence in the era of AIDS. Int J Cancer 1993;54:26-36
CrossRef | Web of Science | Medline
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