In his excellent review, Dr. Mitsuyasu correctly highlights the three most important ingredients that play a role in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma (KS)-Kaposi’s sarcoma herpesvirus/human herpesvirus type 8 (KSHV/HHV-8); altered expression and response to cytokines; and stimulation of KS growth by the human immunodeficiency virus (HIV)-1 trans-activating protein, Tat. Recent studies have provided tremendous insight into the process whereby KSHV/HHV-8 creates the inflammatory-angiogenic state that characterizes KS.
In his excellent review, Dr. Mitsuyasu correctly highlights the three most important ingredients that play a role in the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related Kaposis sarcoma (KS)Kaposis sarcoma herpesvirus/human herpesvirus type 8 (KSHV/HHV-8); altered expression and response to cytokines; and stimulation of KS growth by the human immunodeficiency virus (HIV)-1 trans-activating protein, Tat. Recent studies have provided tremendous insight into the process whereby KSHV/HHV-8 creates the inflammatory-angiogenic state that characterizes KS.
The clinical course of AIDS-related KS is highly variable, ranging from minimal stable disease to explosive growth. The psychosocial burden associated with KS may be profound, a point illustrated both by this review and by the movie, Philadelphia, in which Tom Hanks portrays a gay man with KS. The treatment algorithm put forth by Dr. Mitsuyasu is appropriate; differences between his and my approaches are outlined below.
Creation of an Inflammatory-Angiogenic Environment
KSHV/HHV-8 is a necessary, but not sufficient, cause of KS. The virus encodes proteins that are homologs of interleukin-6 (IL-6), chemokines of the macrophage inflammatory protein family, cell-cycle regulators of the cyclin family, and antiapoptosis genes of the bcl-2 family. The HIV-1 protein, Tat, promotes the growth of spindle cells of endothelial origin, but does so only in the presence of inflammatory cytokines.
The synergy between cytokines and the HIV-1 Tat protein, as well as the immunosuppression associated with AIDS, provide possible insight into the reasons why AIDS-related KS is more aggressive than the classic Mediterranean form, in which the HIV-1 Tat protein does not play a role. The remarkable finding that KSHV/HHV-8 encodes viral IL-6, and the equally remarkable finding that this IL-6, in turn, leads to expression of the angiogenic vascular endothelial growth factor (VEGF), provide a missing link in the chain of events by which KSHV/HHV-8 creates an inflammatory-angiogenic environment.
The major goals of treatment for KS, as outlined by Dr. Mitsuyasu, are palliation of symptoms; shrinkage of tumor to alleviate edema, organ compromise, or psychological stress; and prevention of disease progression. Treatment options depend greatly on the tumor (extent of disease and rate of growth), the HIV-1 viral load, and the host (CD4+ T-lymphocyte count, overall medical condition).
Highly Active Antiretroviral Therapy
Most, if not all, KS patients should be advised to take antiretroviral drugs that will maximally decrease the HIV-1 viral load. This recommendation is based on the increasing recognition that effective antiretroviral regimens are associated with both a decrease in the proportion of new AIDS-defining KS cases and a regression in the size of existing KS lesions. Highly active antiretroviral therapy (HAART) prolongs the time to treatment failure of anti-KS therapies.
Alitretinoin gel 0.1% (Panretin) is a topical, patient-administered therapy for the treatment of KS. Alitretinoin gel, as compared to vehicle gel, is associated with a shorter time to tumor response, more prolonged duration of response, and more prolonged time to disease progression. Responses, which typically occur after 4 to 8 weeks, are seen in patients with a wide range of baseline CD4+ T-lymphocyte counts. Dermal irritation may occur at the site of application.
Other effective local treatments include intralesional chemotherapy, radiation therapy, laser therapy, and cryotherapy. Vinblastine is probably the most widely used intralesional agent, with an excellent response rate of approximately 70%. Radiation therapy can very effectively palliate symptomatic disease that is too extensive to be treated with intralesional chemotherapy, but not extensive enough to warrant systemic therapy. Local therapies, in general, will not affect the development of new lesions in untreated areas.
Interferon-alfa is a biological response modifier that can produce clinically significant responses in KS patients, especially in those with disease limited to the skin and with relatively modest degrees of immunosuppression. Poor tumor response and drug-related toxicity are particularly striking in patients with CD4+ T-lymphocyte counts < 200 cells/µL. For some patients with asymptomatic, but relatively disseminated, cutaneous disease, interferon in combination with antiretroviral agents may be a reasonable option prior to the decision to use chemotherapy.
Current systemic treatments for KS revolve around the newer liposomal anthracyclines, as well as paclitaxel (Taxol). Although Dr. Mitsuyasu provides a section on combination chemotherapy, such as ABV (Adriamycin, bleomycin, vincristine) and BV (bleomycin, vincristine), I would consider these regimens to be passé.
The two currently approved liposomal anthracyclines, liposomal doxorubicin (Doxil) and liposomal daunorubicin (DaunoXome), have become the first-line chemotherapeutic treatments for patients with disseminated, symptomatic KS. Compared to conventional chemotherapy, the liposomal formulations of the anthracyclines provide the theoretical advantage of a longer plasma half-life, higher tumor concentrations of drug, and less toxicity in nontarget organs.
In randomized, multicenter trials, each of these liposomal agents has been found to be superior to conventional chemotherapy (bleomycin [Blenoxane] and vincristine with or without nonliposomal doxorubicin) in terms of response rates and toxicity profiles.[8,9] Side effects are, in general, quite mild; alopecia, neuropathy, and cardiomyopathy, in particular, are unusual with these liposomal preparations.
Paclitaxel is the newest systemic chemotherapeutic agent approved for KS, with striking efficacy (response rates as high as 75%)even for patients with anthracycline-resistant disease.[10,11] The median duration of response of approximately 10 months is among the longest observed for any regimen reported for this disease. Paclitaxel is well tolerated, but the higher prevalences of alopecia, myalgia/arthralgia, bone-marrow suppression, and the need for a 3-hour infusion make paclitaxel less attractive than the liposomal anthracyclines as initial therapy for disseminated disease.
An ongoing study, conducted by the Eastern Cooperative Oncology Group and the AIDS Malignancy Consortium (ECOG/AMC), is currently comparing paclitaxel to liposomal doxorubicin in patients with previously untreated advanced KS.
Antiretroviral Therapy/Paclitaxel: Potential Interactions
The drug metabolism of many of the approved antiretroviral agents, particularly protease inhibitors and nonnucleoside reverse transcriptase inhibitors, involves cytochrome P450 metabolic pathways. Taxanes are oxidized to less active metabolites by hepatic cytochrome P450 enzymes. An ECOG/AMC study is currently assessing the pharmacokinetic interactions between paclitaxel and protease inhibitors. Caution is urged when coadministering agents that utilize the same metabolic pathways.
Given the highly significant role that angiogenesis plays in the pathogenesis of KS, it is not surprising that many, if not most, of the angiogenesis inhibitors in development have been, or are currently being, tested in patients with AIDS-related KS. IM862, an intranasally administered VEGF inhibitor, is being tested in a phase III trial under the auspices of the NCI. In a phase II trial of IM862 in 44 patients, the overall response rate was 36% and adverse events were mild and transient.
Other angiogenesis inhibitors, which have led to durable clinical responses in patients accrued to early trials, include fumagillin, thalidomide (Thalomid), metastat (col-3, a matrix metalloproteinase inhibitor), interleukin-12, and SU-5416 (a VEGF inhibitor). Other potential targets for KS therapies include KSHV/HHV-8, sex hormones, and the process of cellular differentiation.
Each of these targets serves as the rationale for current ongoing pathogenesis-based clinical trials. Virtually all patients with KS can derive benefit from the many approved and investigational agents developed through years of collaborative translational and clinical research.
1. Ensoli B, Gendelman R, Markham P, et al: Synergy between basic fibroblast growth factor and HIV-1 tat protein in induction of Kaposis sarcoma. Nature 371:674-680, 1994.
2. Aoki Y, Jaffe ES, Chang Y, et al: Angiogenesis and hematopoiesis induced by Kaposis sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93:4034-4043, 1999.
3. Mesri EA: Inflammatory reactivation and angiogenicity of Kaposis sarcoma-associated herpesvirus/HHV8: A missing link in the pathogenesis of acquired immunodeficiency syndrome-associated Kaposis sarcoma. Blood 93:4031-4033, 1999.
4. Dezube BJ: AIDS-related Kaposis sarcoma: Clinical features, staging, and treatment. Semin Oncol vol 27, 2000 (in press).
5. Bower M, Fox P, Fife K, et al: HAART prolongs time-to-treatment failure in Kaposis sarcoma: Programs and Abstracts of the 3rd National AIDS Malignancy Conference, Bethesda, MD (abstract). J Acquir Immune Defic Syndr Hum Retrovirol 21(58):a24, 1999.
6. Walmsley S, Northfelt DW, Melosky B, et al: Treatment of AIDS-related cutaneous Kaposis sarcoma with topical alitretinoin (9-cis-retinoic) gel. J Acquir Immune Defic Syndr Hum Retrovirol 22:235-246, 1999.
7. Shepherd FA, Beaulieu R, Gelmon K, et al: Prospective, randomized trial of two dose levels of interferon alfa with zidovudine for the treatment of Kaposis sarcoma associated with human immunodeficiency virus infection: A Canadian HIV Clinical Trials Network Study. J Clin Oncol 16:1736-1742, 1998.
8. Gill PS, Wernz J, Scadden DT, et al: Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposis sarcoma. J Clin Oncol 14:2353-2364, 1996.
9. Northfelt DW, Dezube BJ, Thommes JA, et al: Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposis sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol 16:2445-2451, 1998.
10. Gill PS, Tulpule A, Espina BM, et al: Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposis sarcoma. J Clin Oncol 17:1876-1883, 1999.
11. Welles L, Saville MW, Lietzau J, et al: Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposis sarcoma. J Clin Oncol 16:1112-1121, 1998.
12. Tupule A, Scadden DT, Espina BM, et al: Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposis sarcoma. J Clin Oncol 18:716-723, 2000.
13. Dezube BJ, Von Roenn JH, Holden-Wiltse J, et al: Fumagillin analog in the treatment of Kaposis sarcoma: A phase I AIDS Clinical Trial Group study. J Clin Oncol 16:1444-1449, 1998.
14. Little R, Welles L, Wyvill K, et al: Preliminary results of a phase II study of oral thalidomide in patients with AIDS-related Kaposis sarcoma: Programs and Abstracts of the 2nd AIDS Malignancy Conference, Bethesda, Md (abstract). J Acquir Immune Defic Syndr Hum Retrovirol 17(18):a16, 1998.
15. Cianfrocca M, Cooley TP, Lee J, et al: Angiogenesis inhibitor col-3 in the treatment of HIV-related Kaposis sarcomaA phase I AIDS Malignancy Consortium study: Programs and Abstracts of the 4th National AIDS Malignancy Conference, Bethesda, Md. J Acquir Immune Defic Syndr Hum Retrovirol 2000 (in press).
16. Pluda JM, Wyvill K, Little R: Administration of interleukin-12 to patients with AIDS-associated Kaposis sarcomaPreliminary results of a pilot study: Programs and Abstracts of the 3rd National AIDS Malignancy Conference, Bethesda, Md (abstract). J Acquir Immune Defic Syndr Hum Retrovirol 21(78):a29, 1999.