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
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.
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