In the early 1980s, KS was one of the major initial manifestations
of human immunodeficiency virus (HIV) disease in San Francisco.
Patients presented with disfiguring lesions in sites other than
the lower extremities, where the lesions of the classic variant
of KS were most commonly seen. Extensive facial lesions clearly
marked patients with AIDS-related KS. Visceral disease was found
in the lymph nodes, gastrointestinal tract, and pulmonary parenchyma.
It appeared that patients with widespread, rapidly progressive,
or visceral KS lesions had a poorer prognosis than those with
lesions confined to mucocutaneous or lymph node involvement.
The lack of a good staging system presented a problem. A recommended
staging system, proposed by Krown et al , was never widely
adopted. It used the tumor, immune status, and systemic illness
(TIS) criteria. Under this system, "good-risk" patients
included those with disease confined to the skin and/or lymph
nodes or those with minimal oral disease. "Poor-risk"
patients included those with more extensive oral disease, gastrointestinal
lesions, other visceral lesions, or tumor-associated edema or
Immune status remains the most important predictor of response
to therapy for KS: patients with more than 200 CD4 cells/mm³
are likely to do better than those with more serious immune disruption.
However, this may simply be an illustration of a well-known precept
in oncology: Patients with a good performance status tend to respond
better to treatment than patients with a poor performance status.
In our earliest attempts to standardize treatment efforts when
first confronted with KS in 1981, a simple two-by-two grid was
developed. The four variables were localized vs widespread disease
and indolent vs aggressive disease. Indolent disease, regardless
of whether it was localized or widespread, was treated with radiotherapy.
Aggressive, localized disease was also treated with radiotherapy.
Aggressive, widespread disease was treated with chemotherapeutic
regimens based on those used in the African or classic KS variants.
The nonexperimental treatment regimens currently used (
have not changed significantly since then.
One important lesson we learned early in the epidemic, after some
disastrous results with early chemotherapy, was that observation
alone could also be considered a good option in many patients
with minimal disease. We discovered that we did not need to attack
each individual lesion. We also learned that radiation therapy
was useful in many cases.
In the absence of an accepted staging system, it is difficult
to compare responses to treatment. Certainly, if a patient's lesions
increase in number and size after treatment, it is easy to classify
that as progressive disease. If lesions do not change much, the
category of stable disease or minor response seems correct. Eradication
of all previously detectable disease, including lesions on the
skin, in the mouth, or in the lymph nodes or visceral organs,
indicates a complete response. However, KS has some unusual features
that complicate grading of response.
Figure 1 shows a patient with a KS lesion on the
eyelid before and after treatment with interferon-alfa. This is
a fairly common phenomenon: The raised violaceous lesion flattens
out and becomes hyperpigmented, a condition described as a hemosiderin
tattoo. Although a biopsy specimen does not show the histopathologic
indications associated with active KS, the lesion is still visible.
Should this be considered a partial response or a complete response?
Another such example is the situation seen in patients with KS-related
edema. This can include extensive periorbital involvement to the
point where the patient is unable to open his or her eyes. A course
of radiation or chemotherapy may often dramatically improve the
swelling, but the KS lesions are still present. The complete resolution
of the edema benefits the patient more than grading of partial
response would suggest.
For patients with one or a few isolated KS lesions, commonly used
local interventions include spot radiation or laser therapy, intralesional
chemotherapy, or cryotherapy. Cryotherapy (liquid nitrogen) is
used by some clinicians for treating patients with localized KS
lesions. However, patients may develop a depressed brown lesion
following cryotherapy, which many find less cosmetically acceptable
than the initial KS lesion.
KS-associated lymphedema of the extremities often responds to
radiation treatment delivered in a single course or to systemic
chemotherapy. Patients who want facial lesions eradicated for
cosmetic purposes are also candidates for radiation therapy. Furthermore,
radiation therapy has been of use in patients with pulmonary KS
Pulmonary KS is usually seen in association with extensive cutaneous
disease. In our early experience, two thirds of patients had a
concomitant opportunistic infection at the time of diagnosis of
pulmonary KS . The life expectancy of an untreated patient
diagnosed with pulmonary KS was approximately 6 to 8 weeks, compared
with an 18-month life expectancy for patients without pulmonary
KS. Pulmonary KS is one of the few pulmonary problems in HIV disease
that leads to the development of pleural effusion, in addition
to the common interstitial reticulonodular infiltrates. Patients
with pulmonary KS are also likely to suffer cough and hemoptysis.
Bleeding lesions that can be localized by bronchoscopy may respond
to radiation therapy.
Although radiation is localized therapy, KS associated with HIV
disease is a systemic disease, and chemotherapy is often more
appropriate. Pulmonary KS and rapidly progressive disease are
best managed with systemic chemotherapy. Chemotherapeutic agents
in wide use include the vinca alkaloids, bleomycin (Blenoxane),
doxorubicin, and etoposide (VP-16 [VePesid]).
Some of the earliest work with chemotherapy for KS was performed
by Laubenstein et al . In their original schema, patients with
more indolent disease were treated with intravenous etoposide,
whereas patients with more aggressive disease were treated with
Adriamycin, bleomycin, and vinblastine (ABV), a combination that
had proved useful in African patients with KS. It was soon observed,
however, that patients treated with the more aggressive combination
therapy tended to develop more opportunistic infections than patients
who received the 3-day, single-agent etoposide infusion. This
led us to suspect that perhaps we were contributing to the immune
compromise in some patients by using overly aggressive combination
chemotherapy. This is a problematic conclusion, however, because
the patients who were chosen to receive the combination therapy
were those with severe disease, who may have been predisposed
to the rapid development of opportunistic infections and may have
had a poor prognosis regardless of the intervention.
Ultimately, in San Francisco, we chose a regimen of vinca alkaloids,
alternating vincristine and vinblastine weekly . This regimen
alternates the periods of myelotoxicity from vinblastine and neurotoxicity
from vincristine, apparently delaying the appearance of these
adverse effects. With this approach, we have been able to achieve
a response rate of 33% (primarily partial responses) with minimal
Very early in the epidemic, before we knew that KS was related
to HIV disease, we knew that we were dealing with an immune deficiency
and so began to test biologic response modifiers as a way of supporting
immune function. Interferon-alfa remains the sole biologic response
modifier/antiviral agent that has demonstrated activity for AIDS-associated
KS. Questions about dosing and schedules persist, despite a decade
of widespread use. Recent studies suggest that there may be a
synergistic anti-KS effect in combining interferon-a with zidovudine
(Retrovir) . Interferon has antiangiogenic properties as well,
which may contribute to its anti-KS effect. The response rates
reported with interferon-alfa have ranged from 24% to 46%, similar
to the rates observed in patients treated with alternating weekly
doses of vincristine and vinblastine. One problem, however, is
that the toxicities associated with interferon-alfa are greater
than those seen with the alternating vinca chemotherapeutic regimen.
Other biologic response modifiers have not been promising. Interferon-gamma
produced no response in our patients with KS. Isotretinoin plus
interferon was similarly ineffective .
Antiviral agents alone appear to have no impact on KS lesions.
The first clinical trial performed by the AIDS Clinical Trial
Group (ACTG)--ACTG 001--was a comparison of zidovudine and placebo
in patients with AIDS-related KS. No apparent impact on the KS
lesions was seen in either patient group, although the results
of this trial have never been published.
Zidovudine in combination with interferon-alfa appeared to be
more effective against KS lesions than either agent used alone.
The effect was seen mainly in patients with better overall status
at the onset of therapy. However, the response rate for the combination
was as high as 30% in patients with CD4 counts of less than 200
cells/mm³, compared with a response rate of less than 10%
for interferon-alfa used alone in this subset of patients. Adding
interferon-alfa to an antiretroviral agent may be helpful, but
asymptomatic patients should be warned that the side effects of
interferon, particularly the flu-like syndrome, may be daunting.
Chemotherapeutic agents should be used with caution in patients
who are also receiving antiretroviral therapy, because both regimens
may be myelosuppressive. In addition, vincristine should be used
with caution in patients who are also receiving dideoxynucleosides,
because both are associated with peripheral neuropathy. A related
caveat pertains to combining anti-KS regimens with treatment of
cytomegalovirus (CMV) disease. Ganciclovir (Cytovene) is the first-line
agent for treatment of CMV, and it is often associated with neutropenia.
This causes problems if a doxorubicin-containing anti-KS regimen
is then added. Some of these difficulties can be ameliorated occasionally
by using colony-stimulating factors, but the cost of this approach
can soon become prohibitive.
Because there is still no approach that clearly extends survival
from AIDS-related KS, the decision to initiate treatment must
be made on other grounds. Asymptomatic patients with minimal KS
and relatively high CD4 counts probably should be examined and
have their CD4 levels checked every 3 to 6 months.
The initiation of therapy for palliation and cosmesis is indicated
in a number of situations. Painful or bulky lesions, lesions causing
restricted mobility, and disfiguring lesions may be treated with
local or systemic interventions. Generally, KS lesions are not
painful, but some patients do have painful lesions, especially
on the soles of their feet or in areas that span joints. Lesions
that ulcerate and tend to become infected may benefit from radiation
therapy. Extensive intraoral or pharyngeal lesions, particularly
in the posterior pharynx, can be obstructive and should also be
treated with radiation or laser therapy. In these cases, laser
therapy may be preferred because it avoids the mucositis that
often follows standard radiation therapy for intraoral lesions.
The severity of radiation-induced mucositis often seems greater
than expected from the same amount of radiation delivered to a
patient who does not have HIV disease.
Initiation of treatment of extensive, rapidly progressive, cutaneous
disease requires thoughtful assessment; the risks and costs of
treatment should be weighed against the potential benefits. As
an alternative to embarking on a course of conventional chemotherapy
that probably will be lifelong, patients may be offered the option
of participating in protocols evaluating new agents, if available.
Although treatment of pulmonary KS may frequently require emergency
intervention in previously asymptomatic patients, the decision
of when to begin treatment again becomes more problematic.
Survival for patients with AIDS-related KS in San Francisco was
21.5 months for those diagnosed from 1981 to 1983 and 16.4 months
for those diagnosed from 1984 through 1987. During this period,
the survival of patients initially diagnosed with Pneumocystis
carinii pneumonia improved, whereas survival of those initially
diagnosed with KS worsened. Aggressive therapeutic interventions
have not necessarily produced the desired outcome.
Prolongation of survival should be a goal of newer KS interventions.
Ongoing work with improved delivery forms, inhibitors of viral
proteins, and antiangiogenetic agents and similar new compounds
must all be directed toward this end. In conventional oncologic
approaches, an experimental therapy that improves disease-free
survival but not overall survival, compared with the current standard
therapy, is generally discarded. Quality of life is important,
but, ultimately, we need to return our focus once again to survival.
1. Krown SE, Metroka C, Wernz JC, et al: Kaposi's sarcoma in the
acquired immune deficiency syndrome: A proposal for a uniform
evaluation, response, and staging criteria. J Clin Oncol 7:1201-1207,
2. Kaplan LD, Abrams DI, Volberding PA: Treatment of Kaposi's
sarcoma in acquired immunodeficiency syndrome with an alternating
vincristine-vinblastine regimen. Cancer Treat Rep 70:1121-1122,
3. Laubenstein LJ, Krigel RL, Odajnyk CM, et al: Treatment of
epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin,
bleomycin, and vinblastine. J Clin Oncol 2:1115-1120, 1984.
4. Kaplan LD, Hopewell PC, Jaffe H, et al: Kaposi's sarcoma involving
the lung in patients with the acquired immunodeficiency syndrome.
J Acquir Immune Defic Syndr 1:23-30, 1988.
5. Krown SE, Gold JWM, Niedzwiecki D, et al: Interferon-a with
zidovudine: Safety, tolerance, and clinical and virologic effects
in patients with Kaposi's sarcoma associated with the acquired
immunodeficiency syndrome (AIDS). Ann Intern Med 112:812-821,
6. Rosenthal E, Pesce A, Vinti H, et al: Isotretinoin plus interferon
alpha-2a in AIDS-related Kaposi's sarcoma (abstract PO-B12-1607).
Proceedings of the IX International Conference on AIDS. Berlin,
Germany, June 6-11, 1993.