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The Challenge of Designing Clinical Trials for AIDS-Related Kaposi’s Sarcoma

The Challenge of Designing Clinical Trials for AIDS-Related Kaposi’s Sarcoma

ABSTRACT: Kaposi’s sarcoma (KS) is a frequent cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. Several characteristics of KS pose challenges for the conduct of clinical trials. Kaposi’s sarcoma patients often have multiple, irregularly shaped lesions, making accurate assessment of tumor size difficult. The lesions may have varying degrees of nodularity. Involvement of the lung or other visceral organs often consists of multiple irregular lesions. Conventional oncology staging systems cannot be applied effectively to KS because there is no clear primary lesion. Kaposi’s sarcoma is affected by the status of the underlying HIV infection, and there are reports of KS lesions regressing in response to effective antiretroviral therapy. A system for staging and response assessment in KS, developed by the AIDS Clinical Trials Group (ACTG), has proven to be a useful tool for the conduct of trials in KS. A newer system that also attempts to assess patient benefit in response to therapy is now being developed by the National Cancer Institute, FDA, and AIDS Malignancy Consortium. These tools, as well as careful methodology in the conduct of clinical trials, should help optimize the clinical development and evaluation of new therapies for KS.[ONCOLOGY 12(6):871-884, 1998]

The occurrence, in 1981, of a number of cases of Kaposi’s
sarcoma (KS) in homosexual men in the large coastal cities of the
United States was one of the earliest harbingers of the AIDS
pandemic. Since then, KS has continued to be the most common tumor in
individuals infected with the human immunodeficiency virus
(HIV).[1-4] First described in the 1870s, a classic form of KS is a
relatively infrequent and indolent tumor, occurring predominantly in
elderly men in the Mediterranean region.[5] More recently, in parts
of Africa, KS was noted to occur rather commonly.

African KS patients often have a more aggressive disease course than
do patients with the classic form.[6] Observations in the 1970s
revealed that a subset of patients who had undergone renal
transplantation developed KS.[7,8] However, in the United States, the
AIDS epidemic transformed this disease from a rare condition to a
relatively common medical problem causing substantial morbidity and
mortality. Indeed, the disfigurement resulting from KS is a
constantly visible reminder of the stigma of AIDS. Kaposi’s
sarcoma often causes substantial pain and dysfunction, and is one of
the most distressing aspects of HIV infection for many afflicted patients.

Pathogenesis of Kaposi’s Sarcoma

During the first few years of the AIDS epidemic, relatively little
progress was made toward understanding the pathogenesis of KS. The
effort to understand its pathogenesis, however, was boosted in 1988
by Nakamura, Gallo, and co-workers, who discovered that spindle cells
from KS tumors could be cultured in a conditioned media.[9]
Subsequent studies by Ensoli and other investigators demonstrated
that KS-derived spindle cells produced and responded to a variety of
growth factors (including angiogenic factors).[10,11]

One epidemiologic finding that still puzzled investigators, however,
was that HIV-infected men with a history of sex with men had a
substantially higher incidence of KS than those with other risk
factors.[12] This finding suggested that a second, sexually
transmitted agent caused KS, although, for a number of years, this
agent remained elusive.

In 1994, Moore, Chang, and co-workers reported finding herpes-like
DNA sequences in KS lesions. Subsequent studies revealed that this
represented a new herpesvirus, now termed Kaposi’s
sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8
(HHV-8).[13,14] Essentially, all patients with KS, and a varying
subset of other individuals, are infected with this virus.

Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8
represents an important if not essential factor in the pathogenesis
of KS.[15-21] It has been found to encode for a number of viral
mimics of human cytokines (such as interleukin-6 [IL-6]) as well as
other factors, such as macrophage inflammatory protein chemokines,
that can potentially stimulate spindle cells and angiogenesis.[22,23]
This line of investigation has already provided important insights
into the pathogenesis of KS, and it could result in important leads
for studies of pathogenesis-based therapies. Indeed, at least two
clinical trials, one testing foscarnet (Foscavir) by Dr. Alfred
Friedman-Kien at New York University Medical Center, and the other by
our group at the National Cancer Institute (NCI) focusing on
cidofovir (Vistide), have been initiated to test such hypotheses.

An important feature of KS lesions is that they are quite vascular,
often with a characteristic purplish hue. Spindle cells present in KS
lesions have been found to produce and respond to a number of
angiogenic factors,[10,24] making this disease a possible and
attractive target for antiangiogenic approaches.[25] The current
research effort to identify novel inhibitors of angiogenesis could
benefit therapy for KS.

Certain features of KS facilitate the assessment of treatment
responses in this disease, not the least of which is the fact that
much of the tumor is visible on the skin. At the same time, however,
quantifying treatment response in KS patients can be quite difficult.
Indeed, this disease poses unique challenges with regard to trial
design and execution. These challenges and some of the approaches
that have been used or are being explored to meet them will be
addressed below.

Current Treatment Modalities

Current evidence suggests that, at some stages, the pathogenesis of
KS involves hyperproliferation induced by various viral and cellular
factors. Recent studies reported that late-stage KS may be a clonal
malignancy, but these reports are not definitive.[26,27] There is no
evidence that any therapy for KS can be curative, or that complete
responses necessarily yield prolonged disease-free intervals.
Although there are data suggesting that effective treatment of
advanced visceral disease may prolong survival, no randomized trials
have been conducted to demonstrate that this is, in fact, the case.

At present, the principal goal of therapy is to palliate disease that
is disfiguring, painful, or interferes with function.[28,29] Local
measures for patients with few such lesions include surgical
excision, cryotherapy, laser therapy, direct instillation of
chemotherapeutic agents into the lesions, or radiotherapy.[30,31]
Interferon-alfa (Intron A, Roferon-A) has also demonstrated some
benefit in certain patients with cutaneous disease and relatively
preserved immune function.[32-34]

Chemotherapy

Various forms of cytotoxic chemotherapy have been administered to
patients with more advanced, widespread disease. Some agents with
demonstrated activity include vincristine, vinblastine, bleomycin
(Blenoxane), etoposide, and the anthracyclines.[28,29]

In separate studies, Laubenstein and Gill showed that the combination
of Adriamycin, bleomycin, and vincristine or vinblastine (ABV) could
yield response rates as high as 84% to 88%.[35,36] Until recently,
such regimens comprised standard therapy for patients with advanced
disease. However, the ABV regimens, as originally described, were
rather toxic. Subsequent regimens involving lower doses of
doxorubicin and vincristine were bet-ter tolerated but were
associated with lower response rates of about 28% to 60%.[37,38]

Newer Therapies

During the past few years, two single-agent liposomal anthracycline
preparations have been approved by the FDA: pegylated liposomal
doxorubicin (Doxil) and liposomal daunorubicin (DaunoXome).[39-43] In
randomized, controlled trials, liposomal anthracyclines had better
toxicity profiles and demonstrated equivalent or slightly better
response rates, time-to-treatment failure, and survival than those
achieved with ABV.[38,44] A confounding factor in these evaluations,
however, was the widely variable response rates to ABV reported in
other trials.

Recently, paclitaxel (Taxol), as a single agent, was found to induce
a high percentage of responses even in patients who did not respond
to treatment with anthracyclines.[45,46] Paclitaxel is now approved
for use in patients with refractory disease. However, the cumulative
toxicity, particularly myelosuppression, associated with any of these
chemotherapeutic regimens remains a serious concern.

There is now substantial interest in developing novel therapies aimed
at blocking discrete steps in the pathogenesis of KS. However, as
noted above, the evaluation of such therapies presents a number of
challenges. Consideration of these challenges in the planning and
conduct of clinical trials in KS can help minimize them and optimize
the accurate and efficient clinical evaluation of novel therapies.

Assessment of Tumor Responses

One of the principal factors complicating the performance of
therapeutic trials in KS is the difficulty of assessing response to
therapy.[47,48] For most tumors, a partial response is defined as a
50% reduction in bidimensional tumor measurements sustained for at
least 4 weeks, without the growth of other lesions or the appearance
of new sites of disease. A complete response is defined as the
disappearance of all disease (often with a confirming negative
biopsy) for at least 4 weeks. However, such criteria often cannot be
applied to KS patients. It is not unusual for KS patients to have
more than 100 separate skin lesions, many with exceedingly irregular
borders. Thus, just counting the total number of lesions in such
patients can be difficult, not to mention accurately assessing their
size (Figure 1).

Also, even when therapy is effective, KS lesions often become less
nodular without shrinking in size. If they do shrink, larger lesions
may break up into multiple smaller ones, thereby leading to an even
higher number of total lesions. Bleeding within lesions sometimes
produces a yellow "halo" of hemosiderin breakdown products
or perilesion edema, which further confound accurate size
determinations. Even if tumor cells are eliminated, the skin may be
left with a pigmented "tattoo" that can be hard to
differentiate from a KS lesion unless a biopsy is performed. Finally,
unlike many solid tumors that can be well-documented
radiographically, the assessment of certain aspects of cutaneous KS
(eg, nodularity) is difficult by any means other than physical examination.

Some of these problems were candidly articulated by Volberding et al
in their 1985 paper on the administration of vinblastine therapy to
patients with KS.[49] These authors noted: "The precise
definition of a clinical response is a major difficulty in describing
patients with syndrome-related Kaposi’s sarcoma. Whereas a 50%
decrease in the area or number of measured lesions is readily
acceptable as a partial response, allowance must be made for changes
in tumor nodularity, pigmentation, or both. For this reason, a
subjective component was allowed in our definition of a partial
response. This subjective assessment may obviously introduce a bias
in assessing response rates, but it seems to be an unavoidable area
of difficulty in all clinical trials in this disease."

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