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(Drug information 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(Drug information on vinblastine), bleomycin(Drug information on bleomycin) (Blenoxane), etoposide(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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."
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
