Kaposis sarcoma (KS) is an AIDS-defining neoplasm characterized by the development of lesions that histologically consist of proliferating spindle cells, vascular channels, and inflammatory cells. The typical early presentation consists of painless pink, red, or purple macules or nodules on the skin surface or in the oral cavity. Although the presence of a few skin lesions is not life-threatening, even limited cutaneous KS can have an enormous psychosocial impact, particularly when the lesions occur on exposed areas.
Kaposis sarcoma can disseminate widely in the skin and also involve visceral organs, especially in the gastrointestinal tract and lungs. In the latter case, KS can become life-threatening.
The epidemiology of KS in HIV-infected individuals has long suggested that a transmissible infectious cofactor may be involved in the development of the disease. Current evidence suggests that the recently discovered KS herpesvirus (KSHV) (human herpesvirus type 8 [HHV-8]) may trigger the development of KS lesions.
Among the potential treatments for KS are interferon-alfa (Intron A, Roferon-A), radiation therapy, and various systemic and intralesional chemotherapeutic agents. Antiviral therapies directed at both HIV and HHV-8 are also receiving increasing attention as potential treatments. At present, however, no antiherpesvirus drugs have conclusively demonstrated activity in the treatment of established KS. Indeed, although many agents have been convincingly shown to induce regression of established KS, it remains an incurable disease that, in most patients, can be palliated but not eliminated with currently existing therapies. The therapeutic options for KS need to be viewed in this context.
Decisions regarding the treatment of KS vary with the clinical presentation. However, factors related to the underlying HIV infection may play as important a role in treatment decisions as the volume and location of the tumor itself.
For the purposes of this discussion, we defined limited cutaneous KS as fewer than 10 skin lesions without oral or visceral involvement or tumor-associated edema. Although limited cutaneous KS is not directly life-threatening, it may have an adverse effect on quality of life. In the presence of lesions on exposed areas of the skin, patients are often emotionally devastated and may become socially isolated.
Liquid Nitrogen Cryotherapy
In reviewing some of the local approaches to control individual KS lesions, Dr. Alvin E. Friedman-Kien noted that, as a rule, he favors an approach that begins with local, noninvasive methods in patients with limited disease and progresses to systemic therapy only when local therapy fails. His usual initial approach is liquid nitrogen cryotherapy, which causes a local blister; a scab then forms and eventually sloughs.
In fair-skinned individuals, healing often occurs without significant scarring or discoloration. In those with more pigmented skin (such as Latino or African-American individuals), however, cryotherapy may produce hypopigmentation or hyperpigmentation.
Liquid nitrogen cryotherapy may be best for fairly small patch- or plaque-stage lesions. For thicker, nodular lesions, on the other hand, liquid nitrogen may diminish the size of a lesion but may not make it disappear.
Intralesional injection of the anti- neoplastic agent vinblastine tends to induce a more severe local inflammatory process than does liquid nitrogen, and is associated with significant pain. Moreover, the intense inflammatory process often leads to residual hyperpigmentation at the treatment site. This method may produce acceptable cosmetic results in fair-skinned individuals, however, and may be more effective than cryotherapy for thicker or more nodular lesions.
Intralesional Human Chorionic Gonadotropin
Gill and colleagues have demonstrated that intralesional injection of human chorionic gonadotropin (hCG) induces local KS regression. Dr. Friedman-Kien observed, however, that not all hCG preparations are effective, and that even different lots from the same manufacturer are not equally effective in inducing local KS regression.
Dr. Keith J. Stelzer discussed the merits of radiation therapy for limited, cosmetically disturbing KS lesions. Dr. Stelzer has observed the best cosmetic results following electron-beam radiation with a regimen that delivers a relatively low dose per fraction, titrated to a relatively high total dose. Response does not appear to depend on the size of the lesion.
In a randomized trial, Dr. Stelzers group compared three radiation regimens: 800 cGy in 1 fraction, 2,000 cGy in 10 fractions over 2 weeks, and 4,000 cGy in 20 fractions over 4 weeks (Table 1). Each regimen successfully reduced the palpable lesion, but only the 4,000-cGy regimen caused the disappearance of residual pigmentation in a substantial proportion (45%) of patients.
In addition, the duration of response was significantly better for lesions treated with the 4,000-cGy regimen (approximately 10 months) than with the 2,000- and 800-cGy regimens (6 and 3 months, respectively). Dr. Stelzer noted, however, that 4,000 cGy in 20 fractions may be more likely than the other regimens to be associated with later radiation recall reactions in the event that subsequent systemic chemotherapy is required.. Radiation recall reactions are signs of acute radiation toxicity in previously irradiated areas.
Summarizing his approach to the treatment of individual cutaneous lesions, Dr. Stelzer noted that if cosmetic improvement is the primary aim, a 4,000-cGy regimen over a protracted course is optimal. However, for lesions that are of lesser cosmetic importance (such as those on unexposed body parts) or for treatment of lesions in very ill or symptomatic patients with limited mobility or a short overall life expectancy, one of the more rapid fractionation regimens may produce acceptable local results and may be more compatible with immediate quality-of-life issues than a regimen that requires repeated treatment visits over many weeks. In addition, in patients who are likely to require subsequent systemic chemotherapy for control of disseminated KS, the more rapid fractionation (lower total dose) regimens may offer a lower risk of recall reactions.
Clinicians may question whether radiation therapy increases the risk of a secondary malignancy in a young individual, who, because of advances in HIV treatment, may now have a long survival. Although Dr. Stelzer commented that the overall risk is low (about 0.5% after 20 years in patients without HIV infection), it is not clear whether chronically immunosuppressed patients may be at higher risk.
Observing that young HIV-seropositive patients with basal cell and squamous cell carcinomas in sun-exposed areas are being seen with some frequency in his dermatologic practice, Dr. Friedman-Kien questioned whether radiation therapy to facial KS may also predispose such patients to earlier skin cancers. The data are not yet sufficient to answer this question, however.
There was general consensus that systemic chemotherapy has no role in the management of KS that is characterized by only a few asymptomatic cutaneous lesions, whether on the face or in other locations. Dr. Susan Krown discussed the potential role of systemic interferon-alfa in the treatment of limited, localized KS. She noted that KS can be thought of as a systemic disease that may present locally but that eventually progresses in most patients. Therefore, systemically administered agents that may induce regression of established lesions without severe systemic side effects and that may also prevent the development of new lesions may represent a rational approach in some patients with limited, relatively asymptomatic KS.
Echoing support for this approach, Dr. Constance A. Benson likened the rationale for systemic treatment of early KS to that for preemptive antiviral therapy for activated cytomegalovirus (CMV) infection prior to the development of end-organ disease. She noted that KS, like CMV, may be viewed as a systemic viral infection. Although Dr. Friedman-Kien concurred with the concept of KS as a systemic, HHV-8-related disease, he questioned whether any data support interferons efficacy in preventing the development of new KS lesions and expressed concerns about the toxicity of interferon treatment.
Prevention of the development of new KS lesions by interferon can only be inferred from the long duration of response or stable disease. The roundtable participants who use interferon regularly believe that, at currently used doses (1 to 10 million IU/day), interferon is fairly well tolerated, despite the fact that the higher doses used in early trials of interferon were often associated with significant constitutional, hematopoietic, and hepatic toxicity.
The rationale for interferon-alfa therapy is further supported by its inhibitory effects on HIV and on some of the growth factors associated with KS progression.[8-10] Compared with response rates for other types of local or systemic therapy, lower overall response rates have been reported for interferon-alfa, whether used as high-dose monotherapy or, as is more prevalent today, at lower doses in combination with antiretroviral agents.[11-13] When response to interferon-alfa is achieved, however, it is often quite durable, and in some studies, has been reported to persist for a median of well over a year.
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