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Current Therapeutic Options for Kaposi's Sarcoma

Current Therapeutic Options for Kaposi's Sarcoma

ABSTRACT: Treatment options for patients with acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) have changed very little over the past decade. Research has been hampered by the absence of an accepted staging system for KS and the lack of a uniform definition of response. New advances in understanding the pathogenesis of KS, particularly the role of angiogenesis and growth factors, may help in the future development of additional therapies. At present, available options include radiation therapy, chemotherapy, and biologic response modifiers. Improved delivery systems for existing chemotherapeutic agents may help to target more effective doses to KS lesions and to prevent certain dose-limiting side effects. Our goal should be to recommit ourselves to finding ways to improve the survival of patients with AIDS-related KS, not just to deliver cosmetic or palliative treatments. [ONCOLOGY 10(Suppl):24-27, 1996]

Introduction

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 [1], 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 ulceration.

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 ( Table 1) 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.

Difficulty in Rating Response to Treatment

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.

For example, 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.

Current Treatment Approaches

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 lesions.

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 [2]. 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 [3]. 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.

A Better Combination

Ultimately, in San Francisco, we chose a regimen of vinca alkaloids, alternating vincristine and vinblastine weekly [4]. 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 toxicity.

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) [5]. 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 [6].

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.

When to Treat

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.

Conclusions

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.

References

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, 1989.

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, 1986.

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, 1990.

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.

 
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