Treatment
The treatment of AIDS-related KS requires an individualized approach, based on the extent and location of the lesions, the wishes and treatment needs of the patient, the presence of tumor-associated symptoms (eg, pain, bleeding, edema), the presence of other AIDS-associated illnesses, and the patient's tolerance of medications. Nevertheless, the following general statements can be made:
• Patients with widespread symptomatic disease or life-threatening visceral involvement require prompt, cytoreductive treatment with one or more chemotherapeutic drugs.
• Even in the absence of symptomatic visceral disease, the disfigurement and emotional distress of having these visible reminders of AIDS may mandate treatment for psychological reasons.
• For patients with asymptomatic indolent lesions, aggressive treatment is not mandatory, but these patients may derive substantial benefits from local treatment or investigational therapies that are directed against HIV or HHV-8 or that may interrupt the pathogenesis of KS and/or restore immune competence.
• Given the heterogeneity and unpredictable growth of this tumor, it is often difficult to gauge objective responses. The peculiarities of this multicentric tumor make some subjectivity almost inevitable in gauging treatment responses.
Staging classification for AIDS-related KSTreatment options
With the introduction of protease inhibitors and non-nucleoside reverse transcriptase inhibitors for HIV infection, cases of KS regression with combination antiretroviral therapy have been reported. Because KS seems to be influenced by the state of HIV infection, it is particularly important for patients with AIDS-related KS to have their HIV infection under optimal control. There is no one best anti-HIV regimen, and oncologists should consult with infectious disease specialists familiar with the treatment of HIV infection. Occasionally, a flare in KS tumor progression may be seen when antiretroviral therapy is initiated. Eventually, even with good anti-HIV therapy, some patients with AIDS-related KS will require some form of treatment for their tumor.
Local treatments, including cryotherapy, topical retinoic acid, intralesional chemotherapy and other sclerosing agents, and local irradiation, can produce good local control of tumors. Interferon-alfa (Intron A, Roferon-A) and cytotoxic chemotherapy are effective systemic treatments for patients with more extensive or symptomatic disease. Single-agent or combination chemotherapy is effective in controlling tumors, even in patients with extensive disease and severe immune deficiencies (Table 2). The use of hematopoietic growth factors has facilitated the administration of myelosuppressive treatments, such as interferon-alfa and chemotherapy.
Interferon-alfa. The first treatment licensed for AIDS-related KS was recombinant interferon-alfa. Tumor responses have been seen in approximately 30% of patients treated with subcutaneous (SC) interferon given daily or three times weekly. Current practice is to administer SC interferon-alfa three times weekly. Unmaintained response durations in trials of interferon-alfa monotherapy have ranged from 12 to 24 months in complete responders and from 8 to 12 months in partial responders.
• Duration of therapy—The optimal duration of interferon-alfa treatment is unknown; however, many patients relapse within a few months after discontinuation of therapy. Reinduction of second responses with interferon-alfa after relapse may be unreliable and often is of short duration. It is therefore generally recommended that treatment with interferon-alfa be continued for as long as drug tolerance and tumor responses continue.
• Dose—The optimal dose of interferon-alfa also has not been clearly established. Interferon-alfa is generally administered at either 3 or 5 million units SC three times weekly together with antiretroviral therapy.
• Major dose-limiting toxicities—Major dose-limiting toxicities of interferon-alfa include fever, chills, rigor, and other flu-like symptoms. They are dose-related and often are observed at the initiation of treatment but lessen somewhat with continued use. Neutropenia, elevation of transaminase levels, depression, peripheral neuropathy, and other neuropsychiatric abnormalities may also occur.
• Other side effects—Other side effects include headaches, cognitive impairments, paresthesias, and mild thrombocytopenia. Because the subjective side effects of interferon-alfa are also common in HIV-related or other conditions, care must be taken to avoid ascribing all of these symptoms to drug toxicity and overlooking treatable infections and other conditions.
Sidebar: A phase II study of bevacizumab(Drug information on bevacizumab) in patients with HIV-associated KS who were receiving antiretroviral therapy showed that it was tolerated and had activity in a subset of patients (overall response rate = 31%) (Uldrick TS et al: J Clin Oncol 30:1476-1483, 2012).
Retinoids. Alitretinoin gel 0.1% (9-cis-retinoic acid [Panretin]) has received approval from the US Food and Drug Administration (FDA) for the topical treatment of localized cutaneous KS. This compound inhibits the growth of KS and induces apoptosis of KS cells by binding to retinoic acid receptors on the cell surface.
Chemotherapy for AIDS-related KSPhase III clinical trials comparing alitretinoin three or four times daily with placebo gel demonstrated a 35% rate of complete and partial responses in the alitretinoin-treated patients, vs a rate of 18% in controls. The median time to response to alitretinoin was 29 to 34 days, with a median duration of response of 12 to 16 weeks. Responses were seen in both previously untreated and previously treated KS patients and were not dependent on patients' CD4 cell count.
Local cutaneous adverse reactions to alitretinoin include erythema, skin irritation, skin cracking, flaking, peeling, and desquamation. The severity of these reactions can be mitigated by less frequent dosing, thinner application, or use of topical vitamin E(Drug information on vitamin e).
Alitretinoin should be reserved for patients who do not require systemic treatment for visceral disease. However, it may be used in conjunction with other treatments for cutaneous disease.
Oral alitretinoin has been investigated in patients with AIDS-related KS, and it was found to have a 37% response rate.
Bexarotene (Targretin), an oral retinoid X receptor–selective agonist, has been studied in patients with AIDS-related KS, with an overall response rate of 33% in one study.
Chemotherapy. For patients with more widely disseminated, rapidly progressive, or symptomatic disease, systemic chemotherapy is generally warranted. Chemotherapy drugs are included in Table 2.
• Antiretroviral drugs—A total of 25 anti-HIV drugs have received FDA approval, and more are in various stages of clinical development. When evaluated by an oncologist, the majority of HIV-infected individuals will be taking some anti-HIV drugs. The interactions between cytotoxic chemotherapy and the various anti-HIV drugs have not been fully studied. Thus, oncologists treating patients with AIDS-related KS should continue to monitor them frequently for side effects. Withholding antiretroviral therapy during chemotherapy and then immediately restarting it after giving the chemotherapy drugs may avoid some toxic effects of drug interactions, especially with high-dose therapy.
• Combination regimens—The two most frequently used combination chemotherapy regimens are doxorubicin(Drug information on doxorubicin), bleomycin(Drug information on bleomycin), and vincristine (ABV) and bleomycin and vincristine (BV). These regimens were initially reported to yield tumor response rates in excess of 70% to 90%, with good palliation of symptoms, including decreased edema, decreased pain and, in patients with pulmonary KS, respiratory improvement and alleviation of obstructive symptoms. A beneficial effect of these combinations on survival has not been clearly demonstrated, however.
Early reports of a high response rate with these combination regimens have not been reproduced by later multicenter trials. A conservative response rate of 50% to 60% has been reported in more contemporary phase III trials. The discrepancy in response rates most likely stems from differences in the response criteria used.
• Liposomal anthracyclines—Liposomal anthracyclines (eg, liposomal doxorubicin [Doxil] and liposomal daunorubicin(Drug information on daunorubicin) [DaunoXome]) are also effective in inducing tumor regression in KS. Clinical trials have shown that liposomal anthracyclines as single agents can achieve a response rate equal to or better than that obtained with the ABV combination regimen. As such, the liposomal anthracyclines have become first-line chemotherapy for AIDS-related KS.
The dose-limiting toxicity is neutropenia, and many patients will require the use of granulocyte colony-stimulating factor (filgrastim [Neupogen]) after several cycles of treatment. Other common side effects include nausea, fatigue, anemia, and thrombocytopenia. A palmar-plantar syndrome, characterized by acute painful erythematous swelling of the hands and feet, has been reported with the use of liposomal doxorubicin. Once the symptoms resolved, readministration of liposomal doxorubicin did not necessarily reproduce the syndrome. Neither of the liposomal anthracyclines has been reported to depress left ventricular function.
• Paclitaxel(Drug information on paclitaxel)—Paclitaxel has been shown to produce responses in both chemotherapy-naive KS patients and patients with refractory tumors, including those refractory to liposomal anthracyclines. The dosage is typically 100 to 135 mg/m2 IV given over 3 hours every 2 to 4 weeks. This agent is widely considered the primary second-line chemotherapy for KS.
The dose-limiting toxicity is neutropenia. Other reported toxicities include anemia, stomatitis, alopecia, and fatigue. Neuropathy has not been a major problem with this low-dose approach.
• Investigational agents—Other drugs under investigation for the treatment of KS include a number of other antiangiogenesis compounds. Compounds that may affect HHV-8 gene expression (eg, valproic acid) or signal transduction pathways in KS-infected cells (eg, imatinib [Gleevec] and sunitinib [Sutent]) and a mammalian target of rapamycin inhibitor (eg, sirolimus(Drug information on sirolimus) [rapamycin]) are also in development or in early clinical testing in KS patients. Cidofovir(Drug information on cidofovir) (Vistide) does not appear to be clinically active.
Radiation therapy. Although radiation therapy can easily produce sufficient regression of KS to be useful for palliation of symptomatic disease or cosmetic improvement of disfiguring lesions, this practice has become less common because HAART has changed the natural history of AIDS. More than 90% of lesions will respond (complete responses [CRs] and partial responses [PRs]). Local radiation therapy commonly alleviates pain and bleeding, lessens edema, and shrinks obstructing lesions.
• Treatment technique—For most lesions, a single, shaped, en face x-ray beam of relatively limited penetration or low-energy electron beam (eg, 6 MeV) can be used.
For patients with more widespread tumors of the legs with edema, parallel opposed megavoltage x-ray beams and overlying bolus material are often used to provide homogeneous irradiation to the entire area.
• Dose fractionation regimens—Several dose fractionation regimens have proved effective in AIDS-related KS.
For most cutaneous lesions, a single treatment of 800 cGy will produce a short-term response. For lesions on sensitive structures (eg, penis, hands, conjunctivae), some radiation oncologists attenuate treatment to a total dose of 2,000 cGy administered in 300 cGy increments (accepting a 50% decrease in CR rate), whereas 3,000 cGy delivered over 2 weeks is more typically used for lesions in general.
Prospectively acquired data clearly demonstrate a dose-response relationship for radiation therapy in AIDS-related KS. When compared with 2,000 cGy given in 10 fractions or 800 cGy given in 1 fraction, a dose of 4,000 cGy delivered in 20 fractions over 4 weeks was significantly more effective, as measured by a higher response rate, longer duration of tumor control, and the absence of residual hyperpigmentation. However, the short- and medium-term effects of moderately intense but briefer regimens, such as 3,000 cGy in 10 fractions over 2 weeks, probably are equivalent to those of higher total dose and more protracted regimens, and the moderately intense regimens require only half the time to deliver.
For patients with an anticipated survival of less than 3 months, in whom the response duration may be of less overall importance, a single fraction of 800 cGy is likely to provide the same benefit as the more intensive regimens. In contrast, small lesions in patients who are expected to survive for at least 1 year should be treated with fractionated radiation therapy, such as 3,000 cGy in 10 fractions over 2 weeks.
