Kaposi Sarcoma Treatment & Management

Updated: Apr 16, 2015
  • Author: Lewis J Rose, MD; Chief Editor: Edwin Choy, MD, PhD  more...
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Treatment

Medical Care

All therapies for Kaposi sarcoma (Kaposi's sarcoma, KS) have been markedly influenced by HAART (highly active antiretroviral therapy), which has decreased the incidence and severity of this disease. What followed is primarily related to HIV associated KS.

Antiretroviral therapy

The introduction of HAART (highly active antiretroviral therapy) has significantly reduced the incidence of Kaposi sarcoma and changed its clinical course. Optimal control of HIV infection using HAART is an integral part of successful Kaposi sarcoma therapy. It should be the first step in therapy. Response to such therapy can be anywhere from 20-80% based on stage of disease and the amount of pretreatment. [61]

However, patients with poor-risk Kaposi sarcoma rarely respond to HAART alone. In addition, a flare phenomenon may be noted associated with HAART initiation consistent with a reactivation of the immune system and associated inflammatory response. This occurs in association with increase in CD4 counts and control of HIV viremia. [62, 59] The criteria of for Kaposi sarcoma immune reactivation inflammatory syndrome (IRISI) per the AIDS Clinical Trial Group are as follows:

  1. Starting, restarting, or altering HAART regimen

  2. Increase of CD4 by greater than or equal to 50 cell, mL or a 2-fold increase in CD4 count, and decrease in HIV-1 viral load of greater than 0.5 log

  3. A more-than-expected progression of Kaposi sarcoma within 12 weeks of initiating HAART

In this clinical situation, chemotherapy may be necessary to ameliorate and reverse the disease progression.

The choice of therapy beyond HAART must be individualized and depends on the extent of disease, the presence and nature of the symptoms, the rate of disease progression, and the overall therapeutic goals. Since its inception, HAART treatment has changed the goal in Kaposi sarcoma treatment from short-term palliation to long-term remission and control.

Effective combination antiretroviral therapy usually is comprised of a combination of either a protease inhibitor(PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) with 2 nucleoside reverse transcriptase inhibitors (NRTI). Some evidence suggests a direct antitumor effect on angioproliferative Kaposi sarcoma–type lesions. Yet presently, no level 1 evidence supports this clinically. [63] No difference is apparent between PI-based and NNRTI-based antiretroviral regimens in terms of response of Kaposi sarcoma.

HAART may be tried as the sole modality used in nonvisceral disease. For visceral disease, chemotherapy may be added. For locally symptomatic disease, radiation therapy may be introduced. [7]

Local therapy

Local therapy is best suited for individuals who require palliation of locally advanced symptomatic disease (eg, radiation) or for individuals who have cosmetically unacceptable lesions. This therapy is also well suited for individuals with significant comorbidities and disease refractory to systemic modalities. It can provide better cosmesis, control bulky lesions that cause bleeding, pain or, edema, and treat extensive skin disease. Local therapy fails to halt the development of new Kaposi sarcoma lesions.

Radiation therapy is the most widely used and effective local therapy. This can palliate bleeding, pain, or unsightly lesions. This may be given in the form of low-voltage (100 kv) photons or electron-beam radiotherapy. Responses occur in 80-90% of patients. A higher cumulative dose (40 Gy) results in better local control than lower doses (8 Gy or 20 Gy). Electron beam therapy is reserved for treatment of superficial lesions. This is usually giving once weekly in 4 Gy fractions. Recurrence may be common in adjacent, untreated areas, leading some authors to recommend extended- field radiotherapy to affect a higher cure rate. Patients with HIV are more prone to develop radiation-induced mucositis as well and hyperpigmentation, desquamation, and ulceration of treated lesions. [7, 64, 65]

In patients with widespread skin involvement, extended-field electron beam radiation therapy (EBRT) has been effective in controlling the disease. This approach appears to give better long-term control than piecemeal radiation of individual lesions. This type of therapy is also given in 4-Gy fractions weekly for 6-8 weeks.

Surgical excision may be of benefit for patients with small superficial lesions. The major problem is local recurrence. The presence of clear surgical margins does not mean that Kaposi sarcoma has been permanently controlled at a given anatomical site. Local recurrence is very common. Yet over the course of many years, multiple small excisions may be a reasonable approach to achieve good control of disease.

Intralesional therapy with vinca alkaloids with low-dose vincristine or vinblastine as well as bleomycin has been used in a limited fashion primarily for the classic form of Kaposi sarcoma where localized skin disease predominates. Responses occur in 60-90% of patients with little in the way of systemic side effects with duration of 4-6 months. Dosing is done at about one-tenth the systemic dose of drug with 3- to 4-week intervals between treatment. Side effects include changes in pigmentation, swelling, blistering, ulceration, and pain on injection as well as localized but usually transient neuropathic symptoms. Because the disease recurs in other areas, its use is relatively limited. Also, systemic vinca alkaloid therapy may be equally effective and cause less localized skin toxicity.

Cryotherapy entails liquid nitrogen applied topically and may be useful for small facial lesions less than 1 cm in dimensions. Cryotherapy may cause skin hypopigmentation. It induces response in more than 85% of cases. Cryotherapy has the advantage of short duration, minimal discomfort, and ability to be used repeatedly and in combination with other forms of treatment. [7] It has limited penetration and is not ideal for large, deep lesions.

Laser and surgical therapies can be used locally. Laser photocoagulation can shrink smaller lesions and be used to palliate bleeding and pain in larger lesions. Similar to cryotherapy, it has limited application to deep, bulky lesions. Surgery is usually limited to patients with a visceral crisis such as obstruction or bleeding or for very deep, localized, painful lesions. The risk of transmission of HIV to the operating room team limits its use as well.

Topical retinoids

IL-6 is a cytokine implicated in the pathogenesis of Kaposi sarcoma. In vitro, retinoic acid down-regulates IL-6 receptor expression. A 0.1% (alitretinoin [Panretin]) gel is available commercially and may be applied topically 2-4 times daily. This agent is generally well tolerated but may cause local erythema and irritation. It induces responses in one third to one half of the patients at a time interval of 2-14 weeks after initiation of therapy. [7] Common side effects of local inflammation and depigmentation.

Palliative systemic therapy is indicated for symptomatic or life-threatening visceral disease, rapidly progressive mucocutaneous disease with pain or ulceration, and symptomatic lymphedema. In this setting, few reliable estimates of response rate with HAART alone compared with combined HAART and chemotherapy are available. One trial from South Africa comparing HAART with HAART and chemotherapy showed in the intent to treat patient’s 39% response in HAART alone compared with 66% in HAART plus chemotherapy. Also, 35% of patient in the HAART arm crossed over to require palliative chemotherapy or radiation within 12 months of randomization. These results support that chemotherapy and HAART should be used together in patients with high tumor volume (T1). [66]

No randomized prospective clinical trials compare one adjuvant therapy to the other for classic Kaposi sarcoma.

Endemic Kaposi sarcoma

What follows applies primarily to epidemic Kaposi sarcoma.

Immunomodulation with interferon-alfa has clinical activity in Kaposi sarcoma that may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties. Time to clinical response is long (ie, 4-6 mo). Therefore, it should be reserved for patients who do not require a clinical response. Interferon-alfa is most effective when the CD4 count is greater than 150-200/mm3 or when administered in conjunction with antiretroviral therapy.

Objective response rates have been seen in about 40% of patients. [67, 68] Responses are dependent on extent of disease, immunocompetence of the patient, prior treatment with chemotherapy, presence of circulating acid-labile interferon alpha, and beta-2 microglobulin levels. Immunocompetent patients have about a 4-fold increase in response compared with those with poor prognostic features.

As a rule, combination interferon and chemotherapy has been no better than chemotherapy or interferon alone. This therapy entails subcutaneous administration daily or 3 times weekly. Response may occur with low (1 million U/m2), intermediate (3-10 million U/m2), or high doses (50 million U/m2).

These agents, interferon alpha-2a and interferon alpha-2b, were approved in the pre-HAART era. Interferon-alfa has activity against HIV by suppressing mRNA translation into protein preventing the assembly of intact viral particles. Thus, it has synergy with antiretroviral drugs. High-dose monotherapy was used then because there was little else to offer. High-dose therapy is rarely used today in the era of HAART.

Because HAART alone is quite effective, lower doses of interferon-alpha are now the rule. Dose-limiting toxicity is neutropenia. Phase I trials with interferon and zidovudine have been completed with doses of interferon in the range of 4-5 million units with 200 mg of zidovudine being tolerated. [69] Trials with moderate doses of 1-10 million units combined with less myelosuppressive antiretrovirals are in progress. Toxicity is more common and severe with higher doses; symptoms may include fatigue, flulike symptoms, myalgia, arthralgia, fever, myelosuppression, and hepatotoxicity.

Interleukin-12 has shown a response rate of 71% (95% confidence interval, 48-89%) among 24 evaluable patients in a phase I/II trial. [70]

Chemotherapy is used with palliative intent. Chemotherapy is indicated for symptomatic visceral or rapidly progressive mucocutaneous disease for which a rapid response is desirable. It is used in disseminated disease not amenable to local modalities.

Initially, vincristine-, vinblastine-, and bleomycin-containing regimens were used. Etoposide and doxorubicin regimens were the second-line standards. These agents are capable of achieving rapid tumor regression and palliation of tumor-related symptoms but at a cost of myelosuppression and risk of opportunistic infections.

Combination therapy with regimens such as ABV (actinomycin D, bleomycin, and vincristine) versus single-agent therapy such as doxorubicin cause higher response rates but similar time to progression and overall survival. Prior to the availability of growth factor support, toxicity due to myelosuppression was significant. Combination chemotherapy results in about double the response rate, 45-60% versus 20-25% for single agents.

Several single cytotoxic agents are approved by the Food and Drug Administration (FDA) for AIDS-related Kaposi sarcoma and include liposomal doxorubicin (Doxil) for previously treated patients, liposomal daunorubicin (DaunoXome) for first-line use, and paclitaxel (Taxol) or oral etoposide (Vepesid) for second-line use. The liposomal technology has resulted in higher response rates with less cardiac and myelotoxicity for both liposomal doxorubicin and liposomal daunorubicin because of their more targeted nature. [1, 2, 3] Response rates of up to 80% can be seen with either of these drugs. The same is true for paclitaxel, which can be safely administered to severely immunocompromised patients refractory to other chemotherapeutic agents. [58] Response rates have been seen from 50-71% in two phase II trials for untreated patients. [71, 72]

Studies comparing liposomal preparations to combination chemotherapy regimens such as ABV have not been done in the HAART era. A small multicenter study of only 20 patients with cutaneous Kaposi sarcoma randomized between HAART alone compared with HAART and liposomal doxorubicin showed 76% for the combination compared with 20% for HAART alone. [73] Relapse rate from this approach is about 10-15% a year. Based on this and other data, liposomal doxorubicin is now considered the first line standard of care for Kaposi sarcoma.

In AIDS-associated Kaposi sarcoma, the problem has been balancing the immunosuppressive effects of chemotherapy with its potential benefit. This has required a great deal of finesse in the era of HAART, which can itself cause regression of Kaposi sarcoma. Treatment duration should be to a response plateau with lengthening out of the interval to approximately 6 weeks, a period in which Kaposi sarcoma will progress if treatment is not being administered. Also, recurrence of Kaposi sarcoma after chemotherapy does not necessarily mean resistance, making retreatment with the same regimen a reasonable option.

Because chemotherapy can be given long-term, treatment-related toxicities may prevent its ongoing administration.

Potential new avenues of therapy are being investigated. Because of its highly vascular nature, Kaposi sarcoma has been thought of as a natural target for angiogenesis inhibition. A phase II study of thalidomide in 20 patients with Kaposi sarcoma with HIV serology resulted in a 40% response rate with median duration of response of 7 months. Most of the patients were on HAART. [7] Combination chemotherapy of antiangiogenic and cytotoxic agents is being considered. [70]

Studies are underway involving VEGF pathway with agents such as the VEGF-inhibitors bevacizumab and sorafenib as well as studies with inhibitors of m-TOR such as sirolimus. Lenolidamide, an immune modulating agent is also being studied. [74]

Other compounds such as fumagillin analogs and peptidoglycan analogs produced by bacteria, which are potent blockers of angiogenesis, have shown minimal benefit as single agents. Glufanide disodium, an antiangiogenic dipeptide from solubilized fraction of thymic extract, has shown benefit with response rates of 36% when used as a nasal formulation. [58] Because of its male predominance, another way of treating the disease may be through hormonal manipulation. Work is being done to look at the potential inhibitory effect of beta-HCG.

Because of its etiologic link to Kaposi sarcoma human herpesvirus (KSHV) (HHV-8), antiviral therapy with foscarnet and ganciclovir may be effective. A randomized clinical trial of oral ganciclovir versus ganciclovir ocular implants has shown a lower rate of Kaposi sarcoma. [70]

Further studies are needed in this area. [7] Yet, antiherpes drugs have been ineffective. Activation of drugs by KSHV-kinases is an approach that needs further investigation. Also, the c-kit oncogene is up-regulated by KSHV. This would make it a rational target for blockade.

A small study with imatinib mesylate (Gleevec) has shown response in 4 of 5 patients. [75]

Finally, evaluation of the multiple pathways of potential pathogenesis may lead to inhibitors of both autocrine and paracrine factors. An inhibitor of basic fibroblast growth factor (bFGF) has been studied. Also, newer antiangiogenic compounds such as inhibitors of matrix metalloproteinases and oligonucleotides may show promise. [76]

Despite effective therapies and promising activity of novel agents, the investigation of new targeted therapies continues.

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Consultations

Obtain a radiation oncology consultation when considering the use of radiation as definitive therapy for palliation of locally advanced symptomatic disease or a cosmetically disturbing cutaneous lesion.

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