Kaposi Sarcoma Treatment Protocols

Because the natural history of Kaposi sarcoma (KS) is variable, assessment of therapy may be difficult. Treatment usually is based on the extent of disease and the patient’s immune status. Optimal therapy for KS and acquired immune deficiency syndrome (KS-AIDS) is yet to be determined. The challenge is to treat KS-AIDS effectively without immunocompromising the patient further—or, better, with reconstitution of the immune system.[1, 2, 3, 4, 5, 6, 7, 8]

Management of childhood HIV-associated KS in resource-poor settings is challenging.[9] In addition, no randomized controlled studies of chemotherapy for KS in children have been published.

General treatment approach

Treatment considerations include the following:

• Observation is preferred over beginning treatment for patients with limited asymptomatic lesions

• Treatment of early AIDS-related KS should start with antiretroviral therapy, which often results in KS regression.[10]

• Localized nodular disease may respond well to surgical excision, radiotherapy, and intralesional and outpatient low-dose vinblastine chemotherapy

• The choice of topical therapy depends on the site and extent of the disease and on individual patient status

• Kaposi sarcoma–associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral (ART)-naïve HIV-infected patients is a major contributor to KS-associated mortality in Africa. Increased awareness of this entity is important[11]

• In children with both KS and HIV infection in sub-Saharan Africa, ART together with a chemotherapy regimen appears to be better than the use of either ART or chemotherapy alone[12]

• Treatment of post-transplant KS focuses on reduction of immunosuppression and use of mammalian target of rapamycin (mTOR) inhibitors and/or chemotherapy.[13]  

Radiotherapy

Radiotherapy considerations include the following:

• Radiotherapy often produces good therapeutic results with classic nodular KS but tends to be only palliative in patients with KS-AIDS

• In localized nodular KS, conventional radiotherapy is highly effective

• Electron beam radiation therapy (EBRT) has limited penetration beyond the dermis; it may be a good modality for superficial lesions. EBRT may be given as 4 Gy once weekly for 6-8 wk consecutively.[14]

• Deeper or unresponsive KS may be treated with standard non-EBRT or other approaches

• Initial response to radiotherapy usually is complete, or at least marked, regression of the nodules; the more extensive the involvement, the less responsive the disease tends to be

• Radiotherapy may be more effective on new lesions than on chronic ones and may provide local KS control in patients with KS-AIDS

• Radioisotope scanning using technetium-99m may detect occult KS infiltration in the subcutaneous and muscular tissues and draining lymph nodes; this allows improved efficiency of large-field radiotherapy

• Argon laser photocoagulation therapy also may be successful in classic KS lesions; long-pulse neodymium-doped yttrium aluminum garnet laser treatment may also be beneficial in classic KS[15]

• Low-voltage (100 kV) photon radiation: 8-10 Gy as a single dose or 15-20 Gy over 1wk[16]

• High-dose-rate brachytherapy is another option for cutaneous KS[17]

Chemotherapy

Chemotherapy considerations include the following:

• Systemic vinblastine 4-10 mg IV weekly,[18] at times with one intralesional 0.1 mg injection, is usually best for patients with classic KS and occasionally best for patients with KS-AIDS

• Treatment of classic KS may also be accomplished with topical imiquimod 5% cream applied three times weekly for 24 wk[19]

• A study of paclitaxel as first-line treatment in 10 patients with classic or endemic KS found it to be effective and of low toxicity;  paclitaxel was infused in a dose of 80 or 100 mg/m2 IV every 2 weeks

• An open label, randomized trial in Malawi that included 92 children (46% of them naïve to ART, 11% of them HIV negative) found that oral etoposide was a safe and effective treatment for containing KS and improving quality of life, compared with either intravenous vincristine or vincristine and bleomycin[20]

•  A three-arm, open-label, randomized, non-inferiority trial found that paclitaxel plus ART was superior to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use for advanced AIDS-associated Kaposi sarcoma in resource-limited settings.[21]

• Pomalidomide, an immunomodulatory agent with efficacy against KS,[22]  was approved as a breakthrough therapy in 2020 by the US Food and Drug Administration (FDA) for treatment of adult patients with AIDS-related KS after failure of highly active antiretroviral therapy (HAART), as well as for treatment of KS in adult patients who are HIV negative. The recommended dosage is 5 mg once daily, taken orally with or without food, on days 1 through 21 of each 28‑day cycle until disease progression or unacceptable toxicity, along with continuation of HAART as HIV treatment in patients with AIDS-related KS. 

In patients with KS-AIDS, HAART, with or without local KS therapy, is employed with interferon alfa if the CD4 cell count is < 200/µL or if it is early in the disease course.[23] Dosages are as follows:

• Interferon alfa-2b 5-10 million units SC or IM daily (total weekly dose, 35-70 million units) or

• Interferon alfa-2b 5-10 million units SC or IM three times weekly (total weekly dose, 15-30 million units) or

• Interferon alfa-2b 1 million units SC daily or twice weekly (total weekly dose, 2-7 million units)[24, 25]

In those who have a CD4 cell count < 200/µL or advanced KS-AIDS, pegylated liposomal doxorubicin (PLD) 20 mg/m2 every 2-3 wk is added.[26] Nonresponders are given other cytotoxic agents, such as paclitaxel. A randomized trial that compared paclitaxel and PLD showed comparable response rates, median progression-free survival (PFS), and 2-y survival rates with the two agents but somewhat more grade 3-5 toxicity with paclitaxel[27]

The efficacy of taxanes such as paclitaxel and docetaxel, as agents with antiangiogenic properties, has been shown not only for patients with AIDS-associated KS but also in those with refractory or life-threatening KS without HIV infection.[28] PLD is now being used as a second-line therapy in the treatment of patients with advanced classic KS[29]

Treatment considerations in patients on immunosuppressive therapy include the following:

• In iatrogenic KS, cessation of immunosuppressive therapy may be the most effective treatment.

• Patients on immunosuppressive therapy—specifically, corticosteroids and cytotoxic drugs—may experience partial or complete regression when therapy is discontinued.

• If possible, immunosuppressive medication doses should be reduced or discontinued before specific therapy for iatrogenic KS is initiated.

Follow-up and prevention

See the list below:

• Reducing the human herpesvirus-8 (HHV-8; or Kaposi sarcoma–associated herpesvirus [KSHV]) infection rate should diminish the incidence of KS.

• Screening transplant recipients for HHV-8 infection may be beneficial.

• Use of sirolimus (rapamycin) for transplant recipients provides an approach that is both immunosuppressive and antioncogenic.[30, 31] In comparison with other immunosuppressants—namely, calcineurin inhibitors—sirolimus has the advantage of being associated with a decreased risk of malignancies, including KS; it may also lead to regression of KS.

• Antiviral therapy with foscarnet not only may slow the progression of KS in patients but also may substantially reduce the occurrence of KS in patients with HIV disease.

• Use of HAART appears to reduce the risk of developing new KS significantly.[32]

• After treatment is initiated, follow-up care is important to check for recurrence or visceral spread; follow-up care recommendations may include imaging procedures, laboratory tests (eg, complete blood count [CBC], urinalysis, liver function studies) and monitoring of symptoms potentially related to return of cancer.

• Screening for other types of cancers, particularly lymphomas, is important during follow-up.

Survival data

Prognostic features include the following:

• The clinical KS type (localized nodular disease, locally aggressive disease, or generalized KS) may be the best predictor of prognosis.

• Cutaneous skin testing for anergy has been employed for decades as a good correlate with clinical disease type and prognosis; in addition, the degree of immunosuppression also correlates with clinical type and prognosis.[33, 34]

• Localized nodular KS has a favorable prognosis, with few deaths attributable to KS.

• The prognosis is also excellent when iatrogenic KS in transplant recipients shows regression after suitable therapeutic modification; thus, classic KS has long been regarded as a disorder that most immunocompetent people die with rather than of.

• Locally aggressive KS is not so favorable in prognosis; the African 3-y survival rate of about two thirds, calculated decades ago, remains accurate.

• Generalized KS, the type most common with KS-AIDS, has a 3-y survival rate closer to 0% without therapy, with people dying either of disseminated KS or of an intervening opportunistic infection within 3y of diagnosis, regardless of therapeutic intervention.

• In HIV-associated advanced KS, median survival is 31 mo (range, 1.8-48 mo) in patients treated with protease inhibitor–based HAART, compared with only 7 mo (range, 1-28 mo) in those not receiving HAART.[35]

• Importantly, 81% in the HAART group were alive at 18 mo after the start of chemotherapy, compared with only 12% in the non-HAART group

• Another analysis documented that when KS does develop in patients on HAART, it exhibits a less aggressive clinical pattern in patients already receiving HAART than in those naive to this treatment, but the natural history and outcome are unaltered.[36, 37]

• A 3-y survival rate of 64% with KS-HAART is comparable to the 78% without HAART; median survivals of HIV-infected homosexual men in the good- and poor-risk categories were 27 mo and 15 mo, respectively, for tumor extent; 40 mo and 13 mo for degree of immunosuppression; and 22 mo and 16 mo for HIV-associated systemic disorders, with multivariate analysis indicating that severity of immunosuppression gave the most predictive information.[38]

• In one study of KS-AIDS patients, the overall 5-year survival was 92% for those with early-stage KS and 83% for those with advanced-stage KS; for 140 patients with advanced-stage KS treated with combination antiretroviral therapy and liposomal anthracycline chemotherapy, 5-year overall survival was 85%.[39]

• Outcomes may be suboptimal in resource-poor national areas where expensive options such as liposomal anthracyclines are unavailable (eg, Maputo, the capital of Mozambique).[40]