Approach Considerations
Currently, no treatment is available to eradicate HHV-8 infection. Therefore, there is no cure for Kaposi sarcoma (KS). Instead, the purpose of therapy in all forms of KS is directed at alleviating symptoms and slowing disease progression. Treatment decisions vary depending on KS form, presence of symptoms, and extent of disease.
Classic KS is usually limited to the skin and has an indolent course. A retrospective analysis of 123 patients with classic KS found that the median time to progression with observation alone was 4 months. However, multivariate analysis determined that immunosuppression was the only significant independent factor that predicted disease progression. Therefore, observation alone may be sufficient for immunocompetent asymptomatic patients. [80]
Lower extremity edema can be managed with compression stockings. Local therapies, including surgical resection, radiotherapy, cryotherapy, and intralesional chemotherapy, can be used to treat symptomatic or cosmetically unacceptable lesions. Systemic chemotherapy should be reserved for patients in whom local therapy fails or who have extensive disease. [80]
Therapy for epidemic Kaposi sarcoma centers on the use of highly active antiretroviral therapy (HAART), which has decreased the incidence and severity of this disease. Most good-risk patients show tumor regression with HAART alone. Local therapies can also be implemented for symptomatic or cosmetically disfiguring cutaneous lesions.The least invasive and toxic modality should be used due to high risk for infectious complications in this population. Poor-risk patients usually require a combination of chemotherapy with HAART. Treatment is typically continued until response plateau or unacceptable toxicity.
Iatrogenic or post-transplantation Kaposi sarcoma commonly responds to reduction or discontinuation of immunosuppression. In one study, tapering of immunosuppressive therapy alone led to complete or partial KS regression in 9 of 20 patients. [81] However, this approach may not always be feasible and can place patients at risk for graft rejection.
Several retrospective and prospective studies have shown a benefit of switching from calcineurin inhibitors (eg, cyclosporine, tacrolimus) to a mammalian target of rapamycin (mTOR) inhibitor, specifically sirolimus. Although the exact mechanism is not fully understood, sirolimus is thought to have a direct cytotoxic effect on KS tumor cells due to inhibition of vascular endothelial growth factor, Flk-1/KDR and phosphorylated Akt which are commonly upregulated in Kaposi sarcoma. [82] As in other forms of KS, chemotherapy is commonly reserved for limited disease refractory to local therapy or in patients with disseminated disease.
Of note, the role for antiviral agents against herpes viruses (eg, foscarnet, ganciclovir,valganciclovir) is unclear. These agents usually are ineffective in Kaposi sarcoma, likely because the neoplastic spindle cells harbor a latent HHV-8 infection. However, a study in patients with AIDS and cytomegalovirus (CMV) retinitis found that oral or intravenous ganciclovir (which is approved for use in CMV infection) reduced the risk of Kaposi sarcoma. [83] Further studies are needed in this area. [31] Activation of drugs by Kaposi sarcoma herpes virus (KSHV) kinases is an approach that needs further investigation. Also, the c-kit oncogene is up-regulated by KSHV and would be a rational target for blockade.
A course of antiviral therapy with cidofovir or foscarnet may be considered if there is suspicion for other coexisting HHV-8–related diseases (eg, multicentric Castleman disease, primary effusion lymphoma). [84]
Medical Care
Antiretroviral therapy for AIDS-related Kaposi sarcoma
Optimal control of HIV infection using HAART is an integral part of therapy for AIDS-related Kaposi sarcoma, and should be the first step in therapy. Response to HAART can range from 20-80%, depending on the stage of disease and the amount of pretreatment. [85] Since its inception, HAART has changed the therapeutic goal in Kaposi sarcoma from short-term palliation to long-term remission and control.
Effective combination antiretroviral therapy usually comprises a combination of either a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) with 2 nucleoside reverse transcriptase inhibitos (NRTIs). Some evidence suggests a direct antitumor effect on angioproliferative Kaposi sarcoma–type lesions, but to date no level 1 evidence supports this clinically. [86] No difference is apparent between PI-based and NNRTI-based antiretroviral regimens in terms of response of Kaposi sarcoma. [69]
HAART may be tried as the sole modality in nonvisceral disease. For visceral disease, chemotherapy may be added. For locally symptomatic disease, radiation therapy may be introduced. [31]
However, patients with poor-risk Kaposi sarcoma rarely respond to HAART alone. In addition, approximately 6-39% of patients with AIDS-related Kaposi sarcoma develop immune reconstitution inflammatory syndrome (IRIS) with worsening of Kaposi sarcoma within 3 to 6 months after re-initiating ART. [87] This occurs in association with increase in CD4 counts and control of HIV viremia. [87, 78] The criteria for Kaposi sarcoma IRIS per the AIDS Clinical Trial Group are as follows:
-
Onset after starting, restarting, or altering of the HAART regimen
-
Increase of CD4 count by ≥50 cells/μL or a 2-fold increase in CD4 count, and decrease in HIV-1 viral load of greater than 0.5 log
-
More-than-expected progression of Kaposi sarcoma within 12 weeks of initiating HAART
Risk factors for Kaposi sarcoma–associated IRIS include pulmonary involvement, concurrent or recent use of glucocorticoids, and advanced immunosuppression. Glucocorticoids are generally contraindicated in Kaposi sarcoma due to their stimulatory effect on Kaposi sarcoma spindle cells. [88] 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.
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 reported response rates of 39% to HAART alone versus 66% to HAART plus chemotherapy; in addition,, 35% of patients in the HAART arm crossed over to require palliative chemotherapy or radiation within 12 months of randomization. These results support the use of chemotherapy combined with HAART in patients with high tumor volume (T1). [89]
Systemic therapy for epidemic Kaposi sarcoma
Chemotherapy is the preferred first-line therapy for refractory/relapsed limited cutaneous disease and advanced disease. It 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.
Cytotoxic agents are approved by the Food and Drug Administration (FDA) for AIDS-related Kaposi sarcoma and include the following:
-
Liposomal doxorubicin (Doxil)
-
Liposomal daunorubicin (DaunoXome)
-
Paclitaxel (Taxol)
-
Oral etoposide (Vepesid)
Current National Comprehensive Cancer Network (NCCN) guidelines recommend liposomal doxorubicin (or liposomal daunorubicin) or paclitaxel in the first-line setting. Sirolimus is the first-line recommendation following an organ transplant. [73]
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. [12, 13, 14] 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 whose diseaserefractory to other chemotherapeutic agents. [77] Response rates of 50-71% were reported in two phase II trials. [90, 91]
Several trials have compared pegylated-liposomal doxorubicin with combination chemotherapy and have found it to be as effective as or superior to conventional combination chemotherapy, with higher response rates and lower toxicity. In a randomized phase III trial of 258 patients receiving pegylated-liposomal doxorubicin or doxorubicin/bleomycin/vincristine (ABV) the overall response rate was 46% in the liposomal doxorubicin arm versus 25% in the ABV arm. The median time to treatment failure was similar to both arms, with decreased grade 3-4 adverse events in the liposomal doxorubicin arm. Therefore, single-agent regimens are commonly preferred.
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 of the treatment 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.
In refractory or relapsed cases that progressed despite one or both first-line therapies, options include the following:
-
Pomalidomide,
-
Bevacizumab
-
Etoposide
-
Gemcitabine
-
Imatinib
-
Thalidomide
-
Vinorelbine
However data for these agents are limited and derived from studies with small treatment populations.
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 prompt clinical response. Interferon-alfa is most effective when the CD4 count is greater than 150-200/μL or when administered in conjunction with antiretroviral therapy. Combination interferon and chemotherapy has been no more effective than chemotherapy or interferon alone.
Objective response rates have been seen in about 40% of patients. [92, 93] Responses depend on extent of disease, immunocompetence of the patient, prior treatment with chemotherapy, presence of circulating acid-labile interferon alpha, and beta-2 microglobulin levels. Response rates are about 4-fold higher in immunocompetent patients than in those with poor prognostic features.
Interferon is given by 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).
Interferon alpha-2a and interferon alpha-2b were approved for treatment of Kaposi sarcoma in the pre-HAART era. Interferon-alfa has activity against HIV by suppressing messenger RNA 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 at present; instead, interferon is typically given in doses of 4 to 18 million units, together with antiretroviral therapy. Dose-limiting toxicity is neutropenia.
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 HIV-infected patients with Kaposi sarcoma resulted in a 40% response rate with median duration of response of 7 months. Most of the patients were on HAART. [31] SImilarly, a phase I/II trial evaluating the efficacy of pomalidomide in 22 patients, 77% of whom had relapsed disease, found a 60% overall response rate in the HIV-positive group. [94] Combination chemotherapy with antiangiogenic and cytotoxic agents is being considered. [83]
Bevacizumab is a VEGF inhibitor that has been studied in AIDS-associated Kaposi sarcoma. A phase II study of 17 HIV-infected patients with KS showed a 31% overall response rate, with a complete response seen in 19% of patients. [95]
Other compounds (eg, 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. [77] Because of its male predominance, another way of treating the disease may be through hormonal manipulation. The potential inhibitory effect of beta human chorionic gonadotropin is also under study.
A small study with imatinib mesylate (Gleevec) has shown response in 4 of 5 patients. [96] In a study of nine patients with HIV-associated Kaposi sarcoma, immune checkpoint blockade with nivolumab or pembrolizumab produced partial responses in six patients and complete response in one patient, with low toxicity. [97]
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. [98]
Local Therapy
Local therapy is best suited for patients who require palliation of locally advanced symptomatic disease (eg, radiation) or for those who have cosmetically unacceptable lesions. This therapy is also well suited for patients 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
Radiation therapy is the most widely used and effective local therapy. [99] It can palliate bleeding, pain, and unsightly lesions. Kaposi sarcoma is very radiosensitive, with reported response rates of 68%-92%. A study assessing the efficacy of radiation on 97 previously untreated cutaneous Kaposi sarcoma lesions showed a response rate of 87% with a complete response seen in 30% of treated sites. [100]
The type and dose of radiation varies depending on site, depth, and diameter of lesion. Low-voltage (100 kv) photons or electron-beam radiotherapy may be used. The standard regimen is 24 Gy in 12 fractions; however, hypofractionated regimens (eg, 20 Gy in 5 fractions) have shown to be equally effective. [101] Patients with HIV are more prone to develop radiation-induced mucositis as well as hyperpigmentation, desquamation, and ulceration of treated lesions. [31, 102, 103]
In patients with widespread skin involvement, extended-field external 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 form of therapy is also given in 4-Gy fractions weekly for 6-8 weeks.
Surgical excision
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.
Surgery may also be indicated for 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 in AIDS-associated Kaposi sarcoma.
Intralesional chemotherapy
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, in which 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 treatments. 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, intralesional chemotherapy has relatively limited use. Also, systemic vinca alkaloid therapy may be equally effective and cause less localized skin toxicity.
Cryotherapy
Cryotherapy entails liquid nitrogen applied topically and may be useful for small facial lesions less than 1 cm in dimensions. 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. [31] Cryotherapy may cause skin hypopigmentation. It has limited penetration and is not ideal for large, deep lesions.
Laser therapy
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.
Topical therapies
Interleukin-6 (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 gel (Panretin) 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 after 2-14 weeks of therapy. [31] Common side effects include local inflammation and depigmentation.
Imiquimod, a topical immune response modulator, has shown safety and efficacy in patients with limited cutaneous classic or transplant-associated Kaposi sarcoma. A phase I/II trial of 17 patients showed a 47% response rate in 17 patients receiving imiquimod 5% cream 3 times per week for 24 weeks. [104]
Consultations
Local therapies—including topical agents, cryotherapy, laser therapy, and intralesional therapy—should be administered by a dermatologist who has experience in the treatment of Kaposi sarcoma. 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.
All patients with AIDS-associated Kaposi sarcoma should be referred to an HIV infectious disease specialist. Care coordination between the HIV specialist and oncology team is important. The infectious disease team can help diagnose and treat co-existing opportunistic infections; monitor HIV viral load; and optimize immune system recovery, which is a key component of AIDS-associated Kaposi sarcoma management.
Patients who experience significant Kaposi sarcoma–related lymphedema should be referred to a lymphedema specialist to help improve symptom control.
Complications
The complications of Kaposi sarcoma are largely dependent on the location of lesions. Kaposi sarcoma can involve almost any organ, but the most common visceral sites include the oral cavity, gastrointestinal tract, and respiratory system. Profound lymphedema can result in cellulitis, skin infections, and poor wound healing. Patients with involvement of the gastrointestinal tract can develop anemia from chronic blood loss. Pulmonary involvement can cause life-threatening hemoptysis and refractory pleural effusions requiring long-term indwelling pleural catheter placement.
Prevention
Prevention of exposure to HIV and HHV-8 is the most effective method of preventing Kaposi sarcoma. Sexual abstinence, monogamy, or condom use and avoidance of IV drug use or use of sterile needles and syringes are the best methods.
Similar measures are recommended for those who are already infected with HIV, to prevent infecting others and to avoid co-infection with other sexually transmitted and hematogenous infections. The use of antiretroviral therapy decreases risk of Kaposi sarcoma in patients already infected with HIV and may be equally effective in treating Kaposi sarcoma. [60]
Long-Term Monitoring
Currently, no treatment that can eradicate HHV-8 is available. Therefore, all patients with Kaposi sarcoma are at risk for recurrence or relapse even if they achieve a complete remission. Patients should have routine physical examinations every 3-4 months to assess for any new skin lesions, edema, or symptoms/signs suggestive of visceral involvement.
Patients with AIDS-associated Kaposi sarcoma should also be monitored with a complete blood cell count and differential, complete metabolic profile, T-cell subsets, and HIV viral load. HIV control and immune function are imperative in preventing relapse and progression, so compliance with antiretroviral therapy should be assessed and emphasized at each encounter.
-
Endoscopic view of a Kaposi sarcoma lesion situated in the gastric antrum.
-
Epidemic Kaposi sarcoma (KS). Large violaceous truncal nodules with typical linear and symmetric distribution pattern.
-
Kaposi sarcoma (KS), facial. Confluent, violaceous nodules involving the chest wall; extensive facial involvement with accompanied edema.
Tables
Classification |
Affected Population |
Clinical Course |
AIDS related |
HIV-infected persons (usually those with a low CD4+ count usually) |
Most aggressive (survival improved with antiretroviral therapy) |
Classical |
Eastern European or Mediterranean men |
Indolent (progression over years to decades) |
Endemic |
Subsaharan African children and adults |
Somewhat aggressive |
Iatrogenic |
Patients receiving immunosuppressive therapy (eg, following organ transplantation, for autoimmune disease) |
Somewhat aggressive |
