AIDS-related Kaposi sarcoma: Staging and treatment

INTRODUCTION — Kaposi sarcoma (KS) is a low-grade vascular tumor associated with infection with human herpesvirus 8 (HHV-8), also known as the KS-associated herpesvirus (KSHV).

AIDS-related KS has a variable clinical course, ranging from minimal disease presenting as an incidental finding to a rapidly progressing neoplasm that can result in significant morbidity and mortality, depending upon the specific sites of involvement [1]. In addition to physical symptoms due to tumors, the psychosocial burden associated with KS may be profound and includes emotional distress, guilt, and anger [2].

The staging and treatment of AIDS-related Kaposi sarcoma are discussed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

STAGING AND EVALUATION

Staging system — The most commonly utilized staging system for AIDS-related KS was developed by the AIDS Clinical Trial Group (ACTG) of the National Institute of Health [3]. This system divides patients into good or poor risk prognostic categories, taking into account both the KS and HIV infection.

Patients are categorized according to three parameters (table 1):

●Extent of tumor (T) – A favorable prognosis (T0) is associated with disease limited to the skin or with minimal involvement of the oral cavity. Those with associated lymphedema, more extensive oral cavity involvement, or other visceral disease are considered to have a poor prognosis (T1).

●Immune status (I) – The degree of immunosuppression from the HIV infection is an important prognostic factor. Patients with a CD4 count greater than 200 cells/microL are considered to have a favorable prognosis (I0) while those with a lower CD4 count have classified as poor prognosis (I1).

●Severity of systemic illness (S) – Features associated with a poor risk included the following (S1): a history of opportunistic infection, thrush, B symptoms (fever, night sweats, significant weight loss, diarrhea for more than two weeks). Patients without any of these factors have a more favorable prognosis (S0).

The overall patient assessment requires that good-risk patients have a favorable prognosis according to all three parameters. This was illustrated by an analysis of 144 patients with KS prospectively included in the Swiss HIV Cohort Study [4]. On multivariate analysis, factors significantly associated with death or a need for chemotherapy included tumor stage T1 rather than T0, a CD4 count <200 cells/microL, or a positive test for human herpesvirus 8 (HHV-8) DNA (hazard ratios 5.2, 2.3, and 2.1, respectively).

Although there is no American Joint Committee on Cancer (AJCC) staging system for KS, the AJCC recommends recording the size of the largest lesion, if possible, although this may not be feasible given confluency of lesions [5]. Although the AJCC also notes that previous systems involving the immune status of the patient may be less relevant, given the availability of antiretroviral therapy, it is our view that the immune status of the patient is important. For example, treatment to restore immune integrity with robust CD4+ numbers can in itself result in both regression of some lesions and better response to anti-KS modalities.

Initial evaluation — The initial evaluation of a patient with KS consists of a thorough physical examination with special attention paid to those areas typically affected by the disease, such as the lower extremities, face, oral mucosa, genitalia, gastrointestinal tract, and lungs. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

Evaluation for visceral involvement is guided by symptomatology and basic laboratory testing.

●Testing the stool for occult blood is the simplest way to screen for gastrointestinal involvement. Endoscopy is usually reserved for patients who test positive for occult blood or have gastrointestinal symptoms.

●Chest x-ray is useful to screen for pulmonary lesions. Bronchoscopy should be reserved for those with an abnormal radiograph and persistent respiratory symptoms in the absence of another cause.

CT scanning of the chest, abdomen, and pelvis is typically not necessary.

The CD4 cell count and HIV viral load are important for staging and prognosis, and thus may be useful in making treatment decisions. (See "Techniques and interpretation of measurement of the CD4 cell count in people with HIV" and "Techniques and interpretation of HIV-1 RNA quantitation".)

TREATMENT — The major goals of treatment are symptom palliation, prevention of disease progression, and shrinkage of tumor to alleviate edema, organ compromise, and psychological stress [6].

Systemic treatment with potent combination antiretroviral therapy (ART) is recommended for virtually all patients with AIDS-related KS [6-9]. The need for treatment beyond ART and the choice among the various options depend upon the extent of disease, the rapidity of tumor growth, the HIV-1 viral load, the CD4 cell count, and the patient's overall medical condition [10].

Locally directed therapy is often used to palliate symptoms caused by a specific tumor or to treat cosmetic disfigurement. Systemic therapy is used for more extensive disease but injury to an immune system that is already severely compromised should be avoided whenever possible.

Combined antiretroviral therapy — Combination ART is recommended for virtually all patients with AIDS-related KS, and may be the only therapy required in the absence of specific indications for chemotherapy. For those in whom chemotherapy is indicated, it may be combined effectively and safely with ART. (See 'Systemic therapy' below.)

The introduction of ART has been associated with a substantial decrease in both the incidence and severity of newly diagnosed KS in HIV infected patients. A French database study that included 54,999 patients with over 180,000 patient years of follow-up found that the incidence rate for new cases of KS fell from 32 per 1000 person-years in 1993-1994 to 3 per 1000 person-years after 1999 [11]. Furthermore, the incidence of visceral involvement at presentation fell from more than 50 percent to less than 30 percent. Similar dramatic decreases have been seen in other studies [12,13].

Observational studies indicate that the natural history of AIDS-related KS has changed since the introduction of ART in addition to a decrease in the KS incidence [14,15]. A retrospective study that analyzed KS cases from a database of 4439 persons with HIV infection both before ART (1990 to 1996) and after ART (1997 to 2002) found that the mean CD4 count and the mean HIV RNA levels were similar in the 366 patients from the pre-ART era and in the 40 patients in the post-ART era [15]. However, the overall risk of dying was significantly lower in the post-ART era (hazard ratio, 0.24).

Immune reconstitution due to control of the HIV infection is the most likely explanation for this altered prognosis rather than a direct effect on tumor. Although HIV protease inhibitors have antiangiogenic properties and block the development and progression of KS-like lesions in nude mice [16], there was no difference in the likelihood of clinical response associated with the use of these agents [14,17]. Furthermore, the decreased incidence of KS has been observed with ART regimens that do not contain protease inhibitors [11]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Although treatment with ART causes increases in CD4 counts above the levels typically associated with increased susceptibility to infection, some patients develop HIV-related KS despite apparent correction of their immunodeficiency [18].

Immune reconstitution inflammatory syndrome — The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of host responses that can occur following the initiation of ART. In addition to worsening of symptoms from preexisting infections with IRIS, the initiation of ART has been associated with progression of KS within three to six weeks after starting antiretroviral therapy [19,20]. (See "Overview of immune reconstitution inflammatory syndromes".)

The relationship between IRIS and KS is illustrated by a series of 150 therapy-naive patients who presented with KS, 10 (7 percent) developed progressive KS when ART was initiated [19]. The risk of IRIS appeared to be increased in those with a higher CD4 count or KS-associated edema. Despite the progression of KS, continuation of ART was possible in these patients. Other large series have made similar observations [21].

Factors associated with an increased risk of IRIS in patients initiating ART for HIV include more extensive (T1) KS, a higher HIV viral load, and the use of ART without chemotherapy [21]. Progression of KS in patients with IRIS can be severe and has been associated with death in some cases [21-23].

Local symptomatic therapy — Local treatment modalities are useful for cosmesis or the management of limited, symptomatic bulky KS lesions, but they do not prevent the development of new lesions in untreated areas.

The most widely used local treatment approaches include:

●Intralesional chemotherapy – Intralesional chemotherapy can induce regression of injected tumors and is preferred for small lesions.

Vinblastine is the most widely used agent. It can be injected directly into a KS lesion as a 0.2 to 0.3 mg/mL solution with a volume of 0.1 mL per 0.5 cm² of lesion. Multiple injections may be necessary for larger lesions. A second series of injections is often necessary three to four weeks later. Treated lesions will fade and regress although typically not resolve completely [24-26]. In one series of 42 patients with oral KS, for example, 74 percent showed more than a 50 percent reduction in lesions; palliation was achieved for a mean of 4.3 months [24].

●Radiation therapy – The primary role of radiation therapy is to treat symptomatic disease that is too extensive to be treated with intralesional chemotherapy [27], but is not extensive enough to require systemic therapy. Although discomfort from radiotherapy is frequent, it usually resolves within two weeks of treatment. Radiation therapy does not have a role in patients with extensive KS, as was illustrated by a randomized trial from Zimbabwe [28]. In this trial, radiation therapy did not improve either quality of life or survival compared to supportive care alone in 495 patients who were not treated with antiretroviral drugs.

●Topical alitretinoin – Alitretinoin (9-cis retinoic acid) is available as a topical gel that the patient can apply to treat cutaneous KS lesions. This agent is rarely used, since the topical gel can cause inflammation and lead to pigmentation changes in dark-skinned patients. In two phase III studies involving 402 patients, alitretinoin was associated with a shorter time to response, a longer duration of response, and a longer time to disease progression compared to a placebo vehicle gel [29,30]. In these trials, responses were seen in 35 and 37 percent of patients after 12 weeks of treatment, compared to 7 and 18 percent with placebo. Responses were seen in patients with a wide range of baseline CD4+ lymphocyte counts.

Systemic therapy — For patients who have advanced or rapidly progressive KS, we suggest initial therapy with both systemic chemotherapy and ART [7,9]. When chemotherapy is indicated, we prefer initial treatment with pegylated liposomal doxorubicin [7]. Other options include paclitaxel, bleomycin, vinblastine, vincristine, and etoposide [31]. (See 'Liposomal doxorubicin (preferred)' below and 'Paclitaxel' below.)

Generally accepted indications for adding systemic chemotherapy to ART include:

●Widespread skin involvement (eg, more than 25 lesions)

●Extensive cutaneous KS that is unresponsive to local treatment

●Extensive edema

●Symptomatic visceral involvement

●Immune reconstitution inflammatory syndrome (IRIS) (see 'Immune reconstitution inflammatory syndrome' above)

●Progression of KS on ART alone

Small randomized trials have looked at the role of chemotherapy plus ART versus ART alone, and while typically response rates are higher with the addition of chemotherapy to ART, a survival benefit has not been demonstrated. As examples:

●In one trial, 112 patients who had not received prior ART or chemotherapy for KS were randomly assigned to ART (stavudine, lamivudine, and nevirapine) with or without combination chemotherapy (bleomycin, doxorubicin, and vincristine) [32]. The trial was limited to patients without symptomatic visceral disease or fungating lesions requiring urgent therapy. The overall response rate of the KS was significantly better for patients given chemotherapy plus ART (66 versus 39 percent). However, overall survival was 77 percent for the entire study population and there was no significant difference between the study arms.

●One trial randomly assigned 190 HIV-infected adults with mild to moderate KS initiating ART to immediate etoposide or etoposide upon KS progression [33]. Although immediate etoposide delayed KS progression and decreased time to initial KS response, mortality was similar between the two groups at 48 weeks.

●Finally, in a smaller trial, 28 patients with moderate or advanced KS who were initiating a new ART regimen were randomly assigned to ART plus liposomal doxorubicin or ART alone [34]. Among those receiving chemotherapy with ART, 10 of 13 (76 percent) responded, compared with 3 of 15 (20 percent) with ART alone. Survival results were not reported.

Initial therapy

Liposomal doxorubicin (preferred) — For patients with AIDS-related KS who have an indication for systemic therapy, we suggest initial therapy with pegylated liposomal doxorubicin rather than a combination of older agents or a taxane [7]. Liposomal daunorubicin was previously recommended for use as an option for first-line therapy [7]. However, liposomal daunorubicin is no longer available.

Pegylated doxorubicin has a longer plasma half-life than a nonliposomal formulation. A liposomal formulation has less toxicity in nontarget organs than a conventional anthracycline and provides the theoretical advantage of higher tumor concentrations of drug. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Modification of dose, specific agent, and schedule of administration'.)

Liposomal doxorubicin can reliably shrink tumors, lessen edema, and cause the color of lesions to fade. Response rates range from 30 to 60 percent depending upon the definition of clinical response and the specifics of the various trials. In randomized multicenter trials, it was as effective as or superior to conventional combination chemotherapy (bleomycin and vincristine with or without nonliposomal doxorubicin) in terms of response rates and had a better toxicity profile [35,36]:

●In one trial, 258 patients were randomly assigned to pegylated liposomal doxorubicin (20 mg/m² every three weeks) or a combination regimen of doxorubicin, bleomycin, and vincristine [35]. The response rate (virtually all responses were partial) was significantly higher with pegylated liposomal doxorubicin (46 versus 25 percent), which was also associated with less toxicity. Similar findings were noted in another trial of 241 patients (59 versus 23 percent response rate) [36].

●In a randomized trial of 73 patients with HIV-associated KS, those randomly assigned to liposomal doxorubicin experienced comparable response rates, median progression-free survival, and two-year survival rates as those assigned to paclitaxel [37]. There was, however, a nonsignificant trend towards less frequent grade 3 to 5 toxicity for liposomal doxorubicin (66 versus 84 percent, respectively), making it the preferable option.

Side effects from liposomal doxorubicin are generally mild. In particular, alopecia and neuropathies are unusual in contrast with the side effect profile of conventional combination chemotherapy regimens. The diminished cardiotoxicity with liposomal doxorubicin permits higher cumulative doses of anthracycline to be administered, lengthening the duration over which these agents may be used [38,39]. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

The potential for prolonged control of KS was illustrated by a study of 98 patients treated with ART plus pegylated liposomal doxorubicin between 1997 and 2002 [40]. At a median follow-up of 29 months, 29 patients (30 percent) had died, including three with progressive KS. Among the 61 patients who had a complete or partial response of their KS, only eight (13 percent) relapsed after completing chemotherapy. The optimal duration of therapy with liposomal anthracycline is uncertain. A course of four to six cycles of liposomal doxorubicin followed by a period of observation may be reasonable.

Paclitaxel — Although paclitaxel is potentially more toxic than the liposomal anthracyclines, it has striking efficacy as a subsequent treatment for KS [41-45], and may be an alternative for initial therapy of patients with advanced, symptomatic KS, including those in resource-limited settings without access to liposomal anthracyclines [46].

In a randomized trial, paclitaxel demonstrated similar response rates and survival when compared with pegylated liposomal doxorubicin and improved tumor-related symptoms, although the trial was terminated prematurely due to poor accrual. In this study, 73 patients were randomly assigned to paclitaxel (100 mg/m² every two weeks) or pegylated liposomal doxorubicin (20 mg/m² every three weeks) after the introduction of routine treatment with ART [37]. At a median follow-up of 36 months, response rates for paclitaxel and pegylated doxorubicin were 56 and 46 percent; median progression-free survival was 18 and 12 months; and two-year overall survival was 79 and 78 percent, respectively; these differences were not statistically significant. However, both paclitaxel and liposomal doxorubicin were associated with meaningful improvements in pain and swelling secondary to the tumor.

In resource-limited settings where liposomal anthracycline may not be accessible, paclitaxel plus ART is the preferred initial systemic agent, given better outcomes over other regimens such as oral etoposide and bleomycin plus vincristine [46]. In an open-label, non-inferiority randomized trial, 334 patients with treatment-naïve AIDS-related Kaposi sarcoma in Africa and South America were randomly assigned to one of three treatment arms: oral etoposide, intravenous bleomycin plus vincristine, or standard of care intravenous paclitaxel (100 mg/m² every three weeks) [46]. All patients received ART (combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine) concurrently with chemotherapy. Both the etoposide and bleomycin plus vincristine arms were closed early due to inferiority to paclitaxel. At a median follow-up of approximately 62 weeks, paclitaxel improved 48-week progression-free survival rates relative to oral etoposide (50 versus 20 percent, respectively) and bleomycin plus vincristine (64 versus 44 percent, respectively). Objective response rates were better with paclitaxel versus oral etoposide (58 versus 31 percent, respectively), and comparable between paclitaxel and bleomycin plus vincristine (66 versus 61 percent). However, time to death was similar in all of the groups (48-week death rate of approximately 10 to 11 percent for paclitaxel; 26 percent for oral etoposide; and 19 percent for bleomycin plus vincristine).

Similar outcomes were noted across all treatment arms for HIV-1 plasma RNA level suppression, improvement in CD4 counts, grade ≥3 toxicities, and both AIDS-defining and serious non-AIDS defining events. Paclitaxel plus ART also demonstrated a favorable safety profile; compared with paclitaxel, higher pain scores from peripheral neuropathy were seen for both bleomycin plus vincristine (17 versus 7 percent) and oral etoposide (7 versus 0 percent).

The use of paclitaxel regimens in KS patients is subject to two important interactions:

●Paclitaxel administration requires premedication with glucocorticoids. Because of the concern that steroids may further immunosuppress HIV-infected patients and exacerbate KS, the dexamethasone dose is typically reduced to 10 mg orally 12 and 6 hours prior to chemotherapy, instead of the usual 20 mg dose. (See "Infusion reactions to systemic chemotherapy", section on 'Taxanes'.)

●Paclitaxel is metabolized through the cytochrome P450 enzymes, as are many of the antiretroviral drugs. Profound paclitaxel-related toxicity has been ascribed to an interaction between this drug and antiretroviral drugs in at least two patients [47]. However, others have failed to document alterations in paclitaxel elimination pharmacokinetics in one patient treated concurrently with agents such as ritonavir, saquinavir, and nevirapine [48]. Caution is urged when coadministering these agents. (See "Systemic therapy for malignancy in patients on antiretroviral medications".)

Steroid reduction or withdrawal — In patients being treated with steroids, KS lesions may regress upon reduction or withdrawal of steroids [49,50].

Corticosteroid therapy has been associated with the induction of KS and with the exacerbation of preexisting KS in HIV-infected persons, as well as in non-AIDS patients receiving corticosteroids for organ transplantation, autoimmune disorders, or lymphoproliferative diseases [49]. The association of corticosteroids with KS is important because of the frequent use of these agents in HIV-infected patients with a variety of disorders including immune thrombocytopenia (ITP) and Pneumocystis jirovecii pneumonia.

Subsequent therapy — A number of other agents have been studied in a more limited way in patients with AIDS-related KS, and these may have utility as subsequent-line therapy. The choice amongst them is dependent upon the pace of disease progression and symptoms.

Rapidly progressive disease

Paclitaxel — Paclitaxel is our preferred therapy for patients who have rapid progression after initial treatment with a liposomal anthracycline. The use of paclitaxel as subsequent therapy after liposomal doxorubicin is discussed above. (See 'Paclitaxel' above.)

Vinorelbine — Vinorelbine may be effective in the treatment of patients with AIDS-related KS who have failed other treatments, including other vinca alkaloids. In one series of 35 patients treated with vinorelbine (30 mg/m² every two weeks), three (9 percent) had a complete clinical response, and 12 (34 percent) had a partial response, which lasted for a median of 151 days [51].

Etoposide — Oral etoposide has been reported to have activity in AIDS-related KS when given either in fractionated doses (20 mg/m² every eight hours for 7 of 21 days) [52] or as a once daily dose of 50 mg for 7 of every 14 days [53]. However, oral etoposide was inferior to paclitaxel in a randomized trial. (See 'Paclitaxel' above.)

Gemcitabine — Gemcitabine is a treatment option for patients with chemotherapy-naïve AIDS-related KS who have progressed despite combined ART, particularly in resource-limited settings. In a randomized phase II trial of 70 such patients in Western Kenya, gemcitabine demonstrated similar overall survival and response rates when compared with bleomycin plus vincristine [54,55]. Toxicity rates and improvements in health-related quality of life were also similar between the two groups [54].

Indolent disease (pomalidomide) — For those with indolent, minimally symptomatic disease progression on chemotherapy and combined ART, we offer pomalidomide as an alternative to chemotherapy due to the potential for high response rates, favorable toxicity profile (eg, to avoid the alopecia and peripheral neuropathy associated with taxanes), and convenience of oral administration. However, chemotherapy (with paclitaxel or other agents not previously received) is also a reasonable option in this setting, as pomalidomide has not been directly compared with chemotherapy in randomized trials. (See 'Subsequent therapy' above.)

Pomalidomide is an oral treatment option for patients with AIDS-related KS who have failed combined ART and have progressed on initial chemotherapy with liposomal anthracyclines. Combined ART should be continued concurrently with pomalidomide. ART management is discussed separately. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Patients with AIDS-related KS may experience disease-related cytopenias and peripheral edema. Since pomalidomide can result in myelosuppression and venous thromboembolism (VTE), patients should have close monitoring of complete blood counts and receive appropriate VTE prophylaxis while on therapy. The approach to administration, VTE prophylaxis, and modification of pomalidomide dosing for organ dysfunction are discussed separately. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Pomalidomide'.)

Pomalidomide was investigated in an open-label, single-arm phase I/II trial (12-C-0047) of 28 patients with KS, a majority of whom (75 percent) had previously received chemotherapy [56]. Among the cohort of 18 HIV-positive patients, overall responses were seen in 12 patients (67 percent), including three complete responses (17 percent); median duration of response was 12.5 months. Grade ≥3 toxicities included neutropenia (50 percent), decreased phosphate (25 percent), elevated glucose (7 percent), elevated creatinine, rash, diarrhea, and peripheral edema (4 percent each). Neurologic toxicities related to pomalidomide are discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Pomalidomide'.)

Based on these results, the US Food and Drug Administration (FDA) granted approval for pomalidomide in patients with AIDS-related KS after failure of combined ART [57]. Pomalidomide has not been evaluated as initial therapy or directly compared with other available systemic therapies. Further studies are also needed to evaluate the long-term efficacy of this agent.

Is there a role for interferon alfa-2b? — Interferon alfa-2b produces clinically significant responses in approximately 20 to 40 percent of patients with AIDS-related KS, especially those with disease limited to the skin and relatively modest immunosuppression [58,59]. Interferon alfa-2b is approved by the FDA for the treatment of patients with AIDS-related KS, but it is very rarely used because it has limited availability (as the manufacturer has discontinued production) and other agents have more favorable efficacy and toxicity profiles.

In a randomized trial, patients with AIDS-related KS were treated with zidovudine and interferon alfa-2b at a dose of either one or eight million units subcutaneously per day [59]. With the high-dose regimen, the response rate was much higher (31 versus 8 percent) and the median time to progression longer (18 versus 13 weeks). Responses at both doses were more likely in patients with CD4 counts above 150/microL. However, almost all patients in the high-dose arm required dose reduction for significant toxicity consisting of fever, chills, rigors, neutropenia, hepatotoxicity, and cognitive impairment.

EXPERIMENTAL APPROACHES — Advances in the understanding of the pathogenesis of KS are uncovering potential targets for KS therapies [60,61]. Such targets include angiogenesis, sex hormones, vitamin D and its analogs, and cellular differentiation. Additional studies will be required to determine the role of these experimental therapies in KS patients. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

Anti-HHV-8 therapy — Identification of human herpesvirus 8 (HHV-8) as the etiologic agent of KS provides another potential target for treatment. However, there are no specific anti-HHV-8 therapies available.

Case-control studies of historical cohorts of HIV-seropositive subjects suggest that there is a lower incidence of KS in patients treated with ganciclovir or foscarnet, but not acyclovir [62,63]. Indirect evidence for the efficacy of ganciclovir also comes from a randomized trial in which 377 HIV-seropositive patients with cytomegalovirus retinitis were assigned to receive a ganciclovir intraocular implant plus oral ganciclovir, a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone [64]. Treatment with oral or intravenous ganciclovir reduced the risk of KS by 75 and 93 percent, respectively, compared with placebo.

New agents might inhibit the specific protein products of the virus that contribute to KS spindle cell growth as well as block the effects of the switched-on chemokine receptor. As this work progresses, the primary focus will be to sustain a high level of cellular immunity with antiretroviral therapy so that host defenses can provide the needed surveillance to suppress the neoplasm.

Other agents

●Imatinib – Activation of the platelet-derived growth factor (PDGF) and c-kit receptors (both receptor tyrosine kinases) are important in the growth of KS lesions and imatinib inhibits both of these receptors. In a multicenter phase II study, 30 patients were treated with imatinib for up to 12 months [65]. Patients with symptomatic visceral disease requiring chemotherapy were excluded. Antiretroviral therapy was permitted but not required. Partial responses were observed in 10 patients (33 percent). Treatment was generally well tolerated and nine patients completed the full year of treatment.

●Inhibitors of mTOR pathway – Rapamycin and temsirolimus are inhibitors of the mechanistic target of rapamycin (mTOR) pathway and appear to have activity in patients with KS. The demonstration of patients who had regression of their transplant-related KS when treated with rapamycin indicates that the phosphoinositide 3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR) pathway may be important in the pathogenesis of KS [66]. In another study, seven patients with HIV-related KS were treated with a combination of rapamycin plus antiretroviral therapy [67]. Three patients, all on protease inhibitor containing regimens, had a partial response of their KS to treatment.

●Bevacizumab – Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor, which contributes to the pathogenesis of KS. In a phase II study, treatment of 17 patients with HIV associated KS using bevacizumab resulted in objective responses (complete or partial) in five cases and stable disease in nine additional cases [68].

●Miscellaneous agents – A number of other agents have shown at least some evidence of activity in early studies in patients with AIDS-related KS. These include the angiogenesis inhibitors fumagillin [69] and thalidomide [70], the differentiation-inducing agent 9-cis retinoic acid [71], the matrix metalloproteinase inhibitor COL-3 [72], interleukin-12 [73,74], and intralesional injection of human chorionic gonadotropin [75,76]. There is also emerging information regarding the salutary effects of the protease inhibitor nelfinavir as an anti-KS drug, and clinical trials are ongoing (NCT03077451).

PROGNOSIS — The development of combination ART and its application has led to a striking decrease in the incidence of KS and an improvement in the prognosis of patients with HIV-related KS, which frequently had been associated with early death. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Impact of antiretroviral therapy'.)

The prognosis of patients with HIV-related KS since the introduction of ART is illustrated by a consecutive series of 469 cases treated since 1998 at a single center [77]. Of these, 303 presented with T0 disease (65 percent) and 166 had T1 involvement (35 percent). Those with T0 disease generally were treated with ART alone, unless there was a need for symptomatic treatment of localized lesions, while those with T1 disease were managed with chemotherapy plus ART. For those with T0 disease, the overall five-year survival was 92 percent and for those with T1 disease the five-year survival 83 percent. (See 'Staging and evaluation' above.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Kaposi sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Treatment approach – For HIV-positive patients who develop either limited or advanced Kaposi sarcoma (KS), we recommend that treatment include combined antiretroviral therapy (ART) (Grade 1B). For some patients, ART maybe sufficient to induce regression of the KS. Others will require ART plus local or systemic chemotherapy. (See 'Combined antiretroviral therapy' above and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

●Limited symptomatic disease – For patients who have limited disease causing symptoms or cosmetic disfigurement, we suggest local treatment rather than systemic chemotherapy in addition to ART (Grade 2C). (See 'Local symptomatic therapy' above.)

•Intralesional chemotherapy – For patients with small lesions, we suggest intralesional chemotherapy (Grade 2C).

•Radiation therapy – For those with larger lesions that cannot be managed with intralesional chemotherapy, we suggest radiation therapy (Grade 2C).

●Indications for chemotherapy plus combined ART – Indications for the addition of systemic chemotherapy to ART include extensive cutaneous disease; symptomatic visceral involvement; and cutaneous KS that is unresponsive to local therapy. (See 'Systemic therapy' above.)

Chemotherapy is also indicated for patients with the immune reconstitution inflammatory syndrome (ie, progressive KS within weeks after initiation of ART). (See 'Immune reconstitution inflammatory syndrome' above.)

●Initial therapy – For patients with AIDS-related KS who have an indication for systemic therapy, we suggest initial systemic chemotherapy with liposomal doxorubicin rather than a combination of older agents or a taxane (Grade 2B). However, liposomal doxorubicin may not be available in resource-limited settings, and in such cases, paclitaxel is an acceptable alternative. (See 'Liposomal doxorubicin (preferred)' above and 'Paclitaxel' above.)

●Subsequent therapy – The choice of subsequent therapy is dependent upon the pace of disease progression and symptoms.

For patients with rapid progression on a liposomal anthracycline, we suggest chemotherapy with paclitaxel (Grade 2C). (See 'Paclitaxel' above.)

For patients with indolent progression on a liposomal anthracycline and ART, we suggest the use of pomalidomide as an alternative to chemotherapy, due to the potential for high response rates, favorable toxicity profile, and convenience of oral administration. (See 'Indolent disease (pomalidomide)' above.)