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Kaposi’s sarcoma


1.1 Incidence and mortality

Based on clinical and epidemiological characteristic Kaposi’s sarcoma (KS) has been classified in four groups: classic, endemic, transplant-associated and epidemic KS.
The classic KS affects mainly males over 60 years of age of Ashkenazi Jewish and Mediterranean origin. The endemic KS involves usually the lower extremities and is diffused among children and middle-aged adults in several sub-Saharan countries; this form was diffused far before the HIV epidemy in Africa. The transplant-associated KS is diffused among solid organ transplant recipients, in these subjects the risk of KS is 500-1000-times higher than in the general population and the epidemic KS is associated to the HIV infection and is mainly diffused among homosexual men (Hengge 2002; Schwartz 2004; Simonart 2006; Szajerka 2007).
The incidence of KS is very high in the African continent compared to the other continents. The incidence rate of KS in 2002 is low in northern Africa (less than 0.2 per 100,000), whereas in subsaharian Africa the rate is 12.2 in men, with a peak of 20.1 in middle Africa, and 5.3 in women, with a peak of 8.2 in Eastern Africa (Globcan 2002). In Europe the incidence rate of KS is low, however mediterrean country has higher rates. Actually the highest rates in Europe are in Sicily (30.1 per million in men and 5.5 per million in women between 1976 and 1984) and in Sardinia (24.3 per million in men and 7.7 per million in women between 1977 and 1991 (Simonart 2006; Cottoni  1996; Geddes 1994). In Italy the annual incidence rate of AIDS related KS from 1985 to 1998 is 1.0/100,000  in men and 0.4/100 000 in women (Dal Maso 2005). In Italy in the same period classic KS accounted for 16 and 27% of KS cases below 55 years of age in men and women, respectively, but for 91 and 100% of those above age 55 (Dal Maso 2005). The incidence of epidemic KS reduced in recent times since the introduction of highly active anti-retroviral therapy, in areas where the therapy is available (Franceschi 2008; Schwartz 2004; Portsmouth 2003). In Northern Africa the mortality rate of KS is low (less than 0.2 per 100000), whereas in sub-Saharan Africa the rate is 11.0 in male and 4.9 in women. The Geographical distribution of death rates in Africa follow a similar pattern of incidence (Figure 1) (Globcan 2002).

Figure 1. Mortality and incidence (age standardised) rates for Kaposi sarcoma in Africa


A recent study from Italy on cancer mortality has shown that from 1995 to 2002 in Italy died 1967 persons for whom the death certificate mentioned KS as a cause of death, among these 902 patients had AIDS/HIV and 30 were organ transplant recipients. The ratio of death for classic KS between men and women in this study is 1.9 (Ascoli 2009).
Classic Kaposi’s sarcoma is rarely considered to be an actual cause of death, however there are not population study evaluating this issue and moreover the mortality data for this cancer are not separately identifiable through current conventional mortality coding practices (Ascoli 2009; SEER)
Classic KS is usually an indolent tumours, epidemic KS has a more aggressive course, endemic KS presents in different clinically distinct patterns with a different clinical course. The course of transplant-associated KS may be chronic or rapidly progressive, however after the discontinuation of immunosuppressive therapy the spontaneous remission of the disease is the norm (Hengge 2002; Schwartz 2004)

1.2 Survival

The relative survival rate in Europe from 2000 and 2002 was 80% at 1 year and 61% after 5 years since diagnosis. Among the Eastern Europe, relative survival ranged from 77% (Northern Europe) to 52% (Eastern Europe). Five-year survival was 53% in country with a lower expenditure of health (Total National Expenditure of Health, TNEH per capita less than 1,500 US$), whereas was higher 67% in those countries with a higher expenditure (TNEH per capita more than 2,250 US$) (Rarecare).

1.3 Risk factors

There is a strong epidemiologic evidence that human herpes virus-8 (HHV-8) is directly involved in the development of the four form of KS: HHV-8 infection seems to be a necessary condition. However, the risk of KS associated with HHV-8 infection is low: the prevalence of the infection is quite high world wide (2-10%) but only a small fraction of infected subject developed KS. (Chatlynne 1999; Simmonart 2006). Prevalence of HHV-8 varies  across the world: it is very high in the sub-Saharan Africa, approximately 40% of the population is positive; in the Mediterranean countries the seroprevalence is approximately 10%; whereas in the northern Europe, southeast Asian  and Caribbean countries the seroprevalence rates is in the range of 2-4%. In the United States, a ‘ mixing bowl’ country the seroprevalence is in the range of 20% (Chatlynne 1999). Among men, HHV-8 transmission may occur through sexual activity, particularly sex with other men. No evidence was observed for heterosexual transmission to women (Engels 2007).
Previously to discover of HHV-8, HIV infection was considered as a unique cause of KS. KS was initially seen in about one-third of those with early AIDS (Schwartz 2004).  Nowadays it is assumed that the HIV-1 Tat protein (a product of the transactivator gene) acts as a cofactor in KS development by stimulating angiogenesis; the studies of its antiapoptotic effect in different types of cells seem contradictory (Szajerka 2007).
The immunosuppresion is a risk factor for KS, immunosuppression is not only related to HIV infection but also with immunosoppressive therapies that are common among transplant patients. A study from Italy on kidney transplant patients found that 23% of patients who were HHV-8 positive before transplantation developed KS, whereas only 0.7% of seronegative patients developed the disease. So even if after the trasplantation the seroprevalence of HHV8 increased, the main risk factor was the infection before trasplantation (Schwartz 2004). There is some evidence that KS can regress when the immunosoppressive therapy stops (Haverkos  2008; Puppin 1990; Labre 1991; Bilen 2002). A recent follow-up study of 1844 renal transplant patients in Italy showed a 113-fold increased risk for Kaposi’s sarcoma (Serraino 2005 )
Some risk factors other than HHV-8 and HIV infections has been analyzed. However. these other associations are difficult to study. This is due to the high importance of the two main risk factors (HHV-8 and HIV), to the very low incidence of KS and to the existence of four different types of KS with possible different etiologic patterns.
Ziegler and collegues observed a geographical proximity of African endemic KS to areas containing volcanic clay minerals (Ziegler 1997). In other regions with the presence of iron rich volcanic, mafic minerals in the clay soil (i.e. the East African Rift, Sicily and Sardinia, the Faroe Islands and Iceland) a high incidence of KS was observed (Szajerka 2007). In a study among the population living close to the Mount Vesuvius was found an increased risk of KS among those with birth or residence in areas with volcanic soils (Montella 1997). The exposure to alumino-silicate or iron-rich soil, may be the reason of the increased risk of KS in vulcanica areas (Pelser 2009; Simmonart 2006).
Nitrite use was supposed to be a risk factor for KS. The epidemiology of nitrite use in the United States parallels that of HIV-related KS, and some but not all, epidemiologic studies have shown a statistical association between the development of KS among gay men with AIDS and the use of large quantities of nitrite inhalants when compared with gay men with AIDS, but without KS (Haverkos 2008). However, a recent study on drugs did not find an association beetween nitrite use and KS (Chao 2009). Plausible mechanisms of action have been proposed for nitrites and their metabolites, such as cholesteryl nitrite and nitrosamines, to be carcinogenic, and mutagenesic (Haverkos 2008).
A borderline increase in classic KS risk among elderly subjects originating from Africa or Asia was identified in a case-control study from Israel. The authors believe that genetic and immunologic parameters may alter risk for CKS (Guttmann 2006). The same authors presented a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency (Guttmann 2004). Moreover the higher incidence of KS among Jewish, in mediterranean and subsaharian country support the hypothesis of a genetic component of the tumor (Simmonart 2006)


2.1 Histology

Kaposi’s Sarcoma (KS) is a multifocal angioproliferative disease characterised histologically by neoangiogenesis and proliferating spindle-shaped cells, admixed with a variable chronic inflammatory infiltrate. Spindle tumour cells express many endothelial markers.  HHV-8 can infect endothelial cells and induce KS-like spindle cell morphology in vitro. It has recently been shown that circulating endothelial precursor cells in patients with KS have evidence of HHV-8 infection (Gill 2007).

2.2 Biology

HHV-8, a member of the transforming family of gamma herpes viruses, has been found in all forms of KS and in two lymphoproliferative diseases: primary effusion lymphoma (PEL) and Multicentric Castleman’s disease. The virus encodes a number of genes homologous to human genes involved in cell proliferation, anti-apoptosis, angiogenesis and cytokine action. Multiple signal transduction pathways are activated by HHV-8 and both latent and lytic viral replicative cycles contribute significantly – but differently – to KS development. Extensive evidence indicates that HIV trans-activating protein Tat plays an oncogenic role in the development of KS. Tat promotes tumourigenesis of endothelial cells,  via stimulation of vascular endothelial growth factors, anti-apoptotic activity and HHV-8 replication (Ensoli 2001; Sullivan 2006; Gill 2007). A model of KS pathogenesis involves exposure to HHV-8, alteration in cytokine expression and response to cytokines, modulation of growth by HIV-Tat and, finally, malignant transformation (Cathomas 2003; Sullivan 2006; Pyakurel 2007).


3.1 Signs and symptoms

Typically, the disease presents with disseminated skin lesions, often with lymph node and visceral involvement such as the gastrointestinal tract and lungs. Skin lesions arise as macular or papular eruptions, which progress to nodular plaques or lesions; any area of the skin may be involved. Nodular KS does not usually cause necrosis of overlying skin and rarely invades underlying bone structures.
Lymphoedema, particularly of the face, genitalia and lower extremities, may be out of proportion to the cutaneous disease and may be related not just to lymphatic obstruction, but also to the cytokines involved in the pathogenesis of KS. Lymphadenopathic KS primarily affects peripheral lymph nodes, sometimes causing massive nodal enlargement, and it may be present in the absence of mucocutaneous disease.
Oral cavity KS occurs in approximately 35% of patients and is the initial site of disease in about 15%. Intra-oral lesions most commonly affect the palate and gingiva, and may interfere with nutrition and speech.
Over 50% of patients with skin disease have gastrointestinal lesions. Any segment of gastrointestinal tract may be involved, although the stomach and duodenum are most commonly affected. Gastrointestinal KS is seldom symptomatic, but may cause bowel malabsorption or obstruction, and, rarely, bleeding.
Pulmonary involvement is also quite common and may be life-threatening. In approximately 20% of cases it may occur in the absence of skin lesions. The symptoms, including shortness of breath, fever, cough, haemoptysis and chest pain. Radiologic appearance of pulmonary KS is indistinguishable from that of the more common opportunistic infections. Radiographic findings vary greatly and can include nodular, interstitial and alveolar infiltrates, pleural effusion, hilar and mediastinal adenopathy, and even an isolated pulmonary nodule. The pleural effusions of KS are typically serosanguineous in nature and are associated with KS lesions on the visceral pleura.

3.2 Diagnostic strategy

Although a presumptive diagnosis of KS can often be made readily by a trained observer, a simple skin biopsy can confirm the diagnosis. It is especially important to biopsy lesions that are less typical of KS because other conditions, such as bacillary angiomatosis, may be confused with KS.


4.1 Staging classification

Staging of KS in HIV-infected individuals presents unique challenges. Unlike other solid tumours, KS usually presents multicentrically, without a defined primary site. In addition, there is an intimate link between KS and HIV infection. The AIDS Clinical Trial Group (ACTG) TIS classification  groups patients according to tumour extent (T), immune status (I) and severity of systemic illness (S) (Krown 1989; Krown 1997).

Good risk
T0 Confined to skin and/or lymph nodes and/or minimal oral disease
(confined to palate)
I0 CD4+ lymphocytes > 150/µL
S0 No history of opportunistic infection or thrush; no systemic B symptoms; Karnofsky performance status (PS) > 70
Poor risk
T1 Tumour-associated oedema or ulceration; extensive oral Kaposi’s sarcoma; gastrointestinal Kaposi’s sarcoma; Kaposi’s sarcoma in viscera
I1 CD4+ lymphocytes < 150/µ L
S1 History of opportunistic infection or thrush; systemic B symptoms; Karnofsky performance status < 70; other HIV-related illness.

A re-evaluation of the TIS staging system during the  era of  highly active antiretroviral therapy  (HAART) suggested that only the high tumour burden (T1) and the poor systemic disease status (S1) could identify patients with poor prognosis (Nasti 2003).

4.2 Staging procedures

4.2.1 Staging

Initial assessment consists of a complete physical examination including careful examination of the oral cavity and rectum and a chest roentgenogram. The character of KS lesions, their colour and degree of nodularity, is the most subjective element of the examination, yet it often provides the most important information about response to treatment. Tumour-associated oedema deserves special attention, as it is considered a hallmark of advanced KS. Photographic documentation is an important part of the clinical evaluation (Krown 1989).
Occult blood testing is an excellent screening method for gastrointestinal tract lesions and endoscopy should be reserved for patients with positive test and/or gastrointestinal symptoms. Lesions in the gastrointestinal tract are often recognized easily on endoscopy; however, because the lesions tend to be submucosal, biopsies may not demonstrate KS.
Bronchoscopy is the procedure of choice for pulmonary KS, but gallium–thallium scanning may also be helpful in evaluating an abnormal radiograph. Kaposi’s sarcoma is usually thallium avid and gallium negative, whereas infections are usually gallium avid and thallium negative.

4.2.2 Virological-immunological assessment

The following laboratory tests should be performed for a new patient during initial patient visits: HIV antibody testing (if prior documentation not available) or if HIV RNA is undetectable, on a type 1 level of evidence . CD4 cell count, on a type 1 level of evidence. Plasma HIV RNA, on a type 1 level of evidence. For patients who have pretreatment HIV RNA > 1000 cp/mL, genotypic resistance testing when they enter into care, regardless of whether antiretroviral therapy will be initiated immediately (type 3 evidence) (Hammer 2008). Plasma HHV8 DNA, on a type 3 level of evidence.


5.1 Natural history

5.1.1 General data

KS ranges from an indolent to an aggressive disease with significant morbidity and mortality. However, KS exhibits a less aggressive presentation in patients already receiving HAART compared with patients who are naïve to HAART at KS diagnosis. Patients on HAART have a more indolent disease presentation, with fewer cutaneous lesions and significantly less frequent GI tract involvement compared with HAART-naive group (Nasti 2003).


In the pre-HAART era, the ACTG TIS classification predicted survival in KS patients; CD4 count (I stage) and T stage provided the most predictive information (Krown 1997). In the HAART era, only T and S stages maintained their correlation with survival. Two different risk categories have been identified:  poor risk (T1S1) and  good risk (T0S0, T1S0, T0S1), with  3-year survival rates of 53% and  80-88%, respectively. Furthermore, pulmonary involvement predicts survival better than tumour extension, independent of the S stage and identifies the poorest category (Nasti 2003).


6.1 General strategy

Treatment of KS has changed substantially in the HAART era. The degree of immunocompetence, the extent of tumour burden (T) and its rate of progression, HIV comorbidity and  PS dictate the choice of treatment. However, optimal anti-retroviral therapy is a key component of KS management, on a type C basis.
The use of steroids should be avoided in patients with KS , since numerous studies have demonstrated the ability of corticosteroids to stimulate either  the proliferation of spindle cells as the expression of HHV8 genes ( Hudnall 1998).

6.2 Local therapy

Although the use of local therapy in the management of KS has declined since the introduction of HAART, local treatments may be useful for managing localized bulky KS lesions or for cosmetic reasons. Local treatments are suitable for individual clinical use on a type 1 level of evidence .

6.2.1 Alitretinoin topical gel

Alitrentinoin (9-cis-retinoic acid)  0.1% topical gel has been approved for KS treatment in the USA, but is not  licensed in Europe. The gel, which can be  patient-administered, is applied  to affected areas twice a day, with a gradual increase to 3 or 4 times per day, depending on the patient’s tolerance. In two randomized studies, the response rate after 12 weeks of therapy  ranged from 35 to 37% compared with 7 and 18%  in the placebo patient group. Toxicity consists of local skin reactions ( Walmsley 1999; Bodsworth 2001).

6.2.2 Radiotherapy

Local radiation can effectively palliate symptomatic disease, but even relatively low doses of radiation may be associated with significant toxicity in HIV-infected individuals. For patients with painful isolated lesions, e.g, heavily affected toes, with symptomatic lymphoedema,  or patients whose   poor PS, reduced hepatic and/or bone marrow reserve preclude chemotherapy, radiotherapy may be a viable option on a type C basis.
A randomized study of radiation fractionation for cutaneous KS showed that response rate and duration of local control were better with fractionated regimens
(40 Gy in 20 fractions and 20 Gy in 10 days) compared with an 8.0 Gy single fraction, although toxicity was worse ( Stelzer 1993). A retrospective study of 80 patients,  including some patients with endemic KS, treated with a radiotherapy dose of 8.0 Gy reported an overall response of 74% (Kigula-Mugambe 2005). In another study of 36 patients with KS of the feet, a schedule of 3 fractions/week at a dose of 3.5 Gy per fraction up to a total dose of 21.0 Gy yielded an overall response (OR) rate of
91% with a complete response (CR) of 80% (Gressen 1999 ).

6.3 Systemic Therapy

6.3.1 HAART as anticancer therapy

Regression of KS with HAART has already been documented in many studies and HAART has been associated with prolonged time-to-treatment failure and longer survival among KS patients who have received chemotherapy (Lebbe 1989; Dupont 1989 ; Bower 1999; Vaccher 1999; Cattelan 2001; Krown 2004; Mocroft 2004; Grabar 2006 ; Di Lorenzo 2007). The available evidence suggests that HAART leads to regression of limited KS. On a type C basis, HAART may be the only anticancer therapy in the early stage of disease (T0) and/or for slowly proliferating disease, when the tumour growth is consistent with the long time interval to the development of the HAART anti-KS activity (median 8-12 months) (16-19).
KS may have a recrudescence during the first 2-3 months of HAART, as an immune reconstitution inflammatory syndrome (IRIS). The syndrome is characterized by rapid cancer progression, despite the suppression of HIV and the immune recovery, and usually occurs in patients with high CD4 cell count and/or the presence of neoplastic oedema. The potentialy additive effects of IRIS with steroid use in KS contraindicates its use as an anti-inflammatory therapy. If KS progression is very rapid and/or there is extensive visceral involvement, chemotherapy  may be needed, on a type 3 level of evidence) (Bower 2005).
Two large prospective cohort studies anlaysing the efficacy of HAART regimens based on either non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (IPs) in preventing KS showed that NNRTI-based regimens are at least as effective as PI-based HAART in preventing KS (Portsmouth 2003; Stebbing 2004). However, no randomized trial has been published comparing PI-based HAART and NNRTI-based HAART in the treatment of AIDS-KS.
The mechanisms underlying the  anticancer activity of HAART are not well elucidated, but restored immunity, decreased levels of angiogenic factors that stimulate KS proliferation, and direct angiogenesis-inhibitory effect of PIs could be involved (Sgadari 2002; Sgadari 2003; Srirangam 2006).

6.3.2 Chemotherapy First line chemotherapy

In patients with T1 and/or rapidly proliferating disease, the first-line treatment is chemotherapy plus HAART followed by maintenance therapy with HAART, on a type C basis .
Although several chemotherapeutic agents (i.e., bleomycin, vinblastine, vincristine, vinorelbine, doxorubicin and etoposide) were noted to be effective against KS in the past, current systemic cytotoxic therapy comprises liposomal anthracyclines (pegylated liposomal doxorubicin [PLD] and liposomal daunorubicin) and taxanes.
Liposomal encapsulation alters drug kinetics, resulting in a prolonged half-life. Currently, liposomal antracyclines are considered the standard first-line chemotherapy for advanced KS patients, on the basis of type 1 evidence . In two pre-HAART randomized studies PLD (20 mg/m2 i.v., every 2 weeks) had activity superior to a combination of ABV (doxorubicin, bleomycin, vincristine) or BV (bleomycin, vincristine), with an OR rate ranging from 46 to 59% and a better safety profile (Northfelt 1998 ; Stewart 1998). Whereas a randomized comparison of liposomal daunorubicin at a dose of 40 mg/m2 i.v., every 2 weeks versus  ABV demonstrated equivalence in terms of OR, time to treatment failure and survival (Gill 1996). In a phase II study, liposomal daunorubicin at a dose of 60 mg/m2 i.v., every 2 weeks in patients with pulmonary KS has resulted in clinical benefit and objective response in 59% and 32% of cases, respectively (Tulpule 1998). Myelosuppression remains the most important dose-limiting toxicity of these drugs. Peripheral neuropathy and palmar-plantar erythrodysthesias occur infrequently and cardiotoxicity is rare. Preliminary evidence indicates that the combination of liposomal anthracyclines and HAART is safe and effective, on the basis of type 2 evidence . Moreover, HAART-mediated immunorecovery does not seem to be impaired by concomitant treatment with liposomal doxorubicin (Nunez 2001; Esdaile 2002 ; Martin-Carbonero 2004; Lichterfeld 2005). Salvage chemotherapy

Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity, is effective even in patients with anthracycline resistant-KS. The drug (100 mg/m2 i.v., every 2 weeks), results in an overall response rate of 56-59%, with a median duration of response of 10.4 months. The major side effects include myalgias, arthralgias and myelosuppression (Gill 1999; Tulpule 2002; Stebbing 2003). Based on these data, paclitaxel is now used after failure of first-line systemic chemotherapy , on the basis of type 3 evidence . Since the metabolism of paclitaxel involves the cytochrome P-450 pathway as does PIs and NNRTIs, caution is necessary when the drug is co-administered with HAART. The concomitant use of paclitaxel and HAART appears to be safe and not detrimental to immune function. In one open-label trial 107 patients were treated with paclitaxel (100mg/ m2) and 77% were receiving concomitant first generation PI-based HAART. There was no significant difference in response rate when comparing patients on or not on HAART. The main side effect of the combination was neutropenia, that generally resolved prior to the next cycle (Tulpule 2002). In contrast to these results, several case reports describe severe paclitaxel-related toxicity when used in combination with ritonavir boosted PIs (Bundow 2004 ; Parawesmaran 2002). Although other confounding factors may have been present, these case series serve as a remnider  of the monitoring that is necessary when taxanes and boosted-PIs are coadministered.
Clinical experience with docetaxel is more limited than that with paclitaxel. However, small studies suggest that this alternate taxane can produce frequent severe neutropenia (Lim 2005; Autier 2005).

6.4 Immunotherapy

Alfa-interferon was approved for the treatment of KS many years before the availability of liposomal  anthracyclines  and  HAART. In patients with moderately extensive  cutaneous or mucosal disease, the combination of low dose (=/<18MU/day) alfa-interferon plus zidovudine or didanosine showed a low OR rate, ranging from 10 to 55%. Poor tumour response and higher toxicity was most striking in patients with CD4 < 200/µL. Frequent myelosuppression, hepatic toxicity and constitutional symptoms limited its use (Shepherd 1998; Krown 2002).

6.5 Experimental therapy

The growing knowledge of KS biology provides multiple opportunities for rational targeted therapies. However, preliminary results of small phase I-II studies clinical trials suggest that there may a role for thalidomide (OR 47%) (Little 2000), but neither the optimal dose nor its correlation with clinical response has been defined (Dittmer 2007). Targeted therapy remains investigational treatment.

6.6 Response criteria

Since criteria for response to treatment in early clinical trial have varied considerably, the ACTG (Krown 1989) has recommended the following response criteria.

6.6.1 Complete remission

The absence of any detectable residual disease, including tumour-associated oedema, persisting for at least 4 weeks.

6.6.2 Partial remission

A 50% or greater decrease in the number and/or size of previously existing lesions (skin, oral, measurable or evaluable visceral disease) lasting for at least 4 weeks without the appearance of new skin or oral lesions or new visceral sites of involvement or the appearance or worsening of tumour-associated oedema or effusions, or an increase of 25% or more in the product of bidimensional diameters of any indicator lesion. A 50% decrease in the size of lesions includes a 50% decrease in the sums of the products of the largest perpendicular diameters of bidimensionally measurable marker lesions and/or complete flattering of at least 50% of the lesions  (ie, 50% of previously nodular or plaque-like lesions become macules).

6.6.3  Stable disease

Any response not meeting the criteria for progression or partial remission.

6.6.4    Progressive disease

An increase of 25% or more in the size of previously existing lesions and/or the appearance of new lesions or new sites of disease and/or a change in the character of 25% of more of the skin or oral lesions from macular to plaque-like nodular. The development of new or increasing tumour-associated oedema or effusion is also considered to represent disease progression.

6A Chemotherapy schedules
•    Liposomal Doxorubicin: 20 mg/m2 i.v., every 2 weeks
•    Liposomal Daunorubicin: 40-60 mg/m2 i.v., every 2 weeks
•    Paclitaxel: 100 mg/m2 i.v., every 2 weeks.

6B Infection prophylaxis
Standard opportunistic infection prophylaxis guidelines should be followed when treating  KS patients with chemotherapy, on type C basis (


No data have been published on late sequelae of KS treatment. However, it is known that as HIV-infected patients have lived longer, there has been increasing concern over HAART long-term toxicity. Insulin resistance, hypertriglyceridemia with increases in atherogenic non-high-density lipoprotein cholesterol and coronary artery disease are the most frequent long–term toxicities of PI-based HAART regimens (Carr 1998; Shaly 2007). Whereas, hepatotoxicity and mitochondrial toxicity are in the most cases attributable to NNRTIs-based and nucleoside reverse transcriptase inhibitor (RTI)-based HAART, respectively (Friis-Moller 2007). Recently, in a Swiss cohort study the presence of laboratory adverse events was associated with higher rates of mortality during follow-up, highlighting the importance of adverse events in overall patient management (Keiser 2007). Further studies are also needed to evaluate the short as well as the long-term cross-toxicity of the combined treatment of chemotherapy and HAART.


8.1 General principles and objectives

The management of HIV-infected patients with cancer is a highly specialized activity that requires expertise in clinical oncology, infectious diseases, immunology, pathology and haematology, on a type C evidence basis.
Each HIV-infected patient with cancer entering into care should have regular multidisciplinary follow-up. The purpose is to monitor cancer (response to anticancer therapy, relapse, persistence, progression), HIV infection and response to HAART (plasma HIV RNA, CD4 count), (Hammer 2008), HIV comorbidity  (prevention and treatment of opportunistic infections) (Adult prevention and treatment of opportunistic infections guidelines working group, to monitor acute and late toxicity of both HAART and anticancer therapy, including the impact of chemotherapy on immune system and co-infections (eg HCV, HBV, HPV, EBV), on a type R evidence. The disease evaluation during follow-up consists of careful physical examination; additional studies should only be performed as indicated by the patient’s symptoms, findings on physical examination or laboratory studies, on a type C evidence basis .

8.2 Laboratory tests

To monitor HIV infection see staging procedure section. Laboratory testing will aim at monitoring treatment-related side effects.

8.3 Suggested protocols

A first complete evaluation should be performed 1 month after the completion of treatment. The next evaluation should be scheduled every two months for the first three years, every three-four months thereafter.



Ascoli V, Minelli G, Kanieff M, Crialesi R, Frova L, Conti S. Cause-specific mortality in classic Kaposi’s sarcoma: a population-based study in Italy (1995-2002). Br J Cancer 2009; 101: 1085-1090 [Medline]

Autier J, Picard-Dahan C, Marinho E, Grossin M, Yeni P, Leport C, et al. Docetaxel in anthracycline-pretreated AIDS-related Kaposi’s sarcoma: a retrospective study. Br J Dermatol 2005; 152: 1026-1029 [Medline]

Bilen N, Bayramgurler D, Aydeniz B, Apaydin R, Ozkara SK. Possible causal role of lisinopril in a case of Kaposi’s sarcoma. Br J Dermatol 2002; 147: 1042-1044 [Medline]

Bodsworth NJ, Bloch M, Bower M, Donnell D, Yocum R. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi’s sarcoma. Am J Clin Dermatol 2001; 2: 77-87 [Medline]

Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B. Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi’s sarcoma. AIDS 1999; 13: 2105-2111 [Medline]

Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Mandalia S, et al. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005; 23: 5224-5228 [Medline]

Bundow D, Aboulafia DM. Potential drug interaction with paclitaxel and highly active antiretroviral therapy in two patients with AIDS-associated Kaposi sarcoma. Am J Clin Oncol 2004; 27: 81-84 [Medline]

Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12: F51-F58 [Medline]

Cathomas G. Kaposi’s sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) as a tumour virus. Herpes 2003; 10: 72-77 [Medline]

Cattelan AM, Calabro ML, Gasperini P, Aversa SM, Zanchetta M, Meneghetti F, et al. Acquired immunodeficiency syndrome-related Kaposi’s sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome. J Natl Cancer Inst Monogr 2001; 44-49 [Medline]

Chao C, Jacobson LP, Jenkins FJ, Tashkin D, Martinez-Maza O, Roth MD, et al. Recreational drug use and risk of Kaposi’s sarcoma in HIV- and HHV-8-coinfected homosexual men. AIDS Res Hum Retroviruses 2009; 25: 149-156 [Medline]

Chatlynne LG, Ablashi DV. Seroepidemiology of Kaposi’s sarcoma-associated herpesvirus (KSHV). Semin Cancer Biol 1999; 9: 175-185 [Medline]

Cottoni F, De MR, Montesu MA. Classical Kaposi’s sarcoma in north-east Sardinia: an overview from 1977 to 1991. Br J Cancer 1996; 73: 1132-1133 [Medline]

Dal Maso L, Polesel J, Ascoli V, Zambon P, Budroni M, Ferretti S, et al. Classic Kaposi’s sarcoma in Italy, 1985-1998. Br J Cancer 2005; 92: 188-193 [Medline]

Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, Di TR, De PS, Dezube BJ. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol 2007; 8: 167-176 [Medline]

Dittmer DP, Krown SE. Targeted therapy for Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus. Curr Opin Oncol 2007; 19: 452-457 [Medline]

Dupont C, Vasseur E, Beauchet A, Aegerter P, Berthe H, de TP, et al. Long-term efficacy on Kaposi’s sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. CISIH 92. Centre d’information et de soins de l’immunodeficience humaine. AIDS 2000; 14: 987-993 [Medline]

Engels EA, Atkinson JO, Graubard BI, McQuillan GM, Gamache C, Mbisa G, et al. Risk factors for human herpesvirus 8 infection among adults in the United States and evidence for sexual transmission. J Infect Dis 2007; 196: 199-207 [Medline]

Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P. Biology of Kaposi’s sarcoma. Eur J Cancer 2001; 37: 1251-1269 [Medline]

Esdaile B, Davis M, Portsmouth S, Sarker D, Nelson M, Gazzard B, et al. The immunological effects of concomitant highly active antiretroviral therapy and liposomal anthracycline treatment of HIV-1-associated Kaposi’s sarcoma. AIDS 2002; 16: 2344-2347 [Medline]

Franceschi S, Maso LD, Rickenbach M, Polesel J, Hirschel B, Cavassini M, et al. Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. Br J Cancer 2008; 99: 800-804 [Medline]

Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356: 1723-1735 [Medline]

Geddes M, Franceschi S, Barchielli A, Falcini F, Carli S, Cocconi G, et al. Kaposi’s sarcoma in Italy before and after the AIDS epidemic. Br J Cancer 1994; 69: 333-336 [Medline]

Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin Oncol 1996; 14: 2353-2364 [Medline]

Gill PS, Tulpule A, Espina BM, Cabriales S, Bresnahan J, Ilaw M, et al. Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 1999; 17: 1876-1883 [Medline]

Gill PS. The origin of Kaposi sarcoma. J Natl Cancer Inst 2007; 99: 1063 [Medline]


Grabar S, Abraham B, Mahamat A, Del GP, Rosenthal E, Costagliola D. Differential impact of combination antiretroviral therapy in preventing Kaposi’s sarcoma with and without visceral involvement. J Clin Oncol 2006; 24: 3408-3414 [Medline]

Gressen EL, Rosenstock JG, Xie Y, Corn BW. Palliative treatment of epidemic Kaposi sarcoma of the feet. Am J Clin Oncol 1999; 22: 286-290 [Medline]

Guttman-Yassky E, Cohen A, Kra-Oz Z, Friedman-Birnbaum R, Sprecher E, Zaltzman N, et al. Familial clustering of classic Kaposi sarcoma. J Infect Dis 2004; 189: 2023-2026 [Medline]

Guttman-Yassky E, Dubnov J, Kra-Oz Z, Friedman-Birnbaum R, Silbermann M, Barchana M, et al. Classic Kaposi sarcoma. Which KSHV-seropositive individuals are at risk? Cancer 2006; 106: 413-419 [Medline]

Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300: 555-570 [Medline]

Haverkos HW. Multifactorial etiology of Kaposi’ sarcoma: a hypothesis. J Biosci 2008; 33: 643-651 [Medline]

Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, Schwartz RA, et al. Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman’s disease, and pleural effusion lymphoma. Lancet Infect Dis 2002; 2: 344-352 [Medline]

Hudnall SD, Rady PL, Tyring SK, Fish JC. Serologic and molecular evidence of human herpesvirus 8 activation in renal transplant recipients. J Infect Dis 1998; 178: 1791-1794 [Medline]

Keiser O, Fellay J, Opravil M, Hirsch HH, Hirschel B, Bernasconi E, et al. Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification. Antivir Ther 2007; 12: 1157-1164 [Medline]

Kigula-Mugambe JB, Kavuma A. Epidemic and endemic Kaposi’s sarcoma: a comparison of outcomes and survival after radiotherapy. Radiother Oncol 2005; 76: 59-62 [Medline]

Krown SE, Metroka C, Wernz JC. Kaposi’s sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1989; 7: 1201-1207 [Medline]

Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1997; 15: 3085-3092 [Medline]

Krown SE, Li P, von Roenn JH, Paredes J, Huang J, Testa MA. Efficacy of low-dose interferon with antiretroviral therapy in Kaposi’s sarcoma: a randomized phase II AIDS clinical trials group study. J Interferon Cytokine Res 2002; 22: 295-303 [Medline]

Krown SE. Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol 2004; 22: 399-402 [Medline]

Larbre JP, Nicolas JF, Collet P, Larbre B, Llorca G. Kaposi’s sarcoma in a patient with rheumatoid arthritis possible responsibility of captopril in the development of lesions. J Rheumatol 1991; 18: 476-477 [ Medline]

Lebbe C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi’s sarcoma. AIDS 1998; 12: F45-F49 [Medline]

Lichterfeld M, Qurishi N, Hoffmann C, Hochdorfer B, Brockmeyer NH, Arasteh K, et al. Treatment of HIV-1-associated Kaposi’s sarcoma with pegylated liposomal doxorubicin and HAART simultaneously induces effective tumor remission and CD4+ T cell recovery. Infection 2005; 33: 140-147 [Medline]

Lim ST, Tupule A, Espina BM, Levine AM. Weekly docetaxel is safe and effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer 2005; 103: 417-421 [Medline]

Little RF, Wyvill KM, Pluda JM, Welles L, Marshall V, Figg WD, et al. Activity of thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol 2000; 18: 2593-2602 [Medline]

Martin-Carbonero L, Barrios A, Saballs P, Sirera G, Santos J, Palacios R, et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi’s sarcoma. AIDS 2004; 18: 1737-1740 [Medline]

Mocroft A, Kirk O, Clumeck N, Gargalianos-Kakolyris P, Trocha H, Chentsova N, et al. The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study. Cancer 2004; 100: 2644-2654 [Medline]

Montella M, Franceschi S, Geddes da FM, De MM, Arniani S, Balzi D, et al. [Classical Kaposi sarcoma and volcanic soil in southern Italy: a case-control study]. Epidemiol Prev 1997; 21: 114-117 [Medline]

Nasti G, Martellotta F, Berretta M, Mena M, Fasan M, Di PG, et al. Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer 2003; 98: 2440-2446 [Medline]

Nasti G, Talamini R, Antinori A, Martellotta F, Jacchetti G, Chiodo F, et al. AIDS-related Kaposi’s Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era–the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals. J Clin Oncol 2003; 21: 2876-2882 [Medline]

Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol 1998; 16: 2445-2451 [Medline]

Nunez M, Saballs P, Valencia ME, Santos J, Ferrer E, Santos I, et al. Response to liposomal doxorubicin and clinical outcome of HIV-1-infected patients with Kaposi’s sarcoma receiving highly active antiretroviral therapy. HIV Clin Trials 2001; 2: 429-437 [Medline]

Pelser C, Dazzi C, Graubard BI, Lauria C, Vitale F, Goedert JJ. Risk of classic Kaposi sarcoma with residential exposure to volcanic and related soils in Sicily. Ann Epidemiol 2009; 19: 597-601 [Medline]

Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, et al. A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi’s sarcoma. AIDS 2003; 17: F17-F22 [Medline]

Puppin D, Jr., Rybojad M, de la CC, Morel P. Kaposi’s sarcoma associated with captopril. Lancet 1990; 336: 1251-1252 [Medline]

Parameswaran R, Sweeney C, Einhorn LH. Interaction between HAART and taxanes: a report of two cases. Proc Am Soc Clin Oncol. 2002, 21: A21-29

Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Biberfeld P. KSHV/HHV-8 and HIV infection in Kaposi’s sarcoma development. Infect Agent Cancer 2007; 2:4.: 4 [Medline]


Schwartz RA. Kaposi’s sarcoma: an update. J Surg Oncol 2004; 87: 146-151 [Medline]


Serraino D, Piselli P, Angeletti C, Minetti E, Pozzetto A, Civati G, et al. Risk of Kaposi’s sarcoma and of other cancers in Italian renal transplant patients. Br J Cancer 2005; 92: 572-575 [Medline]

Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 2002; 8: 225-232 [Medline]

Sgadari C, Monini P, Barillari G, Ensoli B. Use of HIV protease inhibitors to block Kaposi’s sarcoma and tumour growth. Lancet Oncol 2003; 4: 537-547 [Medline]

Shepherd FA, Beaulieu R, Gelmon K, Thuot CA, Sawka C, Read S, et al. Prospective randomized trial of two dose levels of interferon alfa with zidovudine for the treatment of Kaposi’s sarcoma associated with human immunodeficiency virus infection: a Canadian HIV Clinical Trials Network study. J Clin Oncol 1998; 16: 1736-1742 [Medline]

Shlay JC, Bartsch G, Peng G, Wang J, Grunfeld C, Gibert CL, et al. Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy. J Acquir Immune Defic Syndr 2007; 44: 506-517 [Medline]

Simonart T. Role of environmental factors in the pathogenesis of classic and African-endemic Kaposi sarcoma. Cancer Lett 2006; 244: 1-7 [Medline]

Srirangam A, Mitra R, Wang M, Gorski JC, Badve S, Baldridge L, et al. Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer. Clin Cancer Res 2006; 12: 1883-1896 [Medline]

Stebbing J, Wildfire A, Portsmouth S, Powles T, Thirlwell C, Hewitt P, et al. Paclitaxel for anthracycline-resistant AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations. Ann Oncol 2003; 14: 1660-1666 [Medline]

Stebbing J, Portsmouth S, Nelson M, Mandalia S, Kandil H, Alexander N, et al. The efficacy of ritonavir in the prevention of AIDS-related Kaposi’s sarcoma. Int J Cancer 2004; 108: 631-633 [Medline]

Stelzer KJ, Griffin TW. A randomized prospective trial of radiation therapy for AIDS-associated Kaposi’s sarcoma. Int J Radiat Oncol Biol Phys 1993; 27: 1057-1061 [Medline]

Stewart S, Jablonowski H, Goebel FD, Arasteh K, Spittle M, Rios A, et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998; 16: 683-691 [Medline]

Sullivan R, Dezube BJ, Koon HB. Signal transduction targets in Kaposi’s sarcoma. Curr Opin Oncol 2006; 18: 456-462 [Medline]

Szajerka T, Jablecki J. Kaposi’s sarcoma revisited. AIDS Rev 2007; 9: 230-236 [Medline]

Tulpule A, Yung RC, Wernz J, Espina BM, Myers A, Scadden DT, et al. Phase II trial of liposomal daunorubicin in the treatment of AIDS-related pulmonary Kaposi’s sarcoma. J Clin Oncol 1998; 16: 3369-3374 [Medline]

Tulpule A, Groopman J, Saville MW, Harrington W, Jr., Friedman-Kien A, Espina BM, et al. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002; 95: 147-154 [Medline]

Vaccher E, di GG, Nasti G, Juzbasic S, Tirelli U. HAART is effective as anti-Kaposi’s sarcoma therapy only after remission has been induced by chemotherapy. J Acquir Immune Defic Syndr 1999; 22: 407-408 [Medline]

Walmsley S, Northfelt DW, Melosky B, Conant M, Friedman-Kien AE, Wagner B. Treatment of AIDS-related cutaneous Kaposi’s sarcoma with topical alitretinoin (9-cis-retinoic acid) gel. Panretin Gel North American Study Group. J Acquir Immune Defic Syndr 1999; 22: 235-246 [Medline]

Ziegler JL, Newton R, Katongole-Mbidde E, Mbulataiye S, De CK, Wabinga H, et al. Risk factors for Kaposi’s sarcoma in HIV-positive subjects in Uganda. AIDS 1997; 11: 1619-1626 [ Medline]


Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy

Prof. Christian Gisselbrecht (Reviewer)
Hôpital Saint-Louis – Paris, France

Dr. Nicholas Mounier (Reviewer)
Hôpital de l’Archet – Nice, France

Dr. Michele Spina (Author)

National cancer Institute – Aviano, Italy

Prof. Umberto Tirelli (Editor)
National cancer Institute – Aviano, Italy

Dr. Emanuela Vaccher (Author)
National cancer Institute – Aviano, Italy