Translational review of AIDS-related Kaposi's sarcoma

Approximately twice as many individuals are living with type 1 human immunodeficiency virus infection (HIV-1), as opposed to cancer and as such improved therapies for HIV-1 with an emphasis on availability of such medicines, is arguably the greatest medical problem of the 21st century. Importantly, these two conditions occur together and cancer remains a common cause of morbidity and mortality in the 60 million individuals infected with this retrovirus. In particular, there is a markedly increased risk of Kaposi's sarcoma, non-Hodgkin's lymphoma and invasive cervical cancer during the course of infection with this retrovirus. Treatment options are limited for patients with advanced acquired immunodeficiency syndrome related Kaposi sarcoma (AIDS-KS). The management of early stage cutaneous AIDS-KS has been revolutionised by the introduction of highly active anti-retroviral therapy (HAART) and for most patients HAART alone will control early stage AIDS-KS. However, patients with advanced stage KS with visceral disease, tumour-associated oedema or extensive oral disease require systemic chemotherapy in addition to their anti-retrovirals. Cytotoxic treatment is complicated however by underlying immunoparesis and options are often limited. Despite these difficulties, outcomes are improving and an increased appreciation of the biological mechanisms underlying viral tumorigenesis will hopefully delineate new therapeutic options and strategies.     

Graduated Systemic Treatment of AIDS-Associated Kaposi Sarcoma

Kaposi sarcoma is a mesenchymal tumor involving blood and lymphatic vessels. It is the most common malignancy in HIV-infected patients and is classified as one of the AIDS-defining diseases. First described as early as 1872, it is only in recent years that deeper insights into the pathogenesis of Kaposi sarcoma have been gained; Kaposi sarcoma represents an extraordinary example of viral oncogenesis and growth control by the immune system. Although the incidence of HIV-related Kaposi sarcoma as the initial manifestation of AIDS has recently decreased, the overall prevalence of the disease remains stable. To date, AIDS-associated Kaposi sarcoma (AIDS-KS) remains a major cause of severe disease complications and fatal outcome in HIV-positive homosexual men. The initial success of systemic interferon-α (IFNα) treatment in AIDS-KS occurred before the identification of the human herpes virus (HHV)-8 (Kaposi sarcoma herpes virus [KSHV]) and in the absence of a coherent view of Kaposi sarcoma pathogenesis. Over the past several years a more comprehensive understanding of how Kaposi sarcoma develops and why the neoplasm occurs at increased virulence in HIV-infected persons has been established. HHV-8 can be found in all types of Kaposi sarcoma, whether related to HIV or not. In the era of highly active antiretroviral therapy (HAART), regression of AIDS-KS has been observed with pure antiretroviral therapeutic regimens. A revival of local therapy of Kaposi sarcoma may occur, if HAART therapy is shown to prevent spreading of Kaposi sarcoma disease. In fact, Kaposi sarcoma is not so much the result of immunodeficiency but the result of immune activation triggered by inflammatory cytokines, which can be partly antagonized by IFNα. In advanced Kaposi sarcoma, conventional chemotherapy used to be a double-edged treatment strategy as it counteracts the reconstitution of the immune system. However, novel agents, for example, pegylated liposomal doxorubicin or daunorubicin, selectively target the tumor with better response rates and less cumulative toxicity than with all other chemotherapies. This article reviews the rationale for and results with graduated systemic therapy of patients with AIDS-KS to yield a more comprehensive treatment approach for this extraordinary malignancy.     

Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives

Kaposi's sarcoma (KS) is the most frequent type of cancer in patients with Acquired Immune Deficiency Syndrome (AIDS). In the western world, its incidence decreased dramatically in the era of highly active anti-retroviral therapy (HAART). In contrast, the incidence of KS has been steadily climbing in parallel with the AIDS epidemic in Africa over the past 10-15 years, being the most common cancer in adult men in countries like Uganda and Zimbabwe. AIDS-KS can be diagnosed at any stage of HIV infection, although it more commonly occurs in the setting of severe immune suppression, especially with an elevated viral load. Up to now, AIDS-KS is still an incurable disease. Its clinical course is variable, ranging from very indolent cases, requiring no or minimal therapy, to a rapidly progressive disease. Various local therapies are available to control small and asymptomatic lesions, while cytotoxic, immunological and biological therapies can be considered for more aggressive disease. The primary goal of therapy in most of the cases is to provide safe and effective palliation, in order to quality of life. Optimal anti-retroviral therapy is a key component of AIDS-KS management. There are still many questions to be answered in the management of patients with AIDS-KS, such as (1) What are the therapeutic agents that should be used in this disease, and in which sequence? and (2) What are the benefits and risks expected with each treatment option? The aim of this review is to discuss the systemic management of AIDS-KS, with special focus on the above mentioned questions.     

Kaposi's sarcoma

Kaposi's sarcoma is a malignant tumor that is one of the major complications with AIDS. This disease is common in male homosexuals, and HHV-8 has been indicated to play a role in its pathogenesis. In treating the lesions that spread over the skin of the entire body, and visceral lesions, mainly of the lung, multidrug chemotherapy has been commonly used, but there are many problems such as myelosuppression and the treatment results are poor in HIV patients with advanced disease. In recent years, however, progress has been made with highly active antiretroviral therapy (HAART), and the prognosis in cases of HIV infection is improving. Moreover, HAART is now coming to be seen as a treatment option for Kaposi's sarcoma itself. In addition, with the use of new drugs such as liposomal doxorubicin, the therapeutic strategy for Kaposi's sarcoma is undergoing great changes.     

Treatment of AIDS-related Kaposi's sarcoma

Kaposi's sarcoma (KS) is the most common malignancy seen in association with AIDS. Important epidemiologic trends in the occurrence of AIDS-associated Kaposi's sarcoma (AIDS-KS) have been identified, and the molecular processes associated with the development of KS are being studied intensively. It is hoped that these studies will ultimately lead to an understanding of the etiology of the disease and to a rational approach to therapy. Treatment with conventional chemotherapy, radiation therapy, biologic therapy, and various local treatment modalities is effective for palliation of clinical problems associated with AIDS-KS, although the toxicities of these approaches may be problematic. Therapy for AIDS-KS must be individualized, with appropriate consideration given to the patient's overall clinical and immunologic status.     

Targeted therapy for Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus

PURPOSE OF REVIEW: To summarize major recent findings on the biology of human herpesvirus-8, i.e. Kaposi's sarcoma-associated herpesvirus, and the implications of these findings for Kaposi's sarcoma treatment. RECENT FINDINGS: Although reduced in incidence in developed countries since the introduction of highly active antiretroviral therapy, Kaposi's sarcoma incidence is still markedly increased in HIV-infected patients in resource-rich areas of the world and is a major complication among HIV-infected individuals in sub-Saharan Africa. The Akt/mammalian target of rapamycin pathway has emerged as a major driving force in Kaposi's sarcoma. In addition, the roles of p53, the Kaposi's sarcoma-associated herpesvirus viral cyclin and nuclear factor-kappaB in the development and progression of Kaposi's sarcoma are being further clarified, and therapeutic agents are being developed that may target these pathogenetic mechanisms. New Kaposi's sarcoma treatments should be considered that target the molecular interface between virus and host. SUMMARY: The growing knowledge of Kaposi's sarcoma biology provides multiple opportunities for rational targeted therapies. Further research is needed to better understand the mechanisms by which Kaposi's sarcoma develops and to develop therapeutic strategies that prevent resistance to treatment.     

Management of AIDS-related Kaposi's sarcoma

The advent of highly active antiretroviral therapy (HAART) has lead to a substantial reduction in the prevalence, morbidity, and mortality associated with AIDS-related Kaposi's sarcoma. Similarly, concomitant advances in chemotherapy and supportive-care protocols have allowed for Kaposi's sarcoma to be managed more effectively in comparison with the pre-HAART era. Furthermore, developments in our understanding of the pathogenesis of Kaposi's sarcoma have identified several molecular targets that can potentially provide new therapeutic strategies. This Review discusses the role of conventional chemotherapeutic and immunomodulatory agents in the treatment of Kaposi's sarcoma and summarises the current status and future prospects of novel molecularly targeted agents in the treatment of this disease.     

The presentation and survival of patients with non-cutaneous AIDS-associated Kaposi's sarcoma.

BACKGROUND: Acquired immune deficiency syndrome related Kaposi's sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease. PATIENTS AND METHODS: From our cohort of 5932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunological and virological characteristics to other individuals with KS. RESULTS: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated oedema (P = 0.046) and non-oral gastrointestinal KS (P = 0.042) were significantly more common in patients with non-cutaneous KS. Only one case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART). CONCLUSIONS: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.     

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.

PURPOSE: To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi's sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. PATIENTS AND METHODS: We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. RESULTS: In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-na?ve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). CONCLUSION: In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).     

Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine

An epidemic of disseminated Kaposi's sarcoma in male homosexuals has recently been described. Forty-one evaluable patients with epidemic Kaposi's sarcoma were treated with etoposide. The majority of these patients had early stage disease, no prior opportunistic infections, and no prior therapy. Twelve patients (30%) achieved complete remission, 19 (46%) partial remission, and ten (24%) no response. With follow-up time to 31 months, the median response duration is nine months. The median survival of patients with complete and partial remissions has not been reached. A combination of doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), bleomycin, and vinblastine (ABV) was used in 31 evaluable patients with epidemic Kaposi's sarcoma. The majority of these patients had late stage disease, prior opportunistic infections, or had failed prior treatment. Seven patients (23%) achieved complete remission, 19 (61%) partial remission, and five (61%) no response. With follow-up time to 24 months, the median response duration is eight months. The projected median survival for all patients treated with ABV is nine months. Both regimens were well tolerated, with an overall response rate of 76% for etoposide and 84% for ABV. However, while successfully treating the Kaposi's sarcoma, the underlying immune deficiency in these patients has persisted. Future treatments of Kaposi's sarcoma will need to focus on reversing the underlying immune incompetence as well as controlling the malignant manifestations of Kaposi's sarcoma arising in relation to the acquired immune deficiency syndrome.     

Management of AIDS-related Kaposi's sarcoma: advances in target discovery and treatment

Kaposi's sarcoma is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. Recent advances in the elucidation of the pathogenesis of KS are uncovering potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation and the Kaposi's sarcoma herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining Kaposi's sarcoma cases and a regression in the size of existing Kaposi's sarcoma lesions, most, if not all, Kaposi's sarcoma patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the US FDA for the treatment of Kaposi's sarcoma; alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors and other pathogenesis-targeted therapies are in early clinical development. Over the next 5 years, we may see even more of these pathogenesis-targeted therapies in trials and just as important we may identify, develop and validate clinically practical tools for assessing the biological effects of these therapies. The next 5 years may also bring a better understanding of the pharmacokinetic interactions among the many agents in the Kaposi's sarcoma and AIDS armamentariums.     

Kaposi's sarcoma and non-Hodgkin's lymphoma in European AIDS cases. No excess risk of Kaposi's sarcoma in Mediterranean countries

Prior to the AIDS epidemic, Kaposi's sarcoma (non-AIDS-KS) in Europe was mainly a disease of elderly Mediterranean men. In 1989 AIDS data from 15 European countries were collected to study proportional trends in AIDS-related Kaposi's sarcoma (AIDS-KS) in order to determine whether specific factors in Southern Europe might be important in the development of KS among AIDS patients. Another AIDS-related cancer, non-Hodgkin's lymphoma (NHL) was included as a malignancy control. Of 22,367 AIDS cases reported, 3,779 (16.9%) were KS and 741 (3.3%) were NHL. A significant, continuous fall in the percentage of AIDS-KS was seen for both homosexual men and other members of exposure groups during the period 1981-89 (p-trend less than 0.0001). The proportion with AIDS-KS decreased from 40.5% in 1983 to 26.5% in 1988 in homosexual men and from 12.2 to 3.6% in other exposure groups, respectively. No significant change was observed in the proportion of NHL cases among any of the risk groups over time, although a tendency towards a slight increase was noted for homosexual men. Comparing proportional trends of KS and NHL geographically, no significant difference was found overall, by time or by exposure group. In conclusion, a specific decline is observed over time for AIDS-KS. However, if geographically-restricted factors are important in the development of non-AIDS-KS in Europe, the same factors do not appear to affect the risk of AIDS-KS.     

Antitumour effects of antiretroviral therapy

Infection by human immunodeficiency virus (HIV) is associated with an increased risk of certain tumours, particularly Kaposi's sarcoma, non-Hodgkin's lymphomas and cervical cancer. However, the incidence of these tumours in HIV-infected patients has decreased significantly since the widespread use of highly active antiretroviral therapy (HAART). This effect cannot be solely explained by the ability of these drugs to suppress HIV replication and thereby reconstitute the immune system. Recent studies have shown that inhibitors of the HIV aspartyl protease, which are widely used in HAART, have direct anti-angiogenic and antitumour effects that are unrelated to their antiviral activity. So these drugs might be used to treat cancer in patients who are not infected with HIV.     

AIDS-related cancer in the era of highly active antiretroviral therapy (HAART): a model of the interplay of the immune system, virus, and cancer. "On the offensive--the Trojan Horse is being destroyed"--Part A: Kaposi's sarcoma

The introduction of highly active antiretroviral therapy (HAART), aimed at controlling human immunodeficiency virus (HIV), has been associated with a dramatic decrease in the incidence of acquired immunodeficiency syndrome-Kaposi's sarcoma (AIDS-KS) and the clinical manifestations of KS appear to be less aggressive. The pathogenesis of AIDS-related KS is related to a system of cytokines (e.g., interleukin-6) driven by autocrine and paracrine loops. More recently, human herpesvirus 8 (HHV-8), was discovered to be the putative etiological agent of this disease. This virus encodes several unique open reading frames that are homologs of human cellular proteins involved in cellular regulations, cell proliferation, apoptosis, and immune regulation. The treatment of this disease depends on whether it is “limited” disease or “extensive” disease. For “limited” disease, local therapy or non-bone marrow suppressive agents should be used. For “extensive” disease, new chemotherapeutic agents, such as liposomal anthracycline, which are active and have little adverse reactions, are indicated. The control of HIV infection continues to be essential. Knowledge of the pathogenesis of the disease has led to the development of novel treatment strategies, aimed at the inflammatory or angiogenesis cytokines necessary for growth or at HHV-8 as the target of therapy.     

Long-term clinical outcome of AIDS-related Kaposi's sarcoma during highly active antiretroviral therapy

The long-term impact of highly active antiretroviral therapy (HAART) in AIDS patients with Kaposi's sarcoma (KS) was evaluated in 22 consecutive, HAART-na?ve KS patients attending a single Italian referral centre for HIV/AIDS. Clinical, virologic and immunologic responses to HAART were assessed at baseline and every three months during the follow-up. Peripheral blood mononuclear cell (PBMC)-associated human herpesvirus 8 (HHV-8) load was also evaluated by real-time PCR in 13 patients with durable clinical KS complete response (CR). In a median follow-up of 40 months (range 17-78), the KS overall clinical response rate was 91%: 18 complete and 2 partial responses were achieved, and two patients experienced disease progression. CR persisted in all 18 patients, including the 5 poor-risk KS patients in whom CR lasted for > 60 months, and was significantly linked to an increase in CD4+ cell counts and a drop in HIV-1-RNA copies. Compared to baseline levels, a decrease in PBMC HHV-8 load was observed at CR, and a significant further reduction was found at the end of follow-up. In this monocentric study, AIDS-KS patients treated with HAART showed high clinical response rate. Patients with CR showed a prolonged remission, lasting more than 5 years in a group of poor-risk patients, and a persistent reduction in circulating HHV-8-infected cells. These findings highlight that HAART deeply modifies the natural history of this tumour in AIDS patients, and that this long-lasting approach may be considered a first-line treatment for the majority of HIV-1-infected patients developing KS.     

Cells derived from sporadic and AIDS-related Kaposi's sarcoma reveal identical cytochemical and molecular properties in vitro

We have established 40 cell cultures from biopsies of 5 patients with sporadic Kaposi's sarcoma (KS) and compared them with cell cultures derived from KS biopsies of AIDS patients. Immunocytochemical staining of sporadic KS cells revealed the same endothelial cell markers as those expressed on AIDS-KS cells, indicating that both types of KS might be of endothelial cell origin. In contrast to clinical features, in vitro growth properties showed no differences. KS cells of both types reveal a low degree of malignancy but can be distinguished from fibroblasts by a higher passage number in low serum concentrations and a more pronounced dependence on platelet-derived growth factor (PDGF). The DNA of 12 cell lines of both types of KS was negative for genomic equivalents of hepatitis B virus (HBV), cytomegalovirus (CMV) and, in the case of AIDS-KS, for human immunodeficiency virus (HIV). No rearrangements or amplifications of several oncogenes, often involved in human tumors, were detected. The expression of these oncogenes by sporadic and AIDS-KS cells, as analyzed by Northern blotting, was comparable to that of normal dermal fibroblasts from the same patients. Our results indicate that the 2 types of Kaposi's sarcoma possess identical cytochemical and molecular properties. They are probably weakly malignant neoplasms of endothelial cell origin, and paracrine growth stimulation appears to be important for their maintenance and progression.     

AIDS-related malignancies: emerging challenges in the era of highly active antiretroviral therapy

Human immunodeficiency virus (HIV)-infected patients are at increased risk of developing cancer, particularly in the later stages of acquired immune deficiency syndrome (AIDS). Despite the advent of highly active anti-retroviral therapy (HAART), malignancy in this population is a leading cause of morbidity and mortality. Kaposi's sarcoma (KS) and AIDS-related non-Hodgkin's lymphoma (ARL) are the most common AIDS-defining malignancies. AIDS-related KS varies from minimal to fulminant disease. Treatment decisions for AIDS-related KS are guided largely by the presence and extent of symptomatic disease. In addition to HAART, excellent treatments exist for both localized disease (topical gel, radiotherapy, and intralesional therapy) and advanced disease (liposomal anthracyclines, paclitaxel). Novel therapies that have become available to treat AIDS-related KS include angiogenesis inhibitors and antiviral agents. ARL comprises a heterogeneous group of malignancies. With the immune restoration afforded by HAART, standard-dose chemotherapies now can be safely administered to treat ARL with curative intent. The role of analogous treatments used in HIV-negative patients, including monoclonal antibodies and autologous stem cell transplantation, requires further clarification in HIV-positive patients. HIV-infected patients also appear to be at increased risk for developing certain non-AIDS-defining cancers, such as Hodgkin's lymphoma and multiple myeloma. Although the optimal treatment of these neoplasms is at present uncertain, recent advances in chemotherapy, antiretroviral drugs, and supportive care protocols are allowing for more aggressive management of many of the AIDS-related cancers. This article provides an up-to-date review of the epidemiology, pathogenesis, clinical features, and treatment of various AIDS-related malignancies that are likely to be encountered by an oncologist practicing in the current HAART era.     

Acquired immunodeficiency syndrome-related lymphoma: clinical aspects

While the widespread use of highly active antiretroviral therapy (HAART) has led to substantial decreases in the incidence of opportunistic infections and Kaposi's sarcoma, a major decrease in lymphoma has not yet occurred. Patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma present with widespread, extranodal disease, often in the presence of systemic "B" symptoms. Factors associated with decreased survival include age greater than 35 years, history of injection drug use, poor performance status, CD4 cell count less than 100/dL, a history of AIDS prior to the diagnosis of lymphoma, stage III or IV disease, and/or elevated lactate dehydrogenase (LDH) levels. Low-dose combination chemotherapy has been associated with complete remission (CR) rates of 41% to 46%, with an overall median survival time of 8.7 months, similar to results achieved with standard-dose therapy, which is associated with greater toxicity. Infusional regimens have been associated with CR rates as high as 94%, and further evaluation is justified. Combination chemotherapy may be given safely with HAART. Treatment of relapsed AIDS-related lymphoma remains problematic.     

Impact of HAART on the clinical management of AIDS-related cancers

The development of HIV-related disease has changed dramatically since the introduction of highly active antiretroviral therapy (HAART) into clinical practice. Since the use of protease inhibitors became widespread, a 30–50% reduction in Kaposi's sarcoma (KS) has been observed. The results of recent studies indicate that HAART may be a useful alternative both to immune response modifiers during less aggressive stages of KS disease and to systemic cytotoxic drugs in the long-term maintenance therapy of advanced KS. The impact of HAART regimens on the incidence of systemic lymphoma (NHL-HIV) remains unclear, but it can be hypothesised that patients treated with HAART may survive longer with continued B cell stimulation and dysregulation resulting in an increased incidence of lymphoma over time. The impact of HAART on survival in patients affected by NHL-HIV has recently been evaluated and a positive correlation between HAART and outcome in these patients has been found. The spectrum of cancers in patients with HIV infection may develop further since these patients survive longer with HAART and with a better control of opportunistic infections. With the increasing use of HAART, the dilemma is whether to institute or continue protease inhibitors use during chemotherapy. Based on the advances in our understanding of HIV-related disease and the availability of new antiretroviral therapies, the choice for anti-HIV agents in patients receiving chemotherapy is important.     

Doxil--pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin (Doxil: PLD) is a liposome-encapsulated form of doxorubicin modified with polyethylene glycol that has been approved for the treatment of AIDS-related Kaposi's sarcoma. The characteristics of PLD are reduction of the severe side effects of cardiac toxicity and myelosuppression seen with doxorubicin, and a higher anti-tumor effect from the selective high maintenance of the drug concentration in the tumor tissue. This does not mean, however, that PLD should be used in the treatment of all patients with Kaposi's sarcoma; in some cases with skin lesions only and local distribution highly active antiretroviral therapy (HAART) alone is effective. While precise criteria for the use of PLD have not been determined, it is used in combination with HAART in patients with rapid progression, edema or strong pain, pulmonary complications, or extensive organ complications, or in cases when tumor progression is not slowed with HAART alone. Common side effects are myelosuppression and digestive symptoms, but when combined with HAART these complications do not become serious enough to lead to a discontinuation of treatment. The advantages of using PLD are less myelosuppression, less drug interaction, and the possibility of switching to outpatient administration. The level of treatment safety, tolerability, and treatment effectiveness makes it possible to investigate vigorous concomitant use with HAART, and expanded indications to other solid tumors may be expected.