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.     

A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma

BACKGROUND: Despite a decreased incidence of AIDS-related Kaposi's sarcoma (KS) due to the advent of highly active antiretroviral therapy, approximately 15% of AIDS patients still develop AIDS-related KS. This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin for the treatment of AIDS-related KS. METHODS. This was a double-blind, multicenter study that randomized patients with AIDS-related KS to six cycles of pegylated liposomal doxorubicin (20 mg/m2; n = 60) or liposomal daunorubicin (40 mg/m2; n = 19) every 2 weeks. Clinical benefit was assessed using patient questionnaires and monitoring of KS-associated symptoms. Tumor responses were assessed using imaging techniques, direct measurement of skin lesions, and photographs, when possible. RESULTS. Clinical benefit was observed in 48/60 patients (80%) receiving pegylated liposomal doxorubicin and was maintained for a median of 62 days (range, 28-107 days). Clinical benefit was achieved by 12/19 patients (63.2%) receiving liposomal daunorubicin and was maintained for a median of 55 days (range, 28-84 +days). Clinical benefit correlated with tumor response. Tumor responses were achieved by 55.0% of patients receiving pegylated liposomal doxorubicin and 31.6% of patients receiving liposomal daunorubicin. Response rates were similar within each treatment group when only those patients without changes in antiretroviral therapy during treatment were considered. Adverse events associated with pegylated liposomal doxorubicin were neutropenia (30%), nausea (28.3%), and asthenia (16.7%). CONCLUSIONS. Pegylated liposomal doxorubicin is safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit, tumor response, or both.     

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.     

Cost-minimisation analysis of pegylated liposomal doxorubicin hydrochloride versus topotecan in the treatment of patients with recurrent epithelial ovarian cancer in Spain

The study consisted of a cost-minimisation analysis since the findings from a multicentre randomised phase III trial showed that pegylated liposomal doxorubicin hydrochloride was at least as efficacious as topotecan. An economic model from the Spanish hospitals perspective was constructed to compare the costs derived from the treatment using both drugs in patients with recurrent epithelial ovarian cancer who failed a first-line platinum-containing regimen. The cost evaluation included direct medical costs: drug, drug administration and costs of managing adverse events. Estimation of resources used in managing adverse events was made retrospectively through an expert panel. Results obtained per patient were: cost of drug and administration, 8647.70 euros for pegylated liposomal doxorubicin hydrochloride and 8519.94 euros for topotecan, while cost of managing adverse events was 967.02 euros in the pegylated liposomal doxorubicin hydrochloride arm and 3304.75 euros for topotecan. The total cost per patient was therefore estimated to be 9614.72 euros for pegylated liposomal doxorubicin hydrochloride and 11 824.69 euros for topotecan, showing that pegylated liposomal doxorubicin hydrochloride produces a cost saving of 2209.97 euros per patient in comparison to topotecan. Sensitivity analyses verified the robustness of the results. These findings suggest that pegylated liposomal doxorubicin hydrochloride is an efficient therapy and can be used as a cost-saving option for treatment of patients with recurrent epithelial ovarian cancer who have failed a first-line platinum-containing regimen.     

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-α 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.     

Current status of liposomal anthracycline therapy in metastatic breast cancer

Doxorubicin is a mainstay for the treatment of metastatic breast cancer (MBC); however, its use is limited by toxicity, particularly cardiotoxicity. Novel drug delivery systems using liposomes have been developed to maintain the clinical utility of conventional doxorubicin while minimizing cardiotoxicity. Three liposomal anthracyclines have been developed: liposomal daunorubicin, nonpegylated liposomal doxorubicin, and pegylated liposomal doxorubicin. Liposomal daunorubicin, currently approved in the United States for the treatment of AIDS-related Kaposi sarcoma, has shown preliminary activity in MBC in a phase I trial; further investigation is ongoing. Nonpegylated liposomal doxorubicin, which is not available in the United States, has demonstrated activity similar to that of conventional doxorubicin (both as a single agent and in combinations). Pegylated liposomal doxorubicin has demonstrated activity in phase II and III trials when used alone or in combination with other chemotherapeutic agents in patients with MBC. It is currently approved in the United States and Europe for AIDS-related Kaposi sarcoma and platinum/paclitaxel-refractory ovarian carcinoma; in Europe and Canada, it is also approved as monotherapy for MBC. In addition, accumulating evidence suggests that the combination of liposomal anthracyclines (pegylated and nonpegylated) and trastuzumab is active, with acceptable toxicity. Based on these encouraging experiences, randomized clinical trials are ongoing or planned to further assess the therapeutic potential of pegylated liposomal doxorubicin as a single agent and in combination with other chemotherapeutic agents and targeted agents, such as trastuzumab, for MBC.     

Liposomal encapsulated anthracyclines: new therapeutic horizons

After two decades of work in liposomal formulations for clinical use, two preparations containing doxorubicin (Doxil, ALZA, Pablo Alto, CA; and Evacet [TLC D-99], The Liposome Company, Princeton, NJ), and one containing daunorubicin (DaunoXome; Gilead Sciences, Foster City, CA) have been undergoing widespread clinical study. Results have lived up to the promise that liposomal encapsulation may lead to toxicity attenuation, while retaining or even enhancing the efficacy of the parent anthracyclines. The eventual role of these agents in clinical practice is being defined in a number of studies that are reviewed herein. Already, approved indications have been achieved for doxorubicin against Kaposi’s sarcoma and ovarian cancers, and for daunorubicin against Kaposi’s sarcoma. The three compounds vary widely in their pharmacology, and these differences may contribute to their preferential localization into certain tumors. Additional indications for these liposomal encapsulated anthracyclines are likely to be established in the ensuing years.     

Liposomal anticancer therapy: pharmacokinetic and clinical aspects

Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma.     

Cardiac safety of liposomal anthracyclines

Anthracyclines have demonstrated antitumor activity in a variety of cancers; however, irreversible cardiac damage is a major dose-limiting toxicity, restricting lifetime cumulative dose. The most successful strategy to improve the cardiac safety of anthracyclines to date involves liposomal encapsulation, which alters the tissue distribution and pharmacokinetics of these agents. The cardiac safeties of liposomal daunorubicin, liposomal doxorubicin (D-99), and pegylated liposomal doxorubicin have been studied in several clinical trials. The lack of published data comparing liposomal daunorubicin with conventional daunorubicin makes it difficult to draw meaningful conclusions regarding the relative cardiac safeties of these formulations. Studies indicate that the risk of anthracycline-induced cardiotoxicity is considerably lower with liposomal doxorubicin formulations than with conventional doxorubicin. Pegylated liposomal doxorubicin has been studied most extensively and has demonstrated the most significant reductions in risk for cardiotoxicity. Compared with conventional doxorubicin, pegylated liposomal doxorubicin has shown similar efficacy with a significantly lower incidence of cardiotoxicity and significantly fewer cardiac events. Although the long-term cardiac safety of these agents is unknown, data suggest that liposomal anthracyclines, particularly pegylated liposomal doxorubicin, may offer a significant clinical benefit for patients with higher risks for anthracycline-induced cardiotoxicity.     

Metastatic Soft Tissue Sarcoma in Adults

In the present paper the treatment of advanced and metastatic soft tissue sarcoma is reviewed with the primary emphasis on chemotherapy. One of the major advances in the treatment of soft tissue sarcomas is their treatment by multidisciplinary teams in specialized centers. Despite optimal local treatment of the primary tumor, disseminated disease will develop in many patients. Consequently, chemotherapy has been extensively studied but, unfortunately, the responsiveness of these tumors to chemotherapy has been disappointingly low. Doxorubicin and ifosfamide appear to be the most effective drugs — the latter with a somewhat higher toxicity at effective dosages. Other drugs with some first line activity are dacarbazine, liposomal doxorubicin and possibly trabectedin (ET-743). Imatinib is very effective in gastrointestinal stromal tumors (GIST) where it is now the treatment of choice. The combination of doxorubicin and ifosfamide increases the response rate without affecting overall survival. For these reasons, single agent doxorubicin is, in many centers, considered the standard treatment for advanced soft tissue sarcoma, and combination chemotherapy should be reserved for special subgroups of patients such as young patients with chemosensitive tumors. Chemotherapy for patients with advanced and metastatic soft tissue sarcoma is inadequate at present and new drugs are desperately needed. Fortunately, exciting new drugs are under development and hopefully they will improve the treatment of patients with this disease.     

Liposomal anthracyclines in metastatic breast cancer: clinical update

Anthracyclines are a mainstay of therapy for patients with metastatic breast cancer. However, their use has been limited by associated toxicities, including myelosuppression, alopecia, nausea and vomiting, stomatitis, and most importantly, cardiotoxicity. Liposomal anthracyclines were developed to increase the therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safety profile. There are currently three liposomal formulations: liposomal daunorubicin, liposomal doxorubicin (D-99), and pegylated liposomal doxorubicin. Only one phase I study has been conducted with liposomal daunorubicin for metastatic breast cancer. Liposomal doxorubicin has shown comparable efficacy with conventional doxorubicin and less toxicity. Pegylated liposomal doxorubicin is the most widely studied of the liposomal anthracyclines and has demonstrated similar efficacy to conventional doxorubicin and a better safety profile, including significantly less cardiotoxicity, in patients with metastatic breast cancer. Pegylated liposomal doxorubicin has shown efficacy as a single agent and in combination with many agents, including cyclophosphamide, paclitaxel, docetaxel, and gemcitabine, with response rates ranging from 33%-75%. Growing evidence supports the use of pegylated liposomal doxorubicin as first-line treatment for patients with metastatic breast cancer, owing to its antitumor activity in both anthracycline-na?ve patients and in patients with previous anthracycline exposure.     

Long-term chemotherapy of HIV-associated Kaposi's sarcoma with liposomal doxorubicin

The aim of this study was to examine the outcome, adverse events and clinical complications of long-term chemotherapy with pegylated liposomal doxorubicin (PegLiposomal DOX) for human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS) in the pre-highly active antiretroviral therapy (HAART) era. A phase II study over a 4-year period in a tertiary care university hospital was carried out. 52 acquired immunodeficiency syndrome (AIDS)-patients with advanced KS received long-term chemotherapy (71+/-51 weeks) with a mean of 22.8+/-18.2 cycles and a mean cumulative liposomal doxorubicin dose of 456+/-364 mg/m(2) (120-1040 mg/m(2)). Tumour burden, duration and dosage of PegLiposomal DOX, adverse events, opportunistic infections, immunological parameters and HIV load were measured. A complete (10%) or partial response (56%) was achieved while on chemotherapy. 10 patients (19%) showed stable disease. Tumour progression was observed in 8 patients (15%). Importantly, chemotherapy with PegLiposomal DOX was also successful after previous cytostatic therapy with bleomycin and vincristine. The most common adverse events included leucopenia, neutropenia, anaemia, and increased liver function tests. 34 patients (65%) developed new opportunistic infections and 29 patients (56%) died during the study period. To conclude, pegylated liposomal doxorubicin is a safe and effective drug for long-term chemotherapy of advanced (AIDS) KS without adverse effects on CD4 cell counts and HIV viral load.     

Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas.

In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the structure of the original tumour. OMS prepared from seven glioma specimens were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), daunorubicin or doxorubicin. After exposure to these drugs, the histology and cell proliferation of the OMS were analysed by immunohistochemistry and image analysis. Furthermore, the expression of P-glycoprotein (P-gp) and multidrug resistance-related protein (MRP), which both can contribute to resistance to daunorubicin and doxorubicin, were immunohistochemically investigated. We found that OMS from gliomas are sensitive for daunorubicin and doxorubicin but not for BCNU in terms of tissue destruction and decrease in cell proliferation. In addition, all gliomas were P-gp and MRP negative, which is in accordance with the sensitivity for daunorubicin and doxorubicin. Considering the potential use of several new alternative drug delivery methods, such as intratumoural implantation of drug-impregnated polymers or liposomal encapsulation of cytostatic drugs, daunorubicin and doxorubicin might be effective in the treatment of malignant gliomas.     

A dose‐finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma

There are few effective therapies for high‐risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose‐finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose‐limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m² monthly with temsirolimus 20 mg/m² weekly. Hematologic toxicity was common but manageable. Dose‐limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co‐administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.     

Phase IV study of liposomal daunorubicin (DaunoXome) in AIDS-related Kaposi sarcoma

The purpose of this article was to study the efficacy and tolerance of liposomal daunorubicin (DaunoXome) in the treatment of AIDS-associated Kaposi sarcoma (KS) as prescribed in France between September 1996 and September 1997. All patients with a positive HIV serology, histologically proven KS, and having received at least one daunorubicin treatment cycle during the study period were eligible for entry. Ninety-four patient files from 13 university hospital departments were retrospectively studied. Of 94 patients, 80% received cytostatic treatment before the first daunorubicin treatment cycle. Initial mean CD4 lymphocyte count was 114/microl. Ninety percent of the patients received highly active antiretroviral treatment (HAART) during daunorubicin treatment. Daunorubicin was administered as single chemotherapy to 70% of the patients. The total number of treatment cycles was 1,422, with a mean number of 16.1 treatment cycles (1-68) per patient and a mean cumulative daunorubicin dose of 674 mg/m2 (40-2,749). According to the AIDS Clinical Trial Group criteria, partial and complete response rates were 26.5% and 11.5%, respectively. A hematopoietic growth factor was prescribed in 29% of the treatment cycles. At the final evaluation, 71% of the patients were alive. No severe cardiotoxic event was observed despite high cumulative drug doses and prolonged follow-up. Since the introduction of HAART, this study constitutes the only evaluation of daunorubicin in a wide population. Our study confirms that daunorubicin is effective in patients with advanced KS. Daunorubicin is well tolerated over the long term in association with HAART.     

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.     

Kaposi's sarcoma unrelated to the acquired immunodeficiency syndrome

Kaposi's sarcoma has achieved considerable notoriety in the past decade because of its association with the acquired immunodeficiency syndrome (AIDS). Nonetheless, this neoplasm continues to affect patients who do not have AIDS, and analysis of such cases may provide information that is useful in understanding the pathogenesis and treatment of Kaposi's sarcoma. Recent data indicate that non-AIDS-related Kaposi's sarcoma shows a predilection for individuals with the HLA-DR5 haplotype and that this genetic locus may affect immune function. In addition, other information suggests that infection with cytomegalovirus may represent the "trigger" for oncogenesis in patients with Kaposi's sarcoma. In view of the latter finding, therapies with such antiviral agents as zidovudine may be indicated in cases of non-AIDS-related Kaposi's sarcoma.     

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer

Caelyx/Doxil is a novel pegylated liposomal formulation of the first-generation anthracycline, doxorubicin. The pharmacokinetics of this polyethylene-glycol-coated liposome are characterized by a reduced volume of distribution, a long intravascular circulating half-life and slow plasma clearance compared with free doxorubicin. This, coupled with a small vesicular size, uniquely promotes the localization of Caelyx/Doxil at tumor sites and explains its altered toxicity profile. The FDA and EMEA have approved its use for the treatment of AIDS-related Kaposi's sarcoma and, more recently, for recurrent epithelial ovarian cancer (EOC). Numerous investigations have focused on its use in the treatment of metastatic breast cancer, as well as recurrent squamous cell cervical carcinoma, soft tissue sarcoma, squamous head and neck cancers, prostate cancers and malignant gliomas. Ongoing clinical studies of combination regimens incorporating Caelyx/Doxil will further clarify its role in the treatment of advanced solid tumors.     

Paclitaxel for AIDS-associated Kaposi's sarcoma

Treatment options are limited for patients with advanced acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS). The management of early stage cutaneous AIDS-KS has been revolutionized by the introduction of highly active antiretroviral therapy and for most patients highly active antiretroviral therapy alone will control early stage AIDS-KS. However, patients with advanced stage Kaposi's sarcoma with visceral disease, tumor-associated edema or extensive oral disease require systemic chemotherapy in addition to antiretrovirals. The standard first-line therapy for these affected individuals is a liposomal anthracycline, and response rates of around 70% are usually achieved. For patients with refractory or recurrent AIDS-KS, treatment algorithms are less well defined. The use of paclitaxel in these circumstances is reviewed.     

Kaposi's sarcoma in heterosexual intravenous drug users

Kaposi's sarcoma is a feature of the acquired immunodeficiency syndrome (AIDS) in male homosexuals and Haitians. In this report the authors describe six heterosexual intravenous drug users who developed Kaposi's sarcoma. They had other characteristics of AIDS including opportunistic infections (oral candidiasis, six patients; Pneumocystis carinii pneumonia, two patients; genital herpes simplex, two patients; disseminated cytomegalovirus, one patient; Mycobacterium avium, one patient) and inversion of the normal ratio of helper-suppressor T-cell subsets in peripheral blood lymphocytes in the two patients in whom it was determined. These observations indicate that intravenous drug users as well as Haitians and homosexual men are at risk for developing Kaposi's sarcoma as part of the acquired immunodeficiency syndrome.