Liposomal Anthracycline Chemotherapy in the Treatment of AIDS-Related Kaposi’s Sarcoma
Liposomal Anthracycline Chemotherapy in the Treatment of AIDS-Related Kaposi’s Sarcoma
In 1981, reports of Kaposis sarcoma in previously healthy, young homosexual men heralded the onset of the epidemic of acquired immunodeficiency syndrome (AIDS).[1-3] Kaposis sarcoma is the most common neoplasm in persons infected with the human immunodeficiency virus (HIV). The number of AIDS-related Kaposis sarcoma (AIDS-KS) cases in the United States is estimated to be close to 20,000. It is the AIDS-defining diagnosis in 15% of the patients with AIDS in the United States.
The overall incidence of AIDS-KS seems to be declining, but the actual morbidity and mortality ascribed to AIDS-KS has increased. This is probably a result of improvements in therapy for opportunistic infections without concurrent improvements in the treatment of AIDS-KS.[6,7] Several treatments have been successfully employed in AIDS-KS, but their toxicity and patients underlying immunodeficiency have limited their usefulness. Also, AIDS-KS produces visceral involvement, especially in the lungs, for which current treatments are less effective than they are for cutaneous disease.[8,9]
Recently, liposomal anthracycline chemotherapeutic agents have been tested for their efficacy in treating AIDS-KS. It was theorized that the histopathology of AIDS-KS and the altered distribution of anthracycline caused by liposomal encapsulation would enhance the efficacy of these drugs while reducing their toxic effects. Preclinical and early clinical testing of liposomal daunorubicin (DaunoXome) and doxorubicin (Doxil) validated this theoretical construct, and recently completed clinical trials have demonstrated the advantages of these new formulations over standard treatment regimens for patients with AIDS-KS.
At present, no cure for AIDS-KS exists. AIDS-KS was rarely considered to be life-threatening in the past, as most patients with the disease ultimately died of opportunistic infections occurring as a result of their profound immunodeficiency. However, its morbidity and mortality may be increasing. This trend has developed as significant improvements in the treatment and prevention of Pneumocystis carinii pneumonia have substantially reduced this opportunistic infection as a cause of competing morbidity and mortality.[6,10] At the same time, no such advances have occurred in the management of AIDS-KS.
As a result, palliative therapy of AIDS-KS is frequently required for elimination or reduction of cosmetically unacceptable lesions, reduction of painful or unsightly edema or lymphadenopathy, and shrinkage of symptomatic oral lesions. Effective treatment is also essential for relief of respiratory symptoms caused by pulmonary involvement, and for relief of obstruction, pain, and hemorrhage caused by gastrointestinal involvement. As with any palliative therapy, treatment for AIDS-KS must be designed in such a way that it helps to curtail tumor progression but does not exacerbate the underlying immunodeficiency or significantly impair a patients clinical status.
A new herpesvirus, human herpesvirus-8 (HHV-8) or Kaposis sarcoma-associated herpesvirus (KSHV) has recently been identified within the tissue and blood of persons with all varieties of Kaposis sarcoma. This new herpesvirus may operate under conditions of HIV-induced immunodeficiency, by mechanisms which are not yet understood, to cause Kaposis sarcoma and certain forms of non-Hodgkins lymphoma. Intensive preclinical investigations are underway to determine whether any specific form(s) of antiviral therapy can affect the growth of HHV-8 and Kaposis sarcoma. It is anticipated that clinical testing of antiviral therapy for AIDS-KS will develop from these efforts. At present, however, the value of antiviral therapy for AIDS-KS remains unproven.
Several strategies currently employed to treat the various clinical problems encountered in AIDS-KS include single-agent and multiagent cytotoxic chemotherapy, treatment with interferon-a, and radiotherapy. For patients with widespread, aggressive AIDS-KS, a combination cytotoxic chemotherapy regimen is usually the therapy of choice. The two most commonly employed combination regimens are bleomycin (Blenoxane) and vincristine (Oncovin) (BV) and Adriamycin, bleomycin, and vincristine (ABV). These regimens are currently considered to be first-line chemotherapy for advanced AIDS-KS, with ABV having been shown to be superior to single-agent therapy. While these regimens control AIDS-KS in many patients, often the disease will eventually progress despite ongoing therapy. In addition, some patients cannot tolerate these regimens because of toxicities, including myelosuppression, neuropathies, nausea, and vomiting.
Encapsulation in liposomes has been shown in animal models and early human trials to reduce certain toxic effects of cytotoxic chemotherapeutic agents, including anthracyclines. For example, it is believed that rapid uptake of doxorubicin-loaded liposomes by fixed macrophages (residing primarily in the liver), followed by slow release from those sites, reduces peak plasma concentrations of doxorubicin. Although this liver deposition phenomenon is useful in reducing side effects, the intrinsic activity of anthracyclines against systemic malignancies is not favorably influenced by encapsulation in conventional liposomes.
The vascular nature of Kaposis sarcoma, however, may favor distribution of liposomes to the tumor tissue in spite of their tendency for hepatic deposition. Histopathologic examination of Kaposis sarcoma shows interlacing spindle cells, endothelial cells, and vascular spaces, which are interspersed with extravasated erythrocytes, infiltrating lymphocytes, and hemosiderin-laden macrophages. The tumor vasculature, therefore, appears to be leaky, potentially able to allow egress of formed blood elements (and liposomes) from the circulation into the tumor stroma. Presant et al substantiated this hypothesis by demonstrating that intravenously administered conventional liposomes loaded with radioactive indium preferentially accumulated within AIDS-KS lesions.
Liposomes modified by surface attachments of polyethylene glycol (pegylated liposomes) have been shown to circumvent uptake by hepatic macrophages and to circulate for prolonged periods in the bloodstream of rodents and dogs. Radioactively labeled pegylated liposomes have been shown to selectively enter implanted animal tumors. In addition, a direct correlation between blood circulation half-life and tumor uptake has been established.
In a preclinical model of Kaposis sarcoma, pegylated liposomes containing colloidal gold particles were shown to selectively accumulate in both early- and late-stage cutaneous lesions. Following intravenous injection of pegylated-liposomal doxorubicin (PEG-LD) into tumor-bearing mice, doxorubicin levels measured in tumors were substantially higher than those seen in animals receiving comparable doses of standard doxorubicin.
Based on these observations, it was hypothesized that treatment with PEG-LD would selectively deliver doxorubicin to tumor sites, including AIDS-KS lesions. If this hypothesis could be validated in patients with AIDS-KS, PEG-LD therapy might be expected to provide disease palliation at relatively lower doses than required with standard doxorubicin therapy, by delivering a greater proportion of an administered dose of doxorubicin directly to AIDS-KS lesions.
The first clinical trial conducted with PEG-LD in AIDS-KS was designed to determine standard pharmacokinetic parameters of the drug in this patient population, and to evaluate the ability of the pegylated liposome to deliver doxorubicin to disease sites.
Eighteen patients with biopsy-proven AIDS-KS were randomly assigned to receive either standard doxorubicin or PEG-LD. Consecutive participants were entered at three dose levels (10, 20, and 40 mg/m2) in ascending fashion. Plasma samples were obtained at successive time-points over the ensuing 96 hours and analyzed for doxorubicin concentration; these data were used to derive pharmacokinetic parameters. In addition, a previously untreated AIDS-KS skin lesion was removed from each participant 72 hours after dosing and analyzed for doxorubicin concentration.
The results shown in Table 1 reveal that 72 hours after administration, doxorubicin levels achieved in AIDS-KS lesions of participants receiving PEG-LD were 5.2 to 11.4 times greater than those in participants given comparable doses of standard doxorubicin. PEG-LD and standard doxorubicin were roughly equivalent in producing toxicities. No toxicities were noted with PEG-LD administration that would not have been expected with standard doxorubicin.
The pharmacokinetic results of this trial are shown in Table 2. PEG-LD clearance ranged from 0.14 to 0.17 L/h/m2 with a volume of distribution (Vd) of approximately 6.5 to 10 L and an area under the concentration-time curve (AUC) ranging from 184µg-h/mL at 10 mg/m2 to 642 µg-h/mL at 40 mg/m2. The distribution half-life of pegylated liposomal doxorubicin was approximately 34 to 44 hours. In contrast, clearance of standard (free) doxorubicin at comparable dose levels has been reported to be much faster (10 to 40 L/h) with a substantially larger apparent volume of distribution (approximately 1,000 L), smaller AUCs (range = 1 to 5 µg-h/mL), and a distribution half-life of 0.08 hours (4.8 minutes).
It was concluded that encapsulation in pegylated liposomes significantly limited the distribution and elimination of doxorubicin and enhanced accumulation of the drug in AIDS-KS lesions in comparison with standard doxorubicin administration. Therefore, it might improve the drugs efficacy and therapeutic index in the treatment of AIDS-KS.
Gill et al evaluated the pharmacokinetic properties of liposomal daunorubicin in 7 patients with AIDS-KS and 10 patients with various other malignancies at doses ranging from 10 to 80 mg/m2 (Table 2). In comparison with corresponding parameters for standard daunorubicin, they noted substantially longer plasma half-lives, greater AUC, slower clearances, and smaller volumes of distribution for all dose levels of liposomal daunorubicin.
As with the case of PEG-LD, the authors concluded that these parameters constitute a pharmacokinetic profile for liposomal daunorubicin that is superior to that of standard daunorubicin, speculating that these characteristics would improve the therapeutic index of the drug. Comparison of the data in Table 2 suggests that PEG-LD has a longer half-life, greater AUC, and slower clearance, whereas liposomal daunorubicin has a somewhat smaller volume of distribution.
Another small clinical trial was conducted to demonstrate the ability of pegylated liposomes to preferentially deliver doxorubicin to AIDS-KS lesions while avoiding normal tissues. Twenty-four patients with AIDS-KS were randomly assigned to receive PEG-LD at doses of 10 or 20 mg/m2. Each patient then underwent simultaneous biopsies of a representative AIDS-KS lesion and a nearby area of normal skin. The tissue concentrations of doxorubicin were determined. Patients were sequentially assigned to undergo the paired biopsies at either 48 hours (8 patients at each dose level) or 96 hours (4 patients at each dose level) after receiving their dose of PEG-LD. The results of this study are contained in Table 3.
PEG-LD was shown to deliver approximately 10 to 20 times more doxorubicin to AIDS-KS lesions than to adjacent normal skin. These findings provided further support for the hypothesis that treatment with PEG-LD could selectively distribute the drug to tumor tissue, with the consequent potential for greater efficacy and reduced toxicity.