Liposomal Anthracycline Chemotherapy in the Treatment of AIDS-Related Kaposi’s Sarcoma

ABSTRACT: The treatments employed for Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome (AIDS-KS) have been limited in their usefulness by toxicities and underlying immunodeficiency in this patient population. Recently, liposomal anthracycline chemotherapeutic agents have been developed and used in AIDS-KS. Liposomal encapsulation may provide greater concentration of anthracycline in the KS lesions when compared with standard anthracycline administration. Also, the favorable pharmacokinetic parameters of the encapsulated formulations—longer half-life, greater area under the concentration-time curve (AUC), and slower clearance—may allow the lesions to be exposed to these cytotoxic agents for longer periods of time. Phase II and III studies testing the safety and efficacy of liposomal anthracyclines demonstrate that they are at least as efficacious as standard regimens, with a better safety profile. [ONCOLOGY 11(Suppl 11):21-32, 1997]

Introduction

In 1981, reports of Kaposi’s sarcoma in previously healthy, young homosexual men heralded the onset of the epidemic of acquired immunodeficiency syndrome (AIDS).[1-3] Kaposi’s sarcoma is the most common neoplasm in persons infected with the human immunodeficiency virus (HIV). The number of AIDS-related Kaposi’s sarcoma (AIDS-KS) cases in the United States is estimated to be close to 20,000.[4] It is the “AIDS-defining” diagnosis in 15% of the patients with AIDS in the United States.[5]

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.

Issues in the Treatment of AIDS-Related Kaposi’s Sarcoma

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 patient’s clinical status.

A new herpesvirus, human herpesvirus-8 (HHV-8) or Kaposi’s sarcoma-associated herpesvirus (KSHV) has recently been identified within the tissue and blood of persons with all varieties of Kaposi’s sarcoma.[11] This new herpesvirus may operate under conditions of HIV-induced immunodeficiency, by mechanisms which are not yet understood, to cause Kaposi’s sarcoma and certain forms of non-Hodgkin’s lymphoma. Intensive preclinical investigations are underway to determine whether any specific form(s) of antiviral therapy can affect the growth of HHV-8 and Kaposi’s 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.[12] 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.[13] 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.

Liposomal Anthracycline Chemotherapy

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.[14] 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 Kaposi’s sarcoma, however, may favor distribution of liposomes to the tumor tissue in spite of their tendency for hepatic deposition. Histopathologic examination of Kaposi’s 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.[15]

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.[16] 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.[17]

In a preclinical model of Kaposi’s sarcoma, pegylated liposomes containing colloidal gold particles were shown to selectively accumulate in both early- and late-stage cutaneous lesions.[18] 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.[19]

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.

Pharmacokinetics and Tumor Localization

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.[20]

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 (V_d) 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 drug’s efficacy and therapeutic index in the treatment of AIDS-KS.

Gill et al[21] 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.[22] 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.

Phase II Clinical Trials

The results of several small phase II clinical trials of liposomal daunorubicin for AIDS-KS are briefly summarized in Table 4.[21,23,24] Partial responses were observed in 40% to 55% of patients treated in these studies, with occasional complete responses also noted. Toxicities were generally reported to be mild and tolerable, with myelotoxicity (primarily neutropenia) being the most common adverse event encountered. Table 4 also includes the results of small phase II clinical trials of PEG-LD therapy for AIDS-KS.[25-31] Partial responses were observed in 73% to 100% of patients treated in these studies. Toxicities were generally reported to be mild, even in patients with advanced HIV disease who had previously received chemotherapy treatments for AIDS-KS.

Efficacy After Failure of Standard Chemotherapy

Enhanced delivery of doxorubicin to AIDS-KS lesions, promising results of small phase II studies, and an altered toxicity profile in preclinical studies raised the possibility that patients who experienced disease progression or toxicity with standard combination chemotherapy might benefit from single-agent salvage therapy with PEG-LD. It was of particular clinical interest to test this hypothesis in patients who had already experienced disease progression on a regimen containing standard doxorubicin. A retrospective analysis was therefore performed to assess the efficacy of PEG-LD treatment in a cohort of severely immunocompromised patients with advanced AIDS-KS who had experienced disease progression or unacceptable toxicity with combination systemic chemotherapy.[32]

Subjects for the analysis were identified from a cohort of 383 patients enrolled in an open-label trial of PEG-LD therapy for AIDS-KS which was carried out at 17 centers between March 1993 and December 1994. A panel of three reviewers independently identified patients within the larger study cohort who had received systemic chemotherapy with at least two concurrently administered agents for treatment of AIDS-KS. Patients experiencing disease progression, as defined by the AIDS Clinical Trials Group (ACTG) criteria,[33] or intolerable toxicity after two cycles of therapy with regimens including bleomycin and/or doxorubicin, were specifically identified. The panel members were blinded to all other aspects of the patients’ clinical status, including the results of their therapy with PEG-LD. Only those patients identified by all reviewers as meeting these criteria were included in the analysis.

Response to therapy was assessed using a modification of the ACTG criteria. In addition, changes in disease-associated pain, edema, lesion color, and lesion flattening were assessed as a means of identifying treatment-induced clinical benefit not well-assessed by the ACTG criteria. Investigators, using their clinical judgment, quantitated adverse events as mild, moderate, or severe and whether or not they were related to the study drug.

Patients received PEG-LD at a dose of 20 mg/m² every 3 weeks. The dose could be reduced or the cycle lengthened if toxicity intervened. Response and clinical benefit were assessed every 3 weeks within 48 hours prior to drug administration. Patients were followed for at least 4 weeks after discontinuation from the study. Use of myeloid colony-stimulating factors was permitted at the discretion of each investigator. The results are provided in Table 5. For purposes of statistical analysis, patients who where found to have progressive disease on their first post-treatment evaluation were designated as treatment failures after one day of the study.

The ability of PEG-LD to induce clinical benefit was assessed by lesion flattening, color improvement, reduction of pain, and reduction in edema. Table 6 shows the percentage of patients with a specific undesirable characteristic at baseline that showed a particular clinical benefit during treatment:

• 48% of patients who had raised indicator lesions at baseline showed complete flattening of all indicator lesions.
• 56% of patients with red or purple indicator lesions at baseline had all the indicator lesions change to a less noticeable color.
• 45% of patients with moderate to severe pain at baseline had a reduction in pain to mild or absent without the aid of analgesics or antidepressants.
• 83% of patients with edema at baseline, had their edema disappear.

Patients with a partial response were more likely to achieve each benefit compared with patients with stable disease or progressive disease. However, beneficial changes in lesion characteristics developed in some patients whose responses did not fulfill protocol criteria for partial response. Patients remained active throughout the study as indicated by a lack of decline in their Karnofsky performance scores.

Twenty-six patients (49%) had more than one clinical benefit. One patient achieved clinical benefit in all four categories at some point during therapy; this patient’s overall response to therapy was graded as a partial response. Nine patients (17%) achieved clinical benefit in three of the four categories at some point during study therapy. Seven of these patients achieved a partial response, and two had stable disease. Sixteen patients achieved clinical benefits in two of the four categories. The clinical benefits were durable, with median duration of 113 days for flattening, ³ 164 days for color improvement, ³ 111 days for pain reduction, and 150 days for edema reduction.

The most common adverse events, deemed by the investigators to be possibly or probably related to PEG-LD, are listed in Table 7. Overall, 76% of patients reported at least one adverse event which was possibly or probably related to PEG-LD, and 30% reported at least one severe adverse event thought to be related to PEG-LD.

Several adverse events occurred that were not expected from the usual toxicity profile of doxorubicin. Palmar-plantar erythrodysesthesia occurred in one patient, and presented as a severe erythematous rash. The rash resolved when therapy was withheld and was managed by resuming therapy at longer dosing intervals.

One patient experienced an infusion-related reaction during his first infusion, characterized by the sudden onset of flushing of the entire body, in association with abdominal pain. The reaction subsided the same day, and the patient was subsequently able to undergo a total of 12 cycles of PEG-LD therapy without further incident when premedicated with prednisolone (Prelone) prior to dosing.

Myelotoxicity was manageable with the use of colony-stimulating factors. The incidence of opportunistic infection was not significantly different from that seen in similar patients with AIDS receiving chemotherapy.[34,35] Toxicities that often accompany doxorubicin-containing combination chemotherapy for AIDS-KS are alopecia, nausea, and vomiting. Although these toxic effects are usually not severe, they do affect a patient’s quality of life.

In the cohort described above, the incidence of alopecia was 9%. Nausea and vomiting occurred in 15% of patients and was not severe in any patient. In contrast, the incidence of nausea and vomiting reported with doxorubicin, ABV, or BV ranged from 50% to 67% in patients with AIDS-KS. Alopecia was reported to occur in 55% to 67% of patients receiving these regimens.[13,34] No clinical evidence of cardiac toxicity or extravasation injury attributable to doxorubicin was seen in the study cohort. Thus, PEG-LD compared favorably with regard to these toxicities.

In summary, the findings of this retrospective analysis demonstrated that PEG-LD was an effective treatment for patients who experienced disease progression or unacceptable toxicity with first-line, systemic combination chemotherapy for advanced AIDS-KS. Pegylated-liposome encapsulation was shown to enhance the efficacy of doxorubicin since patients responded to this therapy after having failed standard doxorubicin. The use of doxorubicin as a single agent in the primary treatment of AIDS-KS has been reported to produce partial responses in 10% to 48% of patients.[13,36] In this study, the partial/complete response rate of 38% overall, and 32% in patients who had already experienced disease progression while receiving doxorubicin, confirms the theory that the longer half-life, greater AUC, and altered distribution characteristics of PEG-LD can enhance the potency of doxorubicin in humans, as has already been observed in animal models.[19]

Randomized Phase III Trials

Liposomal Daunorubicin vs ABV

Based on the encouraging results of pharmacokinetic studies and phase II clinical trials in patients with AIDS-KS, Gill et al conducted a randomized trial to compare the safety and efficacy of liposomal daunorubicin with that of a reduced-dose version of the standard ABV regimen.[37]

Patients enrolled at 13 sites between July 1992 and July 1994 were prospectively randomized to receive either liposomal daunorubicin or the ABV combination. Responses to therapy were assessed using modified ACTG criteria, and toxicities were assessed using standard Southwest Oncology Group (SWOG) criteria. Patients received liposomal daunorubicin at a dose of 40 mg/m², and ABV at doses of 10 mg/m² Adriamycin, 15 units bleomycin, and 1 mg vincristine. Treatments were administered every 14 days and continued until complete response, unacceptable toxicity, disease progression, patient refusal, or death.

A total of 227 evaluable patients were enrolled in the trial, of whom 116 (median CD4+ count of 30 cells/mm³) were randomized to receive liposomal daunorubicin and 111 patients (median CD4+ cell count of 28 cells/mm³) were randomized to receive the ABV regimen. The characteristics of study participants were typical of patients with advanced HIV disease, and there were no significant differences between the groups.

The results, shown in the first half of Table 8, reveal no statistically significant differences in major responses between patients receiving the ABV and liposomal daunorubicin regimens. The difference in median time to treatment failure (115 days in the liposomal daunorubicin group and 99 days in the group receiving the ABV regimen) was not statistically significant, nor were the differences in median survival times and death rates between the treatment arms of the study.

Treatment was discontinued for reasons other than disease progression in 16 patients receiving liposomal daunorubicin and 31 patients receiving the ABV regimen. Among the liposomal daunorubicin patients, reasons for discontinuation included death due to progressive HIV disease (N = 5), patient preference (N = 4), lost to follow-up (N = 3), drug toxicity (N = 3), and opportunistic infection (N = 1). Among the patients who received the ABV regimen, reasons for discontinuation included patient preference (N = 10), death due to progressive HIV disease (N = 5), lost to follow-up (N = 5), opportunistic infection/neoplasm (N = 4), nausea and vomiting (N = 2), neuropathy and alopecia (N = 2), investigator decision (N = 2), and palmar-plantar erythrodysesthesia (N = 1).

Table 9 lists the most common adverse events experienced in the trial. Sixteen patients in the liposomal daunorubicin group experienced acute infusion-related reactions during 27 cycles of therapy. These reactions were characterized by flushing, chest tightness and/or back pain, and were self-limited in all cases.

PEG-LD vs ABV

A randomized, comparative trial was undertaken to compare the safety and efficacy of PEG-LD (20 mg/m²) with ABV (20 mg/m² Adriamycin, 10 mg/m² bleomycin, 1 mg vincristine) in patients with advanced AIDS-KS.[38] Treatments were administered every 14 days to a maximum of six cycles.

A total of 258 patients enrolled at 25 sites from April 1993 to December 1994 were prospectively randomized to either PEG-LD (N = 133) or the ABV regimen (N = 125). The characteristics of the study participants were typical of patients with advanced HIV disease, and there were no significant differences between the groups. The median CD4+ T-lymphocyte count was 13 cells/mm³ in those receiving ABV, and 12.5 cells/mm³ in those receiving PEG-LD.

Responses to therapy were assessed using the modified ACTG criteria described previously. Pulmonary and gastrointestinal involvement with AIDS-KS was inferred at study entry from the appearance of patients’ chest radiographs, respiratory and gastrointestinal symptoms, or reports of previous endoscopic evaluations. Standard World Health Organization criteria were used to assess toxicities.

Results shown in the second half of Table 8 reveal that among patients receiving PEG-LD, one had a complete clinical response (CCR) and 60 had partial responses (CCR + PR = 61/133, 45.9%; 95% confidence interval 37% to 54%). Among patients receiving ABV, 31 had partial responses (PR = 31/125, 24.8%; 95% confidence interval 17% to 32%). This difference was statistically significant (P £ .001). The median duration of response was 90 days with PEG-LD and 92 days with ABV (this difference was not statistically significant). The median time to partial or complete response was 39 days with PEG-LD and 50 days with ABV (P = .014, Log-Rank test). The median time to treatment failure, defined as the time from initiation of therapy to the onset of progressive disease, was 124 days and 128 days with PEG-LD and ABV, respectively (difference not statistically significant). The mean Karnofsky score did not change appreciably from baseline in either group.

Several additional parameters indicative of treatment efficacy were evaluated:

Lesion diameter: The sum of the products of perpendicular diameters of indicator lesions of all patients decreased 24% from baseline to end of treatment in patients receiving PEG-LD and 15% in patients receiving ABV (P < .034).

Lesion flattening: In 96% of PEG-LD patients, at least one indicator was lesion raised at baseline, and in 51% of these patients, all of their indicator lesions were flattened at the end of treatment. In 97% of ABV patients, at least one indicator lesion was raised at baseline, but only 28% of these patients had all of their indicator lesions flattened by the end of therapy. This difference in indicator lesion flattening with the respective therapies was statistically significant (P < .001). The median time required to achieve this benefit was 64 days in the PEG-LD group and 115 days in the ABV group (P < .001).

Lesion color improvement: Only 3% of patients receiving PEG-LD, and 4% of ABV patients had indicator lesions that were all brown at baseline. The balance of the patients had indicator lesions that were erythematous or violaceous and therefore considered to be more disfiguring. By the end of therapy, 50% of PEG-LD and 30% of ABV patients had indicator lesions that were all brown (P < .002). The mean time required to achieve this benefit was 68 days in the PEG-LD group and 69 days in the ABV group.

Pain reduction: Both regimens resulted in a reduction in lesion-associated pain. At baseline, 40% of patients receiving PEG-LD and 47% of patients receiving ABV had no pain; whereas 33% and 31%, respectively, had moderate or severe pain. By the end of treatment 83% and 78% of PEG-LD and ABV patients, respectively, were without lesion-associated pain. Pain relief was achieved without increases or new additions of either analgesics or antidepressants. The median time required to achieve this benefit was 17 days in the PEG-LD group and 15 days in the ABV group.

Intestinal/pulmonary AIDS-KS symptoms: Seventeen percent of patients receiving PEG-LD and 18% of patients receiving ABV had signs or symptoms of intestinal AIDS-KS at baseline. By the end of treatment, 8% of PEG-LD and 16% of ABV patients had such symptoms (P £ .05). Nineteen percent of PEG-LD patients and 23% of ABV patients had signs or symptoms of pulmonary AIDS-KS at baseline. These proportions did not change appreciably over the course of the study in either group.

Quality of life: The quality of life of patients enrolled in the trial was assessed at each study visit. A complete analysis of data obtained from two quality of life instruments was incomplete at the time of this writing. However, in all domains examined, quality of life among patients treated with PEG-LD appeared to compare favorably with that experienced by patients receiving ABV.

A total of 90 patients receiving PEG-LD (68%) and 43 patients receiving ABV (34%) completed the protocol. The mean number of cycles per patient was 5.2 ± 1.4 (standard deviation) for patients receiving PEG-LD and 3.8 ± 1.9 (standard deviation) for patients receiving ABV. Thirty-seven percent of ABV patients and 11% of PEG-LD patients discontinued their participation in the trial because of an adverse event (P < .001). Sixteen patients receiving PEG-LD (12%) and five patients receiving ABV (4%) died during the trial. Kaplan-Meier analysis indicated that this difference was not statistically significant. Seven percent of ABV patients and no PEG-LD patients withdrew because of disease progression.

Some other reasons for discontinuing the study included poor compliance (eight patients receiving ABV, three patients receiving PEG-LD), lost to follow-up (two patients receiving ABV, two patients receiving PEG-LD), intercurrent opportunistic infections (two patients receiving ABV, one patient receiving PEG-LD), and unspecified personal reasons (2 patients receiving ABV, one patient receiving PEG-LD). One patient receiving ABV withdrew early due to lack of response, and one patient receiving PEG-LD had therapy withheld for greater than 14 days.

Table 10 lists the most common adverse events experienced in the trial. Six episodes of acute infusion-related reactions occurred in the PEG-LD group. Flushing, chest pain, dyspnea, difficulty swallowing, hypotension, and/or back pain characterized these reactions. Three cases of palmar-plantar erythrodysesthesia were seen in the PEG-LD group and one case was seen in the ABV group. Two other patients who received PEG-LD developed rashes that were consistent with this syndrome but not explicitly designated as such by the investigator. Alopecia occurred in 42% of patients receiving ABV and in 11% of patients receiving PEG-LD (P < .001).

In summary, the findings of this randomized comparative trial demonstrated that PEG-LD was effective in the treatment of patients with advanced AIDS-KS and was superior to the combination of ABV. Because doxorubicin delivered by pegylated liposomes was able to produce results superior to a proven combination regimen therapy containing doxorubicin, it was concluded that pegylated-liposome encapsulation enhanced the therapeutic effect of doxorubicin.

PEG-LD vs Bleomycin and Vincristine

A randomized trial similar in design to that described above was recently conducted. Treatment with PEG-LD was compared with that of bleomycin and vincristine (BV).[39] Of 116 patients receiving PEG-LD, 7 (5.8%) had a complete response vs 1 (0.8%) of 102 of patients receiving BV. Sixty-three (52%) of those on PEG-LD had a partial response vs 27 (23%) of those on BV (P < .001, Fisher’s Exact test).

These findings provide further confirmation that PEG-LD is superior to the standard combination regimen BV in its effectiveness. With respect to toxicity, PEG-LD was found to cause significantly more neutropenia, but less nausea/vomiting, alopecia, and neuropathy.

Toxicity

In all clinical trials reported to date, the primary toxicity of liposomal anthracycline chemotherapy for AIDS-KS has been myelotoxicity with neutropenia. Nausea, vomiting, alopecia, and neuropathy have all occurred with substantially less frequency with liposomal anthracyclines than is typically observed with standard chemotherapy. Although definitive information is lacking, most investigators have considered the incidence of opportunistic infection to be no greater in patients treated with liposomal anthracyclines than would be anticipated in patients with advanced HIV-related immunodeficiency.

Several unique aspects of the toxicity of liposomal anthracyclines require specific discussion. An acute infusion reaction associated with liposomal anthracycline therapy can occur, with symptoms including flushing, facial edema, headache, back pain, rigors, hypotension, chest/throat tightness, and/or dyspnea. In the safety database provided to the US Food and Drug Administration at the time of licensing of PEG-LD, this infusion reaction was reported to have an incidence of 6.8% (48 of 705 patients treated with PEG-LD). The reaction occurred during the first cycle of therapy in all patients reported, and was self-limited, abating minutes to hours after the infusion was stopped, and usually not recurring with subsequent dosing.

Similar reactions complicated 27 of 994 treatment cycles in the liposomal daunorubicin randomized trial.[37] No specific preventative therapy has been recommended. In the author’s experience, terminating the infusion has usually led to prompt resolution of the symptoms, allowing the infusion to be resumed at a slower rate without subsequent difficulty.

Palmar-plantar erythrodysesthesia has also been associated with liposomal anthracycline therapy. Symptoms include painful macular erythema of palmar and plantar surfaces, similar to those seen with prolonged continuous infusions of doxorubicin and fluorouracil (5-FU). The incidence of this problem was 3.4% (24 of 705 patients) in the safety database for PEG-LD, and it occurred in 0.9% (1 of 116 patients) in the liposomal daunorubicin randomized trial.[37] The problem tends to occur after repeated dosing, especially at higher doses and shorter dosing intervals. Blistering, desquamation, and slow healing occur when treatment is stopped; the problem may recur with re-exposure to the drug.

Concern has been raised regarding the potential for extravasation injury associated with liposomal anthracycline therapy because standard anthracycline formulations can cause significant local injury when they infiltrate into extravascular tissue. In contrast, extravasation PEG-LD produces the histologic appearance of mild to moderate inflammation at subcutaneous injection sites in rabbits, as opposed to the severe inflammation and tissue necrosis caused by standard doxorubicin. At the University of California, San Francisco, we witnessed eight episodes of extravasation without significant clinical sequelae in patients receiving PEG-LD for AIDS-KS.[40] PEG-LD is therefore considered an irritant, not a vesicant.

Therapy with any anthracycline raises concern over the potential for cardiotoxicity. In order to evaluate any cardiotoxicity due to PEG-LD, investigators identified 10 patients with AIDS-KS who had received in excess of 400 mg/m² of PEG-LD and who were willing to undergo endomyocardial biopsy for histopathologic evaluation.[41] Control subjects matched for cumulative standard doxorubicin dose were identified from a database of 131 patients who had undergone biopsies while enrolled in clinical trials using doxorubicin at Stanford University. Anthracycline-induced cardiotoxicity was scored using a well-established six-point scale (0 to 3.0). Matched controls were available for 8 of the 10 PEG-LD patients; the two unmatched patients had received cumulative doses of 780 and 860 mg/m², but the scores of both of these patients were 0.5, indicating no anthracycline-specific toxicity.

In an unblinded comparison of the remaining eight PEG-LD patients with their matched controls, PEG-LD patients had a lower median score (0.5 for PEG-LD vs 2.25 for standard doxorubicin) and the difference between the groups was highly significant (P < .001, paired t-test). These data suggest that PEG-LD is less cardiotoxic than standard doxorubicin at comparable cumulative doses. Published experience with cardiotoxicity related to liposomal daunorubicin has been limited to clinical assessments (radionuclide angiography) performed in conjunction with the various clinical trials of this agent in AIDS-KS patients. On this basis, there appears to be very little cardiotoxicity associated with liposomal daunorubicin.

Future Considerations

Several lines of inquiry are worthy of consideration in future development of liposomal anthracycline chemotherapy for AIDS-KS. While a study of the optimal doses and schedules for delivery of these medications could help achieve more effective and tolerable therapy, this will require a better means of classifying patients clinically, a difficult task due to the highly variable clinical presentation of AIDS-KS. The use of anthracycline chemotherapy in combination with other cytotoxic agents or in conjunction with antiretroviral therapy might also be fruitful.

In this regard, the ACTG has completed a randomized trial comparing PEG-LD to the combination of pegylated-liposomal ABV in patients with advanced AIDS-KS. The data from this trial are being analyzed at this time, and the results should be forthcoming shortly.

Another obvious question relates to the relative value of PEG-LD and liposomal daunorubicin in this setting. When each of these liposomal formulations was compared to ABV (Table 8), the response rate (CR+PR) achieved with PEG-LD (46%) was clearly superior to that of ABV (25% to 28%) or liposomal daunorubicin (25%). A randomized clinical trial to directly compare the two agents is underway, but results are not yet available. In addition, the role of these and other cytotoxic therapies in relation to specific antiviral therapy for HHV-8 awaits the identification of meaningful antiviral treatment strategies.

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