Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 12, No. 1, 114-123, January 2007; doi:10.1634/theoncologist.12-1-114
© 2007 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cooley, T.
Right arrow Articles by Rackoff, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cooley, T.
Right arrow Articles by Rackoff, W.

Sarcomas

A Randomized, Double-Blind Study of Pegylated Liposomal Doxorubicin for the Treatment of AIDS-Related Kaposi’s Sarcoma

Timothy Cooleya, David Henryb, Margaret Tondac, Steven Sund, Martin O’Connellc, Wayne Rackoffd

a Lahey Clinic, Burlington, Massachusetts, USA; b Pennsylvania Hospital, Philadelphia, Pennsylvania, USA; c ALZA Corporation, Mountain View, California, USA; d Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey, USA

Key Words. Pegylated liposomal doxorubicin • AIDS • Kaposi’s sarcoma • Liposomal daunorubicin

Correspondence: Timothy Cooley, M.D., Department of Medical Oncology, Lahey Clinic, 41 Mall Road, Burlington, Massachusetts 01805, USA. Telephone: 781-744-8410; Fax: 781-744-5293; e-mail: timothy.p.cooley{at}lahey.org

Received May 10, 2006; accepted for publication September 29, 2006.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Discuss the current prevalence of Kaposi’s sarcoma complicating HIV infection.
  2. Describe the impact of highly active antiretroviral therapy (HAART) on Kaposi’s sarcoma complicating HIV infection.
  3. Prioritize treatment options for Kaposi’s sarcoma complicating HIV infection.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
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.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Despite a dramatic decline in the incidence of AIDS-related Kaposi’s sarcoma (KS) associated with the introduction of highly active antiretroviral therapy (HAART) [1–11], approximately 15% of AIDS patients still develop the disease [7]. A recent review of the literature found little evidence to support the regression of advanced, symptomatic KS in AIDS patients who were treated with HAART without simultaneous chemotherapy [10]. Moreover, many patients with advanced KS are those for whom HAART therapy for HIV/AIDS has not been effective [10]. A recent study found an increased overall response rate for KS in patients who received both pegylated liposomal doxorubicin and HAART compared with those who received HAART alone [12].

Patients with advanced, symptomatic KS are commonly treated with a combination of HAART and liposomal anthracyclines, such as pegylated liposomal doxorubicin [13]. The polyethylene glycol-coated liposomal formulation of doxorubicin eludes the immune system, thereby increasing the half-life of the liposome in serum and decreasing the toxicities associated with conventional doxorubicin, such as neutropenia, anemia, alopecia, and cardiotoxicity [14–16].

Results of clinical studies have demonstrated the activity and safety of pegylated liposomal doxorubicin as short- and long-term treatment for patients with advanced AIDS-related KS [17–19], even in those who failed prior chemotherapy with conventional anthracyclines [20 –23]. In addition, quality-of-life assessments have shown that patients receiving pegylated liposomal doxorubicin versus a conventional doxorubicin-containing regimen have significantly improved scores [22]. Both pegylated liposomal doxorubicin and liposomal daunorubicin are approved treatments for AIDS-related KS, with the former indicated for a refractory population (i.e., patients who have progressed on prior combination chemotherapy or patients intolerant to such therapy) and the latter as first-line therapy.

The objectives of this study were to evaluate (a) the clinical benefit of pegylated liposomal doxorubicin therapy based on patient self-assessment of improvements in one of five AIDS-related KS symptoms, (b) tumor response as a corollary to clinical benefit, and (c) the safety of pegylated liposomal doxorubicin in this patient population. Liposomal daunorubicin was used as an active control to minimize potential bias in the assessment of clinical benefit, tumor response, and patient safety. The study was not designed to evaluate differences between the treatment groups.


   METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Study Design
This prospective, double-blind, randomized, multicenter, active-control study was conducted to evaluate the clinical benefit, tumor response rates, and safety of pegylated liposomal doxorubicin in patients with AIDS-related KS. In accordance with the Declaration of Helsinki, the study protocol was reviewed and approved by the appropriate institutional review boards, and all patients provided written informed consent prior to study participation. Since clinical benefit was based on the patients’ assessment of improvements with AIDS-related KS-associated symptoms, liposomal daunorubicin was used as an active control to minimize potential bias in the assessment of clinical benefit, tumor response, and patient safety.

Eligibility Criteria
Patients with AIDS-related KS requiring systemic chemotherapy (regardless of prior chemotherapy), a life expectancy of at least 120 days, and at least five measurable mucocutaneous KS lesions were eligible to participate in the study. Patients were required to have one or more of the following five symptoms: (a) KS-associated edema that impaired functional activity of the extremities, groin, or face; (b) symptomatic evaluable pulmonary KS that had been documented by bronchoscopy within 3 months of entering the trial, measurable by x-ray or computed tomography (CT) scan, and was definitely associated with KS and not with any other manifestation of HIV disease; (c) symptomatic evaluable gastrointestinal KS that had been documented by endoscopy within 3 months of entering the trial and was definitely associated with KS and not another manifestation of HIV disease; (d) KS-associated pain reported by the patient to be moderate or severe despite analgesic use; and (e) KS lesions that, according to the patient, were disfiguring and that impaired self-image or daily activities. Patients were also required to have a left ventricular ejection fraction (LVEF) ≥50%; a Karnofsky performance status (KPS) ≥40%; and a hemoglobin concentration ≥9 g/dl, neutrophil count ≥1,200 cells/mm3, platelet count ≥75,000/mm3, and bilirubin and creatinine levels less than 2 times the upper limit of normal.

Patients were excluded if they had received anti-KS therapy within 14 days of study entry or had received treatment with pegylated liposomal doxorubicin or liposomal daunorubicin at any time prior to study entry. Other exclusion criteria were as follows: (a) presentation with clinically significant cardiac disease as defined by histopathologic evidence of anthracycline-induced cardiomyopathy, LVEF <50%, or abnormal wall motion; (b) the onset of or increased therapy for an opportunistic infection within 4 weeks of study entry; (c) the presence of significant non-KS-related pulmonary insufficiency (oxygen saturation >90%); (d) the presence of other active malignancies except basal or squamous cell carcinoma of the skin or in situ cervical or anal carcinoma; (e) neuropsychiatric history or altered mental status that prevented informed consent or compliance with the protocol requirements; and (f) pregnancy or breastfeeding, or any women of child-bearing age not using a medically proven method of birth control. Other cytotoxic chemotherapy and radiation therapy were prohibited during the study, but the use of other medications to treat HIV was not restricted. Patients were withdrawn from the study if KS progressed, if serious or intolerable adverse events occurred that precluded further treatment, if there was a clinical need for alternative/additional cytotoxic chemotherapies or radiation, or if there was evidence of non-compliance or loss to follow-up for ≥5 weeks.

Treatment Plan and Evaluations
Between September 1996 and September 2000, 80 patients with AIDS-related KS were randomized 3:1 to receive pegylated liposomal doxorubicin (20 mg/m2; n = 60) (DOXIL, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ; CAELYX, Schering-Plough Corporation, Kenilworth, NJ) or liposomal daunorubicin (40 mg/m2; n = 20) (DaunoXome, Gilead Sciences, Inc., Foster City, CA) as a 60-minute intravenous infusion every 2 weeks for six cycles.

Patients were assessed at ≤30 days before treatment, at each of the six treatment cycles, and at the end of the study. At each visit, weight, vital signs, and KPS were recorded, and a physical exam was performed. At baseline, lesion measurements and medical interventions for KS-associated symptoms were recorded. The patient assessment of KS-associated symptoms was performed (as detailed below), and bronchoscopy, chest x-ray/CT scan, and endoscopy were performed as appropriate. Chest x-rays or CT scans were repeated monthly in patients with documented pulmonary KS with the same method used throughout the study. In addition, a carcinoma in situ (TxIxSx) disease stage was assigned according to AIDS Clinical Trial Group (ACTG) staging classifications for AIDS-related KS [24]. Cardiac performance was assessed using a 12-lead electrocardiogram, and LVEF was measured using echocardiogram or multigated acquisition scan. Blood chemistries (creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase), complete blood count with differential and platelet count, CD4+ count, a pregnancy test, and an assessment of concomitant medications were performed at baseline. At cycles 2 through 6 and at the end of the study, photographs, lesion measurements, medical interventions, patient assessments of symptoms, evaluation of response, blood chemistry, complete blood count with differential, platelet count, and adverse events were recorded. A final assessment of cardiac performance was performed (as described above) at the end of the study.

To assess clinical benefit, patients completed an 11-item KS symptom questionnaire with five symptom categories: (a) lymphedema, difficulty in wearing clothing and/or shoes or difficulty moving due to swelling; (b) pulmonary KS, shortness of breath and cough; (c) gastrointestinal KS, difficulty swallowing or eating, the ability to eat only small amounts of food, bloating, diarrhea, and nausea or vomiting; (d) disfiguring KS lesions; and (e) KS-associated pain. Patients rated each symptom as absent, present but did not interfere with daily activities, present and somewhat interfered with daily activities, or present and very much interfered with daily activities. Patients were also asked to rate the severity (none, mild, moderate, or severe) of the average pain experienced from KS lesions within the past 2 weeks.

Clinical Benefit
Two definitions of clinical benefit were used in the evaluation of patient responses. Clinical benefit was defined in the protocol as an improvement from baseline in at least one of five AIDS-related KS symptom categories that lasted for ≥28 days in the absence of disease progression or severe drug-induced toxicity. A conservative approach to the assessment of clinical benefit was also defined as an improvement from baseline in at least one AIDS-related KS symptom category that lasted for ≥28 days with no worsening of other symptom categories and no increase in medical interventions either before or during that period. These two analysis approaches were applied independently, such that a single patient may have achieved both the protocol and conservative definitions of clinical benefit.

The patients’ assessments of improvements in the five KS-symptom categories were corroborated by other measurements. For patients with lymphedema, changes in the circumferential measurements of the edema and motion tests were conducted. For patients with lymphedema and disfiguring KS lesions, photographic assessments were conducted at baseline and at each subsequent study visit. For patients with pulmonary disease, x-ray or CT scans were performed monthly, and the selected method was used throughout the study. For patients with gastrointestinal bleeding, blood transfusions that occurred from 1 week prior to baseline through the end of the study were recorded, and stools were checked for occult blood.

Efficacy Endpoints
The primary efficacy endpoint was the proportion of patients who experienced the protocol-defined clinical benefit. Secondary endpoints included (a) the proportion of patients who experienced clinical benefit in each individual AIDS-related KS symptom category based on an improvement from baseline; (b) the duration of clinical benefit; (c) the proportion of patients who experienced clinical benefit based on changes in medical interventions; (d) the response rate (combined complete response [CR] and partial response [PR]); (e) the duration of tumor response; (f) time to progression; and (g) survival. All adverse events were recorded and graded using the National Cancer Institute Common Toxicity Criteria.

Tumor Response
All tumor response classifications, except relapse, were made by comparing lesion characteristics (i.e., size, number, appearance, and sites of involvement) to the baseline tumor evaluations and assessed according to ACTG criteria [24]. A CR was defined as the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks, confirmed by biopsy; clinical complete response (CCR) was designated in the absence of biopsy confirmation. PR was defined as no new lesions (skin or oral) or new visceral sites of involvement, the appearance or worsening of tumor-associated edema or effusions and a ≥50% decrease in the number of lesions lasting for at least 4 weeks, complete flattening of ≥50% of all raised lesions, a 50% decrease in the sum of the products of the largest perpendicular diameters of the indicator lesions, or the patient meeting the criteria for CCR except for the presence of residual tumor-associated edema or effusion. Stable disease (SD) was defined as any response that did not meet the criteria for CR, CCR, or PR. Progressive disease (PD) was defined as new visceral sites of involvement, progression of visceral disease, the development of new or increasing tumor-associated edema or effusion lasting ≥1 week that interfered with the patient’s normal activities, a 25% increase in the number of lesions, a change in the character of ≥25% of previously flat lesions to raised, or a 25% increase in the sum of the products of the largest perpendicular diameters of the indicator lesions. Relapse was defined as the development of progressive disease in the presence of a documented CR, CCR, or PR.

An independent AIDS expert without knowledge of the patients’ treatment evaluated serial patient photographs of indicator lesions and confirmed tumor response and clinical efficacy assessments. Photographs were available for 67/80 (83.8%) patients; of these, 50 patients had photographs that were evaluable for clinical efficacy by assessing serial photographs of disfiguring KS lesions, and 43 patients had photographs that were evaluable for tumor response assessed by bidirectional measurements of index lesions.

Analysis of the Effect of Changes in Antiretroviral Therapy
Tumor response was also assessed among patients whose response was not confounded by analysis of the effect of changes in antiretroviral therapy (ART). ART was not considered to be a confounding factor if (a) patients had received stable doses of antiretroviral medications for the 60 days prior to the start of study medication or had no antiretroviral therapy during the 60 days prior to the start of study medication and (b) antiretroviral therapy had not changed while receiving study medication or was altered after the first day on which a response was reported.

Statistical Analysis
Demographics, ACTG staging of AIDS-related KS (i.e., TxIxSx), number of KS lesions, and KPS were compared between treatment groups at baseline using analysis of variance or a Wilcoxon two-sample test for continuous variables and chi-square, Cochran–Mantel–Haenszel (CMH), or Fisher’s exact tests for discrete variables. The duration of clinical benefit was calculated for each patient using the Kaplan–Meier method. In patients who responded, the duration of the response (CR or PR) was summarized using the Kaplan–Meier method. Fisher’s exact test was used to test for agreement between the occurrence of clinical benefit and the occurrence of a CR or PR. This study was not designed to evaluate differences between pegylated liposomal doxorubicin and liposomal daunorubicin, which was used as an active control.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Disclosure of Potential...
 References
 
Patient Disposition
A total of 80 patients with AIDS-related KS from seven sites were randomized 3:1 to receive pegylated liposomal doxorubicin (n = 60) or liposomal daunorubicin (n = 19). One patient randomized to liposomal daunorubicin was found to have received prior pegylated liposomal doxorubicin therapy, which was unknown until after the first dose; the patient was therefore removed from the study. Although the protocol states that patients with PD discontinue treatment, eight patients continued to receive treatment after the observation of disease progression; data for these patients were censored at the time of PD.

Patient demographics and baseline characteristics were similar between the treatment groups (Table 1Go). As shown in Table 2Go, most patients in both groups had not previously undergone therapy for AIDS-related KS (55.0% for pegylated liposomal doxorubicin and 63.2% for liposomal daunorubicin).


View this table:
[in this window]
[in a new window]

  		Table 1. Patient demographics and baseline characteristics

 

View this table:
[in this window]
[in a new window]

  		Table 2. Prior AIDS-related KS therapy

 
Efficacy
According to the protocol definition, 48/60 (80.0%) patients receiving pegylated liposomal doxorubicin experienced clinical benefit that lasted for a median duration of 62 days (range, 28–107 days; Table 3Go). When the conservative definition of clinical benefit was applied (i.e., improvement in at least one AIDS-related KS symptom category that lasted for ≥28 days without worsening of other symptoms or an increase in medical interventions), 22/60 (36.7%) patients treated with pegylated liposomal doxorubicin experienced clinical benefit that lasted for a mean duration of 42 days (range, 28–106+ days). Patients receiving pegylated liposomal doxorubicin experienced clinical benefit in each of the five KS symptom categories.


View this table:
[in this window]
[in a new window]

  		Table 3. Clinical benefit according to definition and by symptom category

 
Among patients receiving liposomal daunorubicin, 12/19 (63.2%) patients achieved clinical benefit according to the protocol definition that lasted for a median duration of 55 days (range, 28–84+ days). When the conservative definition of clinical benefit was applied, 3/19 (15.8%) patients receiving liposomal daunorubicin experienced clinical benefit. The median duration of clinical benefit using the conservative definition could not be calculated because the Kaplan–Meier estimate was >50% for each time point. Patients receiving liposomal daunorubicin experienced clinical benefit in each of the five KS symptom categories.

Tumor Response
Tumor responses were observed in 55.0% (33/60) of pegylated liposomal doxorubicin patients (Table 4Go), with a median time to tumor response of 30 days and a median time to progression of 154 days. Median time to death could not be calculated. Tumor responses were observed in 31.6% (6/19) of liposomal daunorubicin patients (Table 4Go), with a median time to tumor response of 27 days. Median time to progression and median time to death could not be calculated. Independent photographic review of indicator lesions from the 43 patients with evaluable photographs determined a tumor response rate of 38% (11/29; 1 CCR and 10 PRs) for pegylated liposomal doxorubicin and 21% (3/14; 1 CCR and 2 PRs) for liposomal daunorubicin.


View this table:
[in this window]
[in a new window]

  		Table 4. Onset and duration of tumor responses

 
Considering all patients and using the protocol definition of clinical benefit, 90% (35/39) of patients with a tumor response also achieved clinical benefit. Approximately two-thirds of the patients with SD (63.6%, 21/33) who had no evidence of disease progression on study also experienced clinical benefit. When the conservative definition of clinical benefit was used, 16/39 patients (41%) with tumor responses achieved clinical benefit (Fig. 1Go). A positive correlation between clinical benefit (per protocol and conservative definitions) and tumor response was identified (Pearson correlation coefficient, r = .31 and r =.25; p < .05 by two-tailed Fisher’s exact test or CMH general association adjusted for treatment group).


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		Figure 1. Clinical benefit versus tumor response. A proportion of patients at each level of response also obtained clinical benefit (by the protocol definition). Tumor response and clinical benefit were significantly correlated using both the protocol and conservative definitions of clinical benefit (Pearson correlation coefficient, r = .31 and r = .25, respectively; p < .05 by two-tailed Fisher’s exact test or Cochran–Mantel–Haenszel general association adjusted for treatment group).

 
The Effect of Changes in ART
Seventy-six patients in the study received ART. A change in ART was not considered to confound the assessment of tumor response in 22 patients receiving pegylated liposomal doxorubicin (Table 5Go); 11/22 (50%) patients achieved a tumor response according to the protocol definition, and 10/22 (45%) patients achieved a tumor response according to the conservative definition. Among patients receiving liposomal daunorubicin, 10 patients were not considered to have a confounding change in ART; 5/10 (50%) achieved a tumor response according to the protocol definition; and 2/10 (20%) patients achieved a tumor response according to the conservative definition.


View this table:
[in this window]
[in a new window]

  		Table 5. Tumor responses and clinical benefit in patients without confounding changes in antiretroviral therapy

 
Safety
The median cumulative dose for patients receiving pegylated liposomal doxorubicin was 109.30 mg/m2; the median cumulative dose for patients receiving liposomal daunorubicin was 220.41 mg/m2. A total of 41 (68.3%) patients receiving pegylated liposomal doxorubicin and 12 (63.2%) patients receiving liposomal daunorubicin had delayed, interrupted, or reduced doses during the study. Hematologic toxicity was the primary reason for dose adjustments in both the pegylated liposomal doxorubicin (32.1%) and liposomal daunorubicin (15.8%) groups; other common reasons for dose delay, interruption, or adjustment in patients receiving pegylated liposomal doxorubicin included scheduling problems (26.9%), intercurrent illness (12.8%), and other reasons (14.1%). The most common treatment-related adverse events reported in >10% of patients in either treatment group are summarized in Table 6Go.


View this table:
[in this window]
[in a new window]

  		Table 6. Treatment-related adverse events of all grades reported by >10% of patients in either treatment group

 
Hematologic adverse events consisted primarily of neutropenia; 18/60 (30%) patients receiving pegylated liposomal doxorubicin had neutropenia (15 patients, grade 3; 1 patient, grade 4). One grade 3 and one grade 4 neutropenic event were reported in patients receiving liposomal daunorubicin, which resulted in dose delays. Seven patients receiving pegylated liposomal doxorubicin and two patients receiving liposomal daunorubicin experienced treatment-related anemia; five patients on pegylated liposomal doxorubicin had grade 3 or 4 events. Leukopenia was also reported in both pegylated liposomal doxorubicin and liposomal daunorubicin groups (three and two patients, respectively), whereas thrombocytopenia was seen only in those receiving pegylated liposomal doxorubicin (two patients).

Five (8.3%) patients treated with pegylated liposomal doxorubicin experienced hand-foot syndrome (HFS); all events were considered as being related to treatment (four patients had grade 1/2 HFS; one patient had grade 3 HFS). No patients on liposomal daunorubicin experienced HFS. No patient was withdrawn from the study due to HFS.

A total of 6/78 (7.7%) doses were interrupted because of infusion-related reactions in pegylated liposomal doxorubicin patients—five because of a reaction during cycle 1 and one due to a reaction in cycles 1 and 6. All of the infusion-related reactions were either grade 1 or 2 in severity. No dose interruptions occurred on the liposomal daunorubicin arm due to infusion reactions. No patient was withdrawn from the study due to an infusion-related reaction.

Most patients had pre- and on-study LVEF measurements performed (61.6% and 57.8% of patients receiving pegylated liposomal doxorubicin and liposomal daunorubicin, respectively). Median LVEF was 60% at baseline in each group (ranges, 50%–75% and 44%–76%, respectively), and in the final measurement, which was generally performed at the end of treatment, median LVEF was 58% for pegylated liposomal doxorubicin patients (range, 45%–73%) and 60% for liposomal daunorubicin patients (range, 41%–66%). One patient treated with pegylated liposomal doxorubicin entered the study with a LVEF of 62% with moderate cardiomegaly, left ventricular hypertrophy, and pericardial effusion and developed grade 2 congestive heart failure after six cycles of pegylated liposomal doxorubicin treatment. After hospitalization, the patient was withdrawn from the study (final LVEF, 58%).

Three patients on pegylated liposomal doxorubicin were withdrawn from the study due to adverse events. Only one withdrawal was considered treatment-related; the patient was removed after developing a Pseudomonas aeruginosa infection (sepsis, pneumonia, and urinary tract infection) and eventually died of unknown causes more than 2 months after being withdrawn from the study.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Disclosure of Potential...
 References
 
This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin in the treatment of patients with AIDS-related KS. Previous clinical study results have demonstrated that pegylated liposomal doxorubicin is a safe and effective therapy for advanced AIDS-related KS [17–19] and is associated with improvements in quality of life in these patients compared with a conventional doxorubicin-containing regimen [22].

Patients in both treatment arms achieved clinical benefit in each of the five AIDS-related KS symptom categories. Tumor responses (PRs) were observed in patients receiving pegylated liposomal doxorubicin (55.0%) and liposomal daunorubicin (31.6%). Tumor response and clinical benefit were correlated using either the protocol definition or a more conservative definition of clinical benefit.

This study also demonstrated that 50% of patients without confounding changes in ART obtained a tumor response with pegylated liposomal doxorubicin, and 45% obtained clinical benefit. A recent study by Martin-Carbonero et al. [12] compared the responses of patients with moderate-to-advanced KS to treatment with concomitant pegylated liposomal doxorubicin and HAART or HAART alone [12]. Of 13 patients receiving pegylated liposomal doxorubicin and HAART, there was an overall response rate of 76% (four CRs and six PRs) compared with 20% in patients receiving HAART alone (two CRs and one PR; p = .003). Ten patients receiving HAART alone were rescued using pegylated liposomal doxorubicin; seven experienced disease progression during the first 3 months of HAART. Together, these studies indicate a continued role for chemotherapy to induce regression of advanced AIDS-related KS.

Whereas cardiotoxicity has been associated with nonliposomal formulations of doxorubicin and other conventional anthracyclines, improved cardiac safety has been documented with pegylated liposomal doxorubicin [14–16, 25]. With a median cumulative dose of 109.30 mg/m2 for pegylated liposomal doxorubicin (220.41 mg/m2 for liposomal daunorubicin), no change in median LVEF was observed over the course of this study. A recent case report demonstrated the use of 30 cycles of liposomal doxorubicin (nonpegylated) for a cumulative dose of 1,575 mg/m2 in a single patient with breast cancer, with no deterioration in LVEF [26].


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Disclosure of Potential...
 References
 
Patients with AIDS-related KS receiving pegylated liposomal doxorubicin achieved clinical benefit and tumor response, and tumor response was positively correlated with the achievement of clinical benefit. Moreover, results from this study and those from Martin-Carbonero et al. [12] indicate that even in the era of HAART, chemotherapy still plays an important role in the treatment of advanced AIDS-related KS.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
References
 
T.C. has acted as a consultant for and receives support from Abbott Laboratories, GlaxoSmithKline, Datamonitor, and Bristol-Myers Squibb. D.H. has acted as a consultant for and receives support from Ortho Biotech. M.T., M.O., and W.R. own stock in Johnson & Johnson.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 
This article was written on behalf of the Study 30–38 investigators and was supported by ALZA Corporation and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Principal investigators who participated in this study included D.H. Henry, Graduate Hospital, Tuttleman Center, Philadelphia; Z.P. Bernstein, Roswell Park Cancer Institute, Buffalo, NY; T.W. Cheung, Mount Sinai Medical Center, New York; M. Kroll and S. Miller, Harris County Hospital District, Houston; T.P. Cooley, Boston City Hospital, Boston; A.R. Lopez and R. Mass, Kaiser Permanente Medical Center, Santa Clara, CA; and M. Saleh, University of Alabama at Birmingham, Birmingham, AL. We gratefully acknowledge the many patients and families who made the study possible, as well as the investigators and study center staff.

The work contained herein has not been previously published but was presented as a poster at the 38th Annual Meeting of the American Society of Clinical Oncology; May 18–21, 2002, Orlando.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Disclosure of Potential...
 References
 

  1. Ledergerber B, Telenti A, Egger M. Risk of HIV related Kaposi’s sarcoma and non-Hodgkin’s lymphoma with potent antiretroviral therapy: Prospective cohort study. Swiss HIV Cohort Study. BMJ 1999;319:23–24.[Free Full Text]
  2. Jacobson LP, Yamashita TE, Detels R et al. Impact of potent antiretroviral therapy on the incidence of Kaposi’s sarcoma and non-Hodgkin’s lymphomas among HIV-1-infected individuals. Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 1999;21(suppl 1):S34–S41.
  3. Tam HK, Zhang ZF, Jacobson LP et al. Effect of highly active antiretroviral therapy on survival among HIV-infected men with Kaposi sarcoma or non-Hodgkin lymphoma. Int J Cancer 2002;98:916–922.[CrossRef][Medline]
  4. Jones JL, Hanson DL, Dworkin MS et al. Incidence and trends in Kaposi’s sarcoma in the era of effective antiretroviral therapy. J Acquir Immune Defic Syndr 2000;24:270–274.[Medline]
  5. Buchbinder SP, Holmberg SD, Scheer S et al. Combination antiretroviral therapy and incidence of AIDS-related malignancies. J Acquir Immune Defic Syndr 1999;21(suppl 1):S23–S26.
  6. Rabkin CS, Testa MA, Huang J et al. Kaposi’s sarcoma and non-Hodgkin’s lymphoma incidence trends in AIDS Clinical Trial Group study participants. J Acquir Immune Defic Syndr 1999;21(suppl 1):S31–S33.
  7. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000;92:1823–1830.[Abstract/Free Full Text]
  8. Sparano JA, Anand K, Desai J et al. Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. J Acquir Immune Defic Syndr 1999;21(suppl 1):S18–S22.
  9. Carrieri MP, Pradier C, Piselli P et al. Reduced incidence of Kaposi’s sarcoma and of systemic non-Hodgkin’s lymphoma in HIV-infected individuals treated with highly active antiretroviral therapy. Int J Cancer 2003;103: 142–144.[CrossRef][Medline]
  10. Krown SE. Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: Implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol 2004;22: 399–402.[Free Full Text]
  11. Ives NJ, Gazzard BG, Easterbrook PJ. The changing pattern of AIDS-defining illnesses with the introduction of highly active antiretroviral therapy (HAART) in a London clinic. J Infect 2001;42:134–139.[CrossRef][Medline]
  12. Martin-Carbonero L, Barrios A, Saballs P et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active anti-retroviral therapy alone in HIV patients with Kaposi’s sarcoma. AIDS 2004;18:1737–1740.[CrossRef][Medline]
  13. Cattelan AM, Trevenzoli M, Aversa SM. Novel pharmacological therapies for the treatment of AIDS-related Kaposi’s sarcoma. Expert Opin Investig Drugs 2004;13:501–513.[Medline]
  14. Gabizon AA. Pegylated liposomal doxorubicin: Metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 2001;19:424–436.[CrossRef][Medline]
  15. Safra T, Muggia F, Jeffers S et al. Pegylated liposomal doxorubicin (doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000;11:1029–1033.[Abstract/Free Full Text]
  16. Berry G, Billingham M, Alderman E et al. The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 1998;9:711–716.[Abstract/Free Full Text]
  17. Hengge UR, Esser S, Rudel HP et al. Long-term chemotherapy of HIV-associated Kaposi’s sarcoma with liposomal doxorubicin. Eur J Cancer 2001;37:878–883.[CrossRef][Medline]
  18. Nunez M, Saballs P, Valencia ME et al. Response to liposomal doxorubicin and clinical outcome of HIV-1-infected patients with Kaposi’s sarcoma receiving highly active antiretroviral therapy. HIV Clin Trials 2001;2:429–437.[CrossRef][Medline]
  19. Newell M, Milliken S, Goldstein D et al. A phase II study of liposomal doxorubicin in the treatment of HIV-related Kaposi’s sarcoma. Aust N Z J Med 1998;28:777–783.[Medline]
  20. Northfelt DW, Dezube BJ, Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol 1998;16:2445–2451.[Abstract]
  21. Northfelt DW, Martin FJ, Working P et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: Pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol 1996;36:55–63.[Abstract]
  22. Osoba D, Northfelt DW, Budd DW et al. Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma: A randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine. Cancer Invest 2001;19:573–580.[CrossRef][Medline]
  23. Nasti G, Errante D, Santarossa S et al. A risk and benefit assessment of treatment for AIDS-related Kaposi’s sarcoma. Drug Saf 1999;20:403–425.[CrossRef][Medline]
  24. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: Prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1997;15: 3085–3092.[Abstract]
  25. O’Brien ME, Wigler N, Inbar M et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440–449.[Abstract/Free Full Text]
  26. Jones RL, Berry GJ, Rubens RD et al. Clinical and pathological absence of cardiotoxicity after liposomal doxorubicin. Lancet Oncol 2004;5:575–577.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cooley, T.
Right arrow Articles by Rackoff, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cooley, T.
Right arrow Articles by Rackoff, W.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS