Clinical Benefit Sustained in AIDS-Related Kaposi’s Sarcoma Patients Treated With Pegylated Liposomal Doxorubicin

July 1, 2002

MOUNTAIN VIEW, California-Pegylated liposomal doxorubicin (Doxil, Caelyx) offered a sustained clinical benefit to 37% of patients with AIDS-related Kaposi’s sarcoma vs 16% of patients treated with liposomal daunorubicin (DaunoXome) in a randomized trial comparing the two drugs (ASCO abstract 1640).

MOUNTAIN VIEW, California—Pegylated liposomal doxorubicin (Doxil, Caelyx) offered a sustained clinical benefit to 37% of patients with AIDS-related Kaposi’s sarcoma vs 16% of patients treated with liposomal daunorubicin (DaunoXome) in a randomized trial comparing the two drugs (ASCO abstract 1640).

"In the setting of Kaposi’s sarcoma, clinicians have wondered whether tumor response is correlated with clinically significant improvement," said study investigator Francis Martin, PhD, of Alza Pharmaceuticals in Mountain View, California. "Although the Food and Drug Administration has approved Doxil in Kaposi’s sarcoma on the basis of tumor regression, they also want to know the association between tumor response and benefit to the patients."

In this phase IV, double-blind, multicenter study, 80 patients with AIDS-related Kaposi’s sarcoma were randomized 3:1 to one of two active treatments, either pegylated liposomal doxorubicin at 20 mg/m², or liposomal daunorubicin at 40 mg/m², every 2 weeks for up to six cycles. Baseline characteristics were well balanced, and most patients had newly diagnosed Kaposi’s sarcoma.

Clinical Benefit Shown

Clinical benefit was defined as improvement in at least one of five symptom categories associated with Kaposi’s sarcoma: edema, pulmonary involvement, gastrointestinal involvement, disfiguring lesions, and pain. The final analysis used a more conservative definition of sustained clinical benefit, defined as a sustained improvement lasting at least 28 days in at least one symptom category without worsening of the other symptoms.

Each patient made a biweekly assessment of the five symptom categories using an 11-item questionnaire. An independent blinded reviewer evaluated photographs for disfiguring lesions and edema.

"On the basis of a patient-reported outcomes questionnaire, this study did show that Doxil was associated with improvement in pain, disfiguring lesions, gastrointestinal disease, pulmonary disease, and lymphedema," said study investigator Margaret Tonda, PharmD, of Alza Pharmaceuticals. "Often pain relief is linked to improvement in lymphedema, as obstructed lymphatic drainage by Kaposi’s lesions can cause pain in the feet." In addition to presenting the study results, Dr. Martin and Dr. Tonda offered ONI their perspectives on the trial.

Clinical benefit in at least one of the five symptom categories occurred in 48 (80%) of patients receiving pegylated liposomal doxorubicin and in 12 (63%) of patients receiving liposomal daunorubicin. Sustained improvement in at least one Kaposi’s sarcoma symptom category without worsening of other symptoms occurred in 22 (37%) of patients receiving pegylated liposomal doxorubicin and in 3 (16%) of patients receiving liposomal daunorubicin.

"Not only was Doxil more effective than DaunoXome, but it was effective at about half the dose-equivalent of doxorubicin," Dr. Martin said. "Benefits occur at half the relative dose, allowing patients to remain on treatment longer. Some patients have remained on Doxil for 2 years."

Partial tumor response occurred in 55% of patients receiving pegylated liposomal doxorubicin and in 32% of those receiving liposomal daunorubicin, with a positive correlation between response and transient or sustained clinical benefit. Among patients receiving pegylated liposomal doxorubicin who showed a partial tumor response, 92% experienced a transient clinical benefit, and 42% experienced a sustained clinical benefit lasting at least 28 days. Among those receiving liposomal daunorubicin who showed a partial tumor response, 83% experienced a transient and 33% a sustained clinical benefit.

Photographs showed improvement in 35% of patients treated with pegylated liposomal doxorubicin and 38% of patients treated with liposomal daunorubicin.

Most Toxicities Hematologic

"In general, Doxil is well tolerated," Dr. Martin said. "Toxicities are primarily hematologic, as would be expected from doxorubicin."

Although no new safety issues were identified, 92% of patients on pegylated liposomal doxorubicin and 90% of patients on liposomal daunorubicin experienced adverse events, most commonly neutropenia, nausea, asthenia, anemia, and paresthesia. Discontinuations due to adverse events occurred in four patients receiving pegylated liposomal doxorubicin (5%), including one with treatment-related sepsis. None of the patients receiving liposomal daunorubicin had to discontinue treatment.

Dr. Martin said that pegylated liposomal doxorubicin has been used as the first-line systemic therapy of choice since FDA approval in 1995, even though recent studies suggest that the incidence of Kaposi’s sarcoma has declined since the era of highly active antiretroviral therapy. "Having an effective treatment is still important because Kaposi’s sarcoma can be aggressive, disfiguring, and in some cases invade the viscera," he said.

"Although the incidence of Kaposi’s sarcoma decreased with the adoption of highly active antiretroviral therapy, recent statistics suggest that it is on the rise again," Dr. Tonda said.