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Pegylated Liposomal Doxorubicin Has Important Clinical Utility in Breast Cancer: Presented at IBCC

By Alison Palkhivala

BANFF, AB -- August 8, 2003 -- Pegylated liposomal doxorubicin (PLD, Doxil) has important properties that differentiate it from both free doxorubicin and liposomal doxorubicin, making it just as effective a therapy but with a reduced toxicity profile.

Stephen R. D. Johnston, MD, PhD, consultant in medical oncology, Royal Marsden Hospital, London, United Kingdom, spoke about the clinical utility of PLD in breast cancer here August 1^st at the Second Annual Future of Breast Cancer: An International Breast Cancer Congress.

Liposomes are lipid bilayer spheres into which doxorubicin is concentrated, Dr. Johnston explained. PLD differs from regular liposomal doxorubicin in 2 important ways. "The differences with pegylated liposomal doxorubicin … is this pegylated coat, polyethylene glycol, surrounding the liposome," he said. "The reason for that is twofold -- It alters significantly the way the body handles the liposomes. Firstly, it allows the liposome during its circulation to avoid the reticular endothelial system [which increases its circulation time]. … Secondly, it allows the drug to remain encapsulated within the liposome until it reaches the tumor, and then there is some evidence that, potentially, you could get concentrations specifically of the drug within the tumor."

Two key clinical trials led to the approval of PLD for use in Europe. The first was a phase II study by Wigler et al. presented in 2002 at the annual meeting of the American Society of Clinical Oncology (ASCO, Abstract 177). Patients in this trial received PLD or free doxorubicin as a first-line treatment for metastatic breast cancer.

Wigler and colleagues found that overall and progression-free survival were similar for both therapies, but what differentiated PLD was its lower toxicity profile. Approximately 50% of patients had at least one cardiac risk factor before initiating therapy, and cardiac toxicity was much lower with PLD than with free doxorubicin. As cumulative doses of each drug increased, their differences with respect to cardiac toxicity also widened. PLD-treated patients also experienced less alopecia, nausea, and vomiting.

In the second trial, by Keller et al. and presented at ASCO 2001 (Abstract 115), PLD was compared with a chemotherapy regimen that was left to the discretion of the treating physician, and usually consisted of vinorelbine or mitomycin C plus vinblastine. This time, the therapies were used for salvage in patients for whom taxane therapy failed. Most had also been treated previously with anthracyclines. Again, progression-free and overall survivals were similar between both groups, but PLD resulted in fewer cases of neutropenia and neuropathy.

"Post hoc analysis of patient subgroups revealed that those who had been pre-treated with anthracyclines actually had better response rates with PLD," Dr. Johnston said.

Trials with PLD are ongoing and include studies in which it is being combined with other agents, such as trastuzumab. To date, the only major disadvantage associated with PLD is an increased risk of palmar-plantar erythrodysesthesia (PPE), also known as hand-foot syndrome. This condition is reversible, so physicians should be on the lookout for its early signs, which include intense and painful macular reddening of the palms and soles, vague paresthesia, and edema.

Important benefits of PLD are that it allows for a longer duration of treatment with convenient once a month dosing. Dr. Johnston described the 3 major indications for the agent: as monotherapy for metastatic breast cancer in patients at increased cardiac risk, for advanced ovarian cancer in women for whom first-line platinum-based chemotherapy has failed, and for AIDS-related Kaposi's sarcoma in patients with low CD4 counts and extensive mucocutaneous or visceral disease.

He said the drug is particularly useful for patients who present with hypertension, prior mediastinal irradiation, or a history of heart disease. It is also ideally suited for elderly patients, patients for whom specific toxicities are a particular concern, or for those treated in the adjuvant setting and returning for treatment of metastatic disease.


[Study title: Future role of liposomal pegylated doxorubicin in breast cancer treatment.]

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