Polyethylene Glycol-Liposomal Doxorubicin

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours.

In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials.

PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study.

In patients with advanced AIDS-related Kaposi’s sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response.

As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin’s lymphoma in small, preliminary trials.

The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established.

Polyethylene glycol (PEG)-liposomal doxorubicin consists of doxorubicin entrapped in PEG-coated liposomes. The antitumour activity of doxorubicin may arise mainly from interference with the topoisomerase II-DNA complex, resulting in fragmented DNA; other intracellular damage is caused by free radicals formed when the drug is metabolised. The latter mechanism is thought to be responsible not only for the antitumour activity of doxorubicin but also for adverse effects such as cardiotoxicity.

PEG-liposomal doxorubicin was more effective than standard doxorubicin against human ovarian carcinoma xenografts in mice. The liposomal formulation has also demonstrated activity in vitro against a range of different human tumour cell cultures including breast, ovarian and lymphoma tumour cell types. Higher concentrations of PEG-liposomal doxorubicin than standard doxorubicin were required to inhibit tumour cell proliferation for all cell lines. PEG-liposomal doxorubicin also strongly inhibits the in vitro growth of human Kaposi’s sarcoma spindle cells and Kaposi’s sarcoma lesions.

PEG-liposomal doxorubicin has a different pharmacokinetic profile from that of standard doxorubicin, including a longer circulation time, slower clearance, smaller volume of distribution and a larger area under the plasma concentrationtime curve (AUC). In addition, PEG-liposomal doxorubicin delivers 5.2 to 11.4 times more doxorubicin to Kaposi’s sarcoma lesions than does the same dose of standard doxorubicin.

The plasma concentration profile of PEG-liposomal doxorubicin over a dose range of 10 to 20 mg/m² was reported to be linear, while an increase in dose to 50 mg/m² was associated with a nonlinear profile. After administration of PEG-liposomal doxorubicin 20 and 50 mg/m2, the AUC for doxorubicin was 564 and 902 mg · h/L, respectively, and the peak plasma doxorubicin concentration was 8.6 or 10.1 and 21.2 mg/L, respectively.

Limited data suggest that PEG-liposomal doxorubicin preferentially accumulates in tumour tissue because it has a prolonged circulation time. Once trapped in the tumour tissue interstitial fluid, the liposomes are thought to slowly release doxorubicin which can then enter and damage tumour cells. After PEG-liposomal doxorubicin administration, doxorubicin concentrations were about 10 to 20 times higher in Kaposi’s sarcoma lesions or bone metastases than in normal skin or tumour-free muscle, respectively.

Doxorubicin metabolites (e.g. doxorubicinol) were detected at low concentrations in urine, but were not detected or were detected in low concentrations in plasma after administration of PEG-liposomal doxorubicin. Clearance of single-dose PEG-liposomal doxorubicin 25 to 50 mg/m² administered intravenously was independent of dose. Bile is likely to be the major route of doxorubicin excretion after administration of PEG-liposomal doxorubicin, based on results from animal studies.

The effect of hepatic dysfunction on PEG-liposomal doxorubicin pharmaco-kinetics has not yet been established. However, one study found no significant differences in volume of distribution and plasma clearance between patients with hepatocellular carcinoma receiving single-dose PEG-liposomal doxorubicin 20 or 30 mg/m² intravenously and historical controls.

Ovarian cancer: In a large randomised study, PEG-liposomal doxorubicin 50 mg/m² once every 4 weeks was at least as effective as topotecan 1.5 mg/m² daily for 5 days every 3 weeks in 254 patients with ovarian cancer refractory to first-line platinum-based chemotherapy (overall response rates 12.3 vs 6.5%). The two treatments also produced similar rates of objective tumour response in 220 patients with disease sensitive to first-line platinum-based therapy (28.4 vs 28.8%) in the same study; however, patients receiving PEG-liposomal doxorubicin had significantly longer progression free- and overall survival times.

In subgroup analyses of noncomparative studies, PEG-liposomal doxorubicin 40 or 50 mg/m² every 3 to 5 weeks produced overall response rates of 8.3 to 36.4% in 21 to 82 patients with ovarian cancer refractory or resistant to platinum-and paclitaxel-based chemotherapy.

In small, noncomparative studies, the drug has also shown efficacy in combination with topotecan, ifosfamide or gemcitabine in patients with recurrent or persistent ovarian cancer following platinum-based (and sometimes paclitaxel-based) therapy, and in combination with paclitaxel and carboplatin in chemotherapy-naïve patients with advanced ovarian cancer.

Advanced breast cancer: PEG-liposomal doxorubicin has antitumour activity in patients with metastatic disease that has already been treated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer receiving PEG-liposomal doxorubicin 50 mg/m² every 4 weeks or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) [13 vs 15%; no statistical comparison reported] in a randomised, large study (n = 301) published as an abstract. The combinations of PEG-liposomal doxorubicin and paclitaxel or vinorelbine in previously treated patients produced promising overall response rates of 48% and 18 to 36%, respectively, in small studies (n < 35).

Of 71 patients 28.2% experienced responses with PEG-liposomal doxorubicin in a multicentre study (39% of patients in this study were pretreated with chemotherapy).

Kaposi’s sarcoma: In randomised trials, PEG-liposomal doxorubicin monotherapy 20 mg/m² every 2 to 3 weeks produced overall response rates of 46 to 77% in 126 to 258 patients.

The drug was significantly more effective than the commonly used regimen of bleomycin plus vincristine and standard doxorubicin (ABV). In two studies, PEG-liposomal doxorubicin 20 mg/m² every 2 to 3 weeks also produced a greater response than bleomycin plus vincristine (BV). This response was only significantly greater in the larger of these studies. There was a trend towards longer mean duration of survival in patients receiving PEG-liposomal doxorubicin than those receiving BV (239 vs 160 days) and a similar median duration of survival to ABV (approximately 160 days).

Alone and in combination with BV (DBV), PEG-liposomal doxorubicin produced similar overall response rates in chemotherapy-naive patients; an interim analysis of this study determined that significantly fewer patients had died while receiving PEG-liposomal doxorubicin than while receiving DBV (18 vs 28%).

PEG-liposomal doxorubicin also has advantages over ABV in terms of improvements in health-related quality of life, and over both ABV and BV in reducing disfiguring characteristics and pain of indicator lesions.

When substituted for standard doxorubicin in the commonly used standard doxorubicin plus cyclophosphamide, vincristine and methylprednisolone (CHOP) regimen, PEG-liposomal doxorubicin produced responses in all eight of the elderly patients with aggressive non-Hodgkin’s lymphoma receiving treatment. In other preliminary data, PEG-liposomal doxorubicin monotherapy produced overall response rates of 80 and 83% in patients with refractory non-Hodgkin’s lymphoma.

Preliminary results from a trial in 509 patients with metastatic breast cancer found a significantly lower risk of cardiac adverse events in patients receiving PEG-liposomal doxorubicin compared with standard doxorubicin.

Of 66 patients with solid tumours from pooled tolerability data who had received a cumulative dosage of >400 mg/m² and had their left ventricular ejection fraction (LVEF) measured at baseline and follow-up, 12% experienced cardiotoxicity in the form of a decrease in LVEF of ≥20% from baseline or a change to <45%. Cardiotoxicity was also experienced by 1.4 to 3.4% of 45 to 132 patients with ovarian or breast cancer who received cumulative doses of PEG-liposomal doxorubicin ranging from 45 to 1301 mg/m². 1.7 to 4.3% of patients with Kaposi’s sarcoma who received PEG-liposomal doxorubicin 20 mg/m² every 2 or 3 weeks experienced cardiac-related adverse events thought to be possibly or probably related to PEG-liposomal doxorubicin. Significantly fewer cardiac histo-pathological changes were observed with a mean cumulative PEG-liposomal doxorubicin dose of 623 mg/m² than in a historical patient group matched for cumulative dose who received standard doxorubicin.

The most common adverse events (grade I to IV severity) associated with PEG-liposomal doxorubicin as monotherapy in 512 patients with ovarian cancer were palmar-planter erythrodysaesthesia (PPE) [46.1%], stomatitis (38.9%) and nausea (38.1%) in pooled data. Reported haematological events included leucopenia (33.2%), anaemia (32.2%), neutropenia (31.6%), and thrombocytopenia (10.7%).

Haematological adverse events and alopecia were significantly less likely to occur with PEG-liposomal doxorubicin than with topotecan in patients with relapsed ovarian cancer in a randomised trial; however, PPE and stomatitis were significantly more common with PEG-liposomal doxorubicin than with topotecan.

The tolerability profile of PEG-liposomal doxorubicin in patients with Kaposi’s sarcoma differs from that in patients with solid tumours, possibly because of differences in dosages and concomitant therapies.

Myelosuppression is the dose-limiting adverse event experienced by patients with Kaposi’s sarcoma receiving PEG-liposomal doxorubicin; myelosuppression occurred in about 50% of patients in pooled tolerability data. Leucopenia was the most frequent event; neutropenia, thrombocytopenia and anaemia were also common.

PEG-liposomal doxorubicin appears to have similar overall incidences of adverse events as BV and ABV. However, PEG-liposomal doxorubicin was associated with less constipation and paraesthesia than BV and less nausea and/or vomiting, alopecia and peripheral neuropathy than ABV, but more leucopenia and opportunistic infections than BV and more mucositis and/or stomatitis than ABV.

In the US, PEG-liposomal doxorubicin is indicated for the treatment of metastatic ovarian carcinoma that has progressed during paclitaxel- and platinum-based chemotherapy regimens or within 6 months of completing these treatments, and for the treatment of AIDS-related Kaposi’s sarcoma in patients with disease that has progressed during prior combination therapy, or in patients intolerant to such therapy. In Europe, the drug is indicated for the treatment of advanced ovarian cancer that has failed platinum-based chemotherapy regimens and the treatment of AIDS-related Kaposi’s sarcoma as either first- or second-line therapy. However, in these countries the drug is not to be used in the treatment of Kaposi’s sarcoma that may be treated effectively with local therapy or systemic interference. PEG-liposomal doxorubicin has not yet been approved for the treatment of metastatic breast cancer, multiple myeloma or non-Hodgkin’s lymphoma.

The recommended dosage of PEG-liposomal doxorubicin in patients with ovarian cancer is 50 mg/m2 administered intravenously once every 4 weeks. The drug should be administered by infusion at an initial rate of 1 mg/min, which can be increased if no infusion-related adverse events occur so that administration is completed in 1 hour. PEG-liposomal doxorubicin 20 mg/m2 as a 30-minute intravenous infusion once every 2 to 3 weeks is recommended for patients with Kaposi’s sarcoma. In both cancer types, treatment should continue for as long as patients respond satisfactorily and can tolerate therapy.

A delay or reduction of dosage is recommended if patients develop adverse events such as PPE, haematological adverse events or stomatitis. Precautions taken to avoid cardiotoxicity when administering standard doxorubicin should also be followed with PEG-liposomal doxorubicin. The cardiac function of patients receiving PEG-liposomal doxorubicin should be carefully monitored.