The usefulness of doxorubicin (Adriamycin) in the treatment of a variety of malignancies is limited by its concomitant toxicity. The encapsulation of chemotherapeutic agents, including doxorubicin, in liposomes has shown in animal and human models to reduce certain toxic effects. A roundtable discussion focusing on Single-Agent Pegylated Liposomal (Stealth) Doxorubicin in Cancer: Current Status and Future Applications was convened on November 22, 1996, in Tucson, Arizona, to gather existing and evolving data on its use in the treatment of cancer and to describe its current status and its future applications in the delivery of cancer chemotherapy.
It appears from preliminary studies that pegylated liposomal doxorubicin (PEG-LD) (Doxil) behaves as a next-generation anthracycline with the potential for use in combination regimens. A number of interesting questions have been raised concerning this investigational new agent: Is the use of PEG-LD superior to that of conventional liposomal doxorubicin formulations and/or conventional doxorubicin delivery in terms of overall efficacy or safety? What dose of PEG-LD is equivalent to that of conventional doxorubicin? Is PEG-LD non-cross-resistant with traditional doxorubicin? In what tumor types is this liposomal formulation effective? Can it be used in combination with other chemotherapeutic agents?
The first contributor, Dr. Frank Martin, an expert in the synthesis and use of liposomes, reviews the pharmacology of pegylated liposomal drug delivery, from the initial discovery of liposomes in the 1960s through the development and commercial availability of several liposomal anthracycline agents. Although liposomes have existed since the primordial soup, it was only 20 years ago that investigators fully realized the therapeutic potential of these agents, with research and development accelerating very rapidly over the past 15 years.
This technology holds the most promise when the pathobiology of the disease places limitations on the delivery of cytotoxic drug therapy. AIDS-related Kaposis sarcoma (AIDS-KS) provides an excellent model, and Dr. Donald Northfelt discusses the use of PEG-LD chemotherapy in the treatment of this disease. The vascular nature of Kaposis sarcoma may favor the distribution of liposomes to the tumor tissue, and leaky tumor blood vessels are believed to allow PEG-LD to preferentially gain access to the tumor stroma. Additionally, the liposomes small size and long half-life enhance the efficacy and limit the toxicity of PEG-LD.
Perhaps the most exciting area for exploration of these agents is in the treatment of solid tumors. Dr. Simon Stewart discusses the biodistribution and pharmacokinetics of indium 111-labeled Stealth liposomes in solid tumors and shares his groups recent work, which elucidates the selective delivery away from the reticuloendothelial system, into the tumor bed. He also discusses the potential use of liposomes to deliver radiosensitizing diagnostics to the sites of cancer.
Dr. Franco Muggia relates his groups clinical experience and recently published phase II data on the activity of PEG-LD in platinum- and paclitaxel-resistant epithelial ovarian cancers. In women with widely metastatic disease, this therapy has the potential to offer many months of extended life with tolerable toxicity. This treatment promises to enhance available treatment options in women with refractory disease, especially those who previously have undergone treatment with high-dose chemotherapy with autologous bone marrow support and total abdominal radiation.
Last year, nearly 182,000 cases of invasive breast cancer were observed in women in the United States. Although only 10% of breast cancers are metastatic at presentation, another 15% will eventually metastasize and require systemic chemotherapy as palliation. Dr. Mohammad Jahanzeb reports on the rationale for trials using PEG-LD in refractory breast cancer.
Because toxicity of chemotherapy is of great concern to both physicians and patients, the evolving safety profile of PEG-LD warrants discussion and is addressed in my article reviewing its safety in various malignancies. It clearly has been observed in seriously ill AIDS-KS patients that PEG-LD has superior efficacy and safety advantages over combination therapy with doxorubicin plus bleomycin (Blenoxane) plus vincristine (Oncovin). Studies support continued safety advantages as the drug is escalated in dose in other solid tumors but with some unique differences. As in studies with AIDS-KS, PEG-LD is associated with remarkably less alopecia, nausea/emesis, and cardiotoxicity when compared with conventional doxorubicin. Grades 3 and 4 myelosuppression also appear to occur with a somewhat decreased incidence. The dose-limiting toxicity of this new agent is palmar-plantar erythrodysesthesia, the incidence of which is managed through dose and schedule adjustments. Recent safety and toxicity data from evolving clinical trials are reviewed, and the impact of dosing schedule on the incidence and severity of toxicities associated with PEG-LD therapy is discussed.
In the final article, Dr. Frank Martin examines potential applications of PEG-LD in combination preclinical studies with currently available agents, such as the taxanes, vinorelbine (Navelbine), and gemcitabine (Gemzar)