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By Mohanakrishnan Menon, MD
Optimizing the therapeutic benefits of chemotherapeutic agents while reducing the potential toxicity has led to novel drug delivery systems. A promising advance is the use of liposomes, which selectively deliver a greater dose of chemotherapy to tumor tissue.
Anthracyclines are active against a variety of tumors but are associated with significant cardiac toxicity in the form of congestive heart failure in approximately 5% of patients. Encapsulating the free drug, doxorubicin in stealth liposomes, which evade detection by the reticuloendothelial system (RES), is an attempt to reduce cardiac toxicity and increase tumor response to the drug.
Liposomes are the small vesicles of spherical shape with an average diameter of 50-100 nm that are produced from neutral phospholipids and cholesterol. They can carry small drug molecules, proteins, nucleotides, and even plasmids. The lipid bilayer entraps an aqueous core that can carry hydrophilic drugs while the hydrophobic core of the phospholipid bilayer can incorporate lipid soluble drugs.1
Up to 70% of a dose of conventional liposomal preparations is taken up by the RES in the liver, spleen, and marrow, limiting its usefulness in targeting non-RES tissue. Stealth liposomes are so named because they evade detection and uptake by the RES, thus substantially increasing their half-life.
Stealth liposomes, as shown in the Figure, have their surface coated with a hydrophilic polymer, such as polyethylene glycol, by a process often known as pegylation. The polymer is thought to attract a water shell, resulting in a decrease in the absorption of protein opsonins on the liposomal surface. This, in turn, decreases the liposome uptake by the reticuloendothelial system, and extends the circulation time.
Lengthening the circulation time of liposomes appears to increase their localization into tissue capillaries by increasing permeability in a variety of solid tumors. Liposomes are usually smaller than 100 nm in diameter and are able to pass through these pores. This is supported by colloid gold-containing stealth liposomes which can be seen microscopically in the tumor tissue. Normal tissue with intact capillaries is essentially impermeable to the liposomes. This method of increasing the drug concentration in tumor tissue is known as passive targeting. The volume of distribution is much smaller for liposomes as compared to free drug because the liposomes are confined to the vasculature or central compartment and tissues with increased vascular permeability.
The pharmacokinetic properties of doxorubicin 25 mg/m2 administered as free drug, in conventional liposomes and pegylated liposomes, to patients with a variety of solid tumors is given in the Table.
Mechanism of Action
On localization of the liposome to the tumor tissue, there is a slow, sustained release of the drug in its free form, which appears to be responsible for the therapeutic effects. There is no evidence to suggest uptake of liposomes by tumor cells. In patients with AIDS-related Kaposi’s sarcoma (AIDS-KS), the doxorubicin level was 5-11 times higher with pegylated liposomal doxorubicin (PLD) in lesions biopsied 72 hours after administration of equivalent doses of free doxorubicin and non-pegylated liposomal drug.5
|Table-Pharmacokinetic Properties of Doxorubicin 25 mg/m2|
|Formulation||1st t1/2 (h)||2nd t1/2 (h)|
|Conventional liposomal doxorubicin3||0.29||6.7|
|Pegylated liposomal doxorubicin2||3.2||4.5|
PLD (Doxil or Caelyx) is approved by the FDA for treatment for Kaposi’s sarcoma and refractory ovarian carcinoma. Its role is being explored in Phase II trials in a variety of cancers including breast, lung, and soft tissue sarcoma.
Available Treatment Data
Kaposi’s Sarcoma: PLD is FDA approved for first line treatment of Kaposi’s sarcoma. A phase III Trial with 241 patients compared PLD 20 mg/m2 to bleomycin 15 units/m2 and vincristine 2 mg every three weeks for six cycles showing a higher response rate of 58% for the PLD arm vs. 23.3% for the other arm.4 There was a lower incidence of nausea, vomiting, and peripheral neuropathy in the PLD arm. The incidence of mucositis, however, was higher in the PLD arm. In another trial comparing PLD 20 mg/m2 to doxorubicin 20 mg/m2, vincristine 1 mg and bleomycin 20 mg/m2 every 14 days for six cycles showed a response rate of 45.9 for the PLD arm vs. 24.8 for the combined arm.5 The toxicity profile also favored the PLD arm.
Ovarian Cancer: PLD is FDA approved for ovarian cancer refractory to front-line regimens using paclitaxel and platinum agents that is either progressing on therapy or within six months of completion of previous therapy. In a Phase II trial including 35 patients with refractory ovarian cancer, an overall response rate of 26% was observed to PLD 50 mg/m2 every three weeks. Responses lasted for 8-21 months and compared favorably to other salvage regimens, including carboplatin (4-7 months) and paclitaxel 5-6 months.6
Breast Cancer: Phase II trials are currently ongoing for metastatic breast cancer. A phase III trial reported at the 35th Annual Society Meeting of the American Society of Clinical Oncology (ASCO) this year by Batist and colleagues used the non-pegylated liposomal form of doxorubicin (TLC 99) compared to doxorubicin in combination with cyclophospamide in 297 patients with metastatic breast cancer. It showed no significant difference in response rates, median progression-free survival, and duration of survival. However, a lower incidence of congestive heart failure (0 vs 5 patients) and myelosuppression was noted. The regimen used 600 mg/m2 of cyclophospamide and 60 mg/m2 of both doxorubicin dosage forms every three weeks.7
A Phase II trial to assess safety and tolerability with paclitaxel by P. J. Woll used a regimen of paclitaxel 175 mg/m2 every three weeks with Caelyx 30 mg/m2 every three weeks or 60 mg every six weeks. Toxicities were hand foot syndrome, mucositis, and neutropenia.8
Lung Cancer: Koletsky and associates reported at the Society Meeting of the ASCO this year on 28 patients who received PLD as second-line treatment of advanced non-small-cell lung carcinoma after platinum-based therapy. No objective responses were seen, but disease stabilization for more than six months was seen in three patients.9
Soft Tissue Sarcoma: A randomized Phase II trial by EORTC presented at the Society Meeting of the ASCO reported the results from a study of 94 patients treated either with doxorubicin or Caelyx. The latter, as per preliminary results, was shown to have equivalent activity with a better toxicity profile in the form of lesser incidence of alopecia and Grade 4 neutropenia. Cardiac toxicity resulted in stopping treatment in one patient on doxorubicin.10
Side Effects and Toxicity Profile
Cardiac Toxicity: Doxorubicin cardiomyopathy occurs in about 5% patients. The incidence increases sharply beyond a lifetime cumulative dose of 450-550 mg/m2. Clinical experience with PLD beyond cumulative doses of 500 mg/m2 is limited. The manufacturer does not recommend using a dose greater than 550 mg/m2. Currently available patient data and animal models suggest a reduction in cardiotoxic potential using PLD. Theoretical reasons for possible reduced toxicity include reduced uptake in the cardiac tissue and lower peak levels of doxorubicin due to a slow release of liposomal contents.
Myelosuppression: Leucopenia was the dose-limiting adverse effect in patients with AIDS-KS occurring in up to 60% of the patients. Concomitant factors in this population include HIV disease and numerous medications.
Hand Foot Syndrome or Palmar Plantar Erythrodysesthesia (PPE): An increase in the incidence of PPE has been seen with PLD. It is characterized by skin eruptions on the palms and soles, with pain, inflammation, and in some patients, ulceration, and desquamation. The precise mechanism of developing PPE is unclear. It may be related to prolonged exposure to extravasated liposomes due to breakage of small capillaries in the pressure sensitive areas of the palms and soles. Alternatively it may be caused by tissue accumulation with a prolonged exposure to keratinocytes. The likelihood of developing PPE can be reduced either by spacing the dosage intervals or reducing the dose.
Incidence of alopecia was reduced, as well as the vesicant reaction to local infiltration in comparison to free doxorubicin.
Other Pegylated Products
Due to the prolonged circulatory half life, pegylated liposomes have been evaluated in other situations as well. Pegylated forms of cisplatin SPl-077 are reportedly effective in murine models and are still in the process of early clinical evaluation. Pegylated forms of isoniazid (INH) and rifampin are being evaluated for treatment of tuberculosis. Similar forms of amphotericin are being evaluated in fungal infections. Radiolabelled technitium and indium in pegylated liposomes are being explored for anatomic localization of inflammation.
The pegylated liposomal form of doxorubicin has a proven benefit and is approved for therapy of Kaposi’s sarcoma and refractory ovarian carcinoma. It’s role in other tumors and other clinical situations is still being evaluated. Other agents encapsulated in stealth liposomes will hopefully find a variety of applications in the future. (Dr. Menon is a fellow in Medical Oncology at Roswell Park Cancer Institute, Buffalo, NY.)
1. Markman M, et al. Disease management of solid tumors and emergent role of pegylated liposomal doxorubicin. Drugs 1997;54(Supp 4):1-35.
2. Gabizion A, Catene R, Uziely B, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene glycolcoated liposomes Cancer Res 1994;54:987-992.
3. Cowens JW, Creaven PJ, Greco WR, et al. Initial clinical trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res 1993;53:2796-2802.
4. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. J Clin Oncol 1998;16:683-691.
5. Northfelt DW, Dezube BJ, Thommes JD 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 trial. J Clin Oncol 1998;16:2445-2451.
6. Muggia FM, Hainsworth J, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: Anti tumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15: 987-993.
7. Batist G, Rao SC, Ramakrishnan G, et al. Phase III study of liposome encapsulated doxorubicin (TLC99) in combination with cyclophospamide in patients with metastatic breast cancer. Proceedings of 35th Annual society meeting of ASCO. 1999;18:127a.
8. Woll PJ, Carmichael J, Chan S, et al. Phase II study on the safety and tolerability of Caelyx/Doxil in combination with paclitaxel in the treatment of metastatic breast cancer. Proceedings of 35th Annual Society meeting of ASCO. 1999;18:117a.
9. Koletsky A, Jahanzeb M, Radice P, et al. Pegylated liposomal doxorubicin as second line of advanced non small cell carcinoma (NSCLC) after platinum based therapy: A Randomized Phase II trial. Proceedings of 35th Annual Society meeting of ASCO. 1999;18:512a.
10. Judson I, Radford J, Blay J-Y, et al. A randomized Phase II trial of Caelyx/Doxil versus doxorubicin in advanced or metastatic soft tissue sarcoma (STS)—An EORTC Soft Tissue and Bone Sarcoma Group (STBSG) trial. Proceedings of 35th Annual Society meeting of ASCO. 1999;541a.