Introduction
The majority of anticancer drugs are nonspecific, cytotoxic agents that damage tumor cells as well as normal healthy tissue. Given their narrow therapeutic index, antineoplastic drugs have the potential for serious side effects. A variety of drug-delivery systems are currently being used in an effort to make anticancer agents more efficient and less toxic. Liposomal encapsulation of chemotherapeutic agents represents one method of achieving this goal.
Ideal Candidates for Drug-Delivery Systems
First described by Bangham more than 30 years ago,[1] liposomes have undergone significant refinements over the decades to evolve into important modern-day drug carriers. Liposomes are spherical vesicles comprised of an outer phospholipid membrane with an internal aqueous compartment. Water-soluble drugs can be contained in the aqueous compartment while hydrophobic drugs incorporate within the lipid bilayer.
Liposomes are ideal candidates for drug-delivery systems. As a result of their similarity to biological membranes, they are safe, biocompatible, and biodegradable. Liposomes are extremely versatile macromolecules. By manipulating certain physical parameters such as phospholipid composition, size, or membrane characteristics, liposomes can be engineered to efficiently encapsulate and effectively transport a variety of drugs. Small changes in these parameters can also have profound effects on the pharmacokinetic and pharmacodynamic profiles of a drug.[2-9]
The advancement of the liposomal drug-delivery system in the oncology field was predicated on preclinical and clinical data demonstrating the benefits of liposomal encapsulation of chemotherapeutic agents. Some of the liposomal preparations significantly increase the half-life of the incorporated agent vs that of the free drug.[10-13]
Shielding the free drug within a liposome protects it from plasma protein interaction and metabolic degradation. As a result, pharmacokinetic parameters of the free drug are altered by liposomal encapsulation. Indeed, chemotherapeutic agents incorporated into liposomes exhibit longer circulation lifetimes with a greater area under the curve, lower rate of clearance, and smaller volume of distribution as compared with that of the free drugs.[13-19] The narrow therapeutic index of many small-molecule chemotherapeutic drugs is, in part, a consequence of their large volume of distribution. Incorporation into liposomes significantly reduces the volume of distribution, thereby decreasing the toxicity to normal tissue and increasing the amount of drug that can be effectively delivered to the tumor.[20,21]
Doxorubicin(Drug information on doxorubicin)">Advantages of Liposomal Encapsulation of Doxorubicin
The anthracycline doxorubicin is one of the most important cytotoxic agents used in anticancer therapy. It has significant clinical activity in hematologic malignancies, such as lymphomas and leukemias, as well as in numerous solid tumors. However, our ability to achieve maximum clinical efficacy with doxorubicin is limited by the development of irreversible cardiotoxicity and multidrug resistance (MDR).
Myelosuppression is the dose-limiting toxicity, but cardiotoxicity remains the therapy-limiting toxicity. In order to avoid this complication, therapy is generally discontinued when the cumulative dose reaches 450-500 mg/m2, at which point the risk of cardiotoxicity is significant.[22-24] Liposomes have been successfully employed to circumvent some of the limitations of free doxorubicin. Liposomal encapsulation of doxorubicin significantly alters its pharmacokinetic profile, attenuates its toxicity patterns in clinical settings, and demonstrates in preclinical trials an ability to reverse multidrug resistance.[25-28]
Alters Pharmacokinetic Profile
Numerous phase I studies have clearly demonstrated significantly higher areas under the curve for liposomal-encapsulated doxorubicin (LED) than for similar intravenous bolus doses of free doxorubicin.[29-32] Free doxorubicin reaches a peak concentration within minutes after administration and has a terminal elimination half-life of 30 hours. Depending on the specific liposomal formulation, doxorubicin-containing liposomes can increase the area under the curve by 20 to 600 times.[31,32] Therefore, the pharmacokinetic pattern of liposomal-encapsulated doxorubicin more closely mimics the prolonged infusion regimen of doxorubicin, which has demonstrated less systemic toxicity, most notably diminished cardiotoxicity and gastrointestinal toxicity.[33]
Attenuates Toxicity Patterns
Additionally, liposomal-encapsulated doxorubicin exhibits a much smaller volume of distribution as compared with free doxorubicin. The estimated volume of distribution for free doxorubicin is approximately 25 L/kg, or 1,875 liters for a 70-kg person, reflecting significant tissue uptake.[34,35] In contrast, liposomal preparations can reduce the volume of distribution by 10- to 60-fold.[10-12,31,32] The relatively large size of liposomes probably accounts for the marked reduction in the volume of distribution.
These large macromolecules are usually unable to traverse the small endothelial gaps of normal tissue, especially cardiac endothelial cells.[21,36] Indeed, a large body of clinical data supports findings that cancer patients treated with liposomal-encapsulated doxorubicin have a significant reduction in cardiac toxicity.[37-41] Diminished hematologic toxicity (myelosuppression), gastrointestinal toxicity (nausea/vomiting), mucositis, and venous sclerosis have also been noted with liposomal-encapsulated doxorubicin.[37]
Shown in Preclinical Trials to Reverse Multidrug Resistance
Multidrug resistance is an important impediment that is difficult to circumvent in the treatment of cancer. Overexpression of P-glycoprotein (Pgp170) in neoplastic cells can lead to marked resistance to doxorubicin. Preclinical studies have demonstrated liposomal modulation of MDR.[25-28] In one study, liposomal-encapsulated doxorubicin was shown to prevent effective multidrug resistance by binding to the P-glycoprotein plasma membrane pump expressed by the multidrug resistant genes.[27] This may help explain why liposomal-encapsulated doxorubicin has been effective in the treatment of various chemotherapy-refractory cancers.[42-44]
Extensively Studied in Treatment of Advanced Breast Cancer
Liposomal doxorubicin is steadily proving to be an important antitumor agent. It has been extensively studied in the treatment of advanced breast cancer, ovarian cancer, and Kaposi’s sarcoma.
The first phase II study of liposomal-encapsulated doxorubicin in advanced breast cancer included 20 patients who had not received anthracycline treatment within the past year.[42] Sixteen of the 20 patients received doxorubicin doses of 75 mg/m2 every 3 weeks, while the four remaining patients, all of whom had undergone extensive radiotherapy, received either 45 or 60 mg/m2.
Overall, five patients demonstrated a complete response in their index lesion, while four others demonstrated objective disease regression. The mean duration of response was 7 months.
Most patients had some degree of myelosuppression, but the mean nadir leukocyte count for all the cycles was only 3,740/mL, and no patient developed sepsis or infection. Other toxic effects included two episodes of grade 4 nausea/vomiting, two episodes of mild stomatitis, and complete alopecia in all patients.
Cardiotoxicity was also assessed. Two patients had left ventricular ejection fraction decreases (13% and 17%), and endomyocardial biopsies performed on five patients who received cumulative doses of more than 500 mg/m2 revealed four grade 0 and one episode of grade 1 structural changes. These data demonstrate the clinical activity of liposomal-encapsulated doxorubicin against breast cancer, and suggest that liposomal-encapsulated doxorubicin causes less cardiotoxicity, myelosuppression, and gastrointestinal toxicity than equivalent doses of free doxorubicin.
Subsequent trials in advanced breast cancer have demonstrated good response rates and a favorable toxicity profile, especially reduced cardiotoxicity.[39,45] A recent phase III trial was reported comparing cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) and either TLC D-99 or standard doxorubicin as first-line treatment of metastatic breast cancer.[46] Response rates were 43% in both arms with a median survival of 21.2 months for the TLC D-99 patients and 16.4 months for those receiving standard doxorubicin. As expected, those treated with TLC D-99 had significantly less cardiotoxicity and grade 4 myelosuppression.
Clinical Response Against Refractory Ovarian Cancer
Favorable results have also been demonstrated in patients with refractory ovarian cancer. A phase II trial of liposomal doxorubicin was conducted in 35 women with ovarian cancer refractory to platinum- and paclitaxel(Drug information on paclitaxel) (Taxol)-based regimens.[47] Patients received 50 mg/m2 IV every 3 weeks. Nine clinical responses were observed (one complete response and eight partial responses) in 35 patients (25.7% response rate). The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24 + months (median: 11 months).
Four patients developed fever and grade 3 neutropenia, while ten developed grade 3 hand-foot syndrome. No cases of alopecia, cardiotoxicity, phlebitis, or hepatic dysfunction were observed. This result suggests that liposomal doxorubicin might be useful as second-line therapy for this disease, and the lack of moderate-to-severe myelosuppression indicates that it can potentially be integrated into combined drug modalities for ovarian cancer without requiring dose attenuation.
Favorable Response Among Kaposi’s Sarcoma Patients
Patients with Kaposi’s sarcoma also respond favorably to this formulation. A number of phase II and III trials have shown liposomal doxorubicin to be an effective agent in the treatment of AIDS-associated Kaposi’s sarcoma. Single-agent therapy produced a significantly better overall response rate with much less toxicity and greater patient compliance vs a multidrug regimen.[44,48-50] Future trials, testing the formulation in combination with other active agents, are planned.
A 48-year-old female presents with complaints of irregular vaginal bleeding and postcoital bleeding. Images from a PET/CT and pelvis MRI reveal characteristic findings. What is your diagnosis?
