A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: an updated review.
Cancer, which is associated with the rapid and uncontrolled proliferation of cells, is a leading cause of death worldwide. In 2015, it is estimated that there will be 1, 658, 370 new cases of cancer and account for 589, 430 death around the world.  There are three distinct approaches to the treatment of cancer, which includes surgical excision, irradiation, and drug therapy. [1, 2] In terms of drug therapy, side effects are almost inevitable and are a common cause of therapeutic limitation. 
Doxorubicin is a very potent cytotoxic anticancer that directly inhibits topoisomerase II and nucleic acid synthesis.  As a result, the proliferation of cancer cells will be terminated. However, anticancer treatment of doxorubicin is always limited by its severe side effects such as cardiotoxicity like as dysrhythmia and heart failure.  Fortunately, this limitation could be resolved through the clinical application of liposomes. [2-4]
Liposomes are bilayered phospholipid vesicles with an aqueous core that can encapsulate both hydrophilic and hydrophobic drugs.  In fact, liposomes can retain the drugs until being disrupted, indicating that they can promote sustained release formulation of drugs. [1-4] Besides, they are also concentrated in malignant tumors, so that enhance the selectivity of the anticancer drugs with reduced toxicity. [2-4]
There are several liposomal formulations of anticancer drugs authorized by United State Food and Drug Administration including doxorubicin.  A long-acting form of doxorubicin encapsulated in liposomes has been marketed since the mid-1990s for the treatment of various malignancies. [2-4] It is also known as Doxil in the USA or Caelyx in Europe.  This liposomal formulation contains polyethylene glycol (PEG) coated-liposomal doxorubicin, which is capable of targeting doxorubicin to tumor sites. In the present, liposomal doxorubicin is a therapeutic option in the treatment of AIDS-related Kaposi's sarcoma, metastatic breast cancer, advanced ovarian cancer, and relapsed/refractory multiple myelomas. 
To investigate the differences among the formulations of doxorubicin in vivo, a literature search is conducted. It is hypothesized that liposomal doxorubicin encompasses increased efficacy and better toxicology profile compared to nonliposomal conventional doxorubicin.
PHARMACOLOGICAL ACTION OF DOXORUBICIN
Although the exact mode of action remains unknown, the potency of doxorubicin is believed to be associated with topoisomerase II, which is a DNA gyrase and is responsible for the relaxation of supercoiled structure of DNA during transcription. [2, 3] Specifically, doxorubicin intercalates in the DNA and stabilizes the DNA-topoisomerase II complex during the transcription process thus prevents the relaxation of the DNA double helix and promotes termination of the process.
Nevertheless, therapeutic limitations of doxorubicin involve severe adverse effects such as dysrhythmia, heart failure, leukocytopenia, moderate to severe nausea, and vomiting and hemorrhage. [2-4] Its cardiotoxicity such as dysrhythmia and heart failure arises from the formation of cytotoxic free radicals in the heart tissue. [2-4] Therefore, this problem can be resolved by increasing the specificity of doxorubicin through the utilization of liposomes. [2-4]
CLINICAL APPLICATION OF LIPOSOMES IN CHEMOTHERAPY OF CANCER
Liposomes feature an aqueous core, one or more phospholipid membranes with/without coating groups on the surfaces of the membranes. [2, 3] These amphiphilic characteristics allow liposomes to carry both hydrophobic and hydrophilic drugs within the lipophilic bilayer or aqueous compartment.  For instance, hydrophilic drugs dissolve in the aqueous core or adsorb on the hydrophilic head of the phospholipid bilayer whereas lipophilic drugs are filled with the hydrophobic tails of the bilayer. [2-6]
There are numerous liposome-based anticancer agents being marketed as a liposomal preparation, which are commonly known as Caelyx/Doxil, Myocet, DOX-SL, Lipo-Dox, and DaunoXome. Myocet, Caelyx/Doxil, Liposomal Doxorubicin SUN, and Lipo-Dox are liposomal formulations of doxorubicin whereas DaunoXome is the liposomal formulation of Daunorubicin. [2, 3, 6]
LIPOSOMAL FORMULATION OF DOXORUBICIN
Specifically, the liposome formulated in Caelyx/Doxil is a type of small unilamellar vesicles (SUV), which is a type of liposomes with a single bilayer and is 30-100 nm in size. [2, 3, 6] Apart from that, the liposome in the formulation is coated with a hydrophilic polymer, PEG, indicating that it is able to escape from mononuclear phagocytic system uptake and to target the tumor cells through the enhanced permeability and retention effect. [2, 6] Doxorubicin in the formulation is manifested in a form of doxorubicin sulfate complex and is covered in the aqueous core of liposome. [2, 3]
The main difference between Lipo-Dox and Caelyx/Doxil is the type of liposome being used. The lipid membrane of Caelyx/Doxil is made of hydrogenated soybean phosphatidylcholine and coated with PEG-distearoylphosphatidylethanolamine (HSPC/PEG-DPSE) whereas the membrane of Lipo-Dox is made of distearoylphosphatidylcholine (DSPC) coated with the same coating material PEG-DSPE.  Since DSPC has a higher transition temperature than HSPC, Lipo-Dox offers higher stability and longer half-life compared to Caelyx/Doxil. 
Liposomal Doxorubicin SUN contains a liposome coated with sodium methoxy PEG-40-carbonyl-DPSE.  Although its coating material is different to Caelyx/Doxil, it is proven to be therapeutically equivalent to Caelyx/Doxil. 
Myocet is a type of non-pegylated liposomal doxorubicin (non-PLD) composed of SUV. Similar to Caelyx/Doxil, doxorubicin is located within the aqueous core of the liposome but is manifested in a form of doxorubicin citrate complex. [2, 5]
Data sources and selection
In respect of research strategies, a search of PubMed, Cochrane Library, and EMBASE using the MeSH search terms doxorubicin, liposome, and cancer was performed. Additional search terms are the brand name of doxorubicin which includes DOX-SL, Lipo-Dox, Doxil, Caelyx, Lipo-Dox, and DaunoXome. All articles being reviewed were primary sources and published within the last 5 years (2010-September 2015) except one primary source, which is thought to be vitally important for the quality of life analysis. Apart from that, secondary sources such as textbook, systematic reviews, and meta-analysis were used as a background reference to support the analysis of the primary sources [Table 1].
Large area under the curve (AUC), slow clearance rate (CL), small distribution volume (VD), and long elimination half-time (t 1/2) characterize the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). [8, 9, 22] The VD of PLD is close to the blood volume so that the PK of PLD undergoes single compartment model. [8, 9] The pegylated lipids in the liposomes result in a long circulation half-time, typically 3-4 days. [8, 9]
Nonliposomal conventional doxorubicin has a large VD indicating that a significant amount of the drug is taken up in normal tissues. [8, 22] Apart from that, the AUC for conventional nonliposomal doxorubicin is about three orders of magnitude smaller than PLD resulting in a CL rate about three orders of magnitude larger. The t% for conventional doxorubicin is about 20-25 h. [8, 9]
Non-PLD has a shorter t% than PLD but a longer t% than conventional nonliposomal doxorubicin.  It is due to the absence of PEG coating in the formulation, which indicates that it can be easily taken up by the reticuloendothelial system (RES) and undergo metabolism. 
Despite the fact that there are imperative benefits associated with PLD and non-PLD than nonliposomal conventional doxorubicin, its interpatient variability in terms of PKs are more clinically significant in comparison to conventional nonliposomal doxorubicin. [8, 9]
Regarding the nonliposomal conventional doxorubicin, factors contributing to interpatient variability are hepatic impairment, patient age and polymorphism in efflux transporter and metabolizing enzymes.  Doxorubicin is hepatically cleared by carbonyl reductases (CBR) and cytochrome P-450 enzymes, especially CBR1, CBR3, CYP3A4, CYP2C9, and CYP2D6, which implies that genetic polymorphism of CBR affects the CL of doxorubicin.  In relation to that, patients with hepatic impairment as well as elderly population are less capable to metabolize doxorubicin due to their insufficient metabolizing enzymes of doxorubicin.  Apart from that, a various subfamily of ATP-binding cassette (ABC) is responsible for pumping out doxorubicin, including ABCB1, ABCB5, ABCB8, ABCC5, and ABCG2. Provided that, polymorphism of the efflux transporter ABC can positively or negatively affect the plasma concentration of doxorubicin. 
In comparison to conventional nonliposomal doxorubicin, PLD and non-PLD undertake a more complicated metabolizing pathway.  Theoretically, the CL of liposomes depends upon the RES, involving monocytes, macrophages, and dendritic cells. Hence, besides the metabolism of doxorubicin in the aqueous core, the CL of both PLD and non-PLD bears upon the immune system as well as the RES function of different individuals. [8, 9, 22] Deterioration of immunity is common in the aging population, which is scientifically known as immunosenescence.  Hence, the CL of doxorubicin in an elderly patient is further reduced which is possible to prolong t% and AUC of doxorubicin. In spite of the unclear reason, gender is discovered to be an important contributing factor for the CL of liposomal doxorubicin. Clinical significantly, female patients have a lower CL of liposomal doxorubicin than male patient.  Although the exact reason for this phenomenon remains unknown, it is thought to be closely associated with the hormone. As hormone plays a key role in the immunosuppressive and immunostimulatory activity, the reason behind this observation can be rationalized.  There are many factors contributing to the immune status of individuals, indicating the dramatic interpatient variability of liposomal doxorubicin.
Other factors contributing to interpatient variability of PLD are body fat composition and genetic viability.  The phenomenon of significantly increased AUC of PLD as a result of high intraabdominal fat content had been observed. In terms of genetic viability, higher VD and CL rate had been detected in Asian in comparison to European. 
The efficacy of the different formulations which involve doxorubicin was evaluated based on response rate, including complete response, partial response, and overall response. The survival rate, which includes overall survival and progression-free survival, is also deemed to be an indicator of efficacy. [16, 7, 10, 13, 22, 24]
The efficacy of PLD as a single agent in the treatment of metastatic breast cancer has been confirmed. However, there is a lack of scientific consensus that the liposomal formulations of doxorubicin increase the survival rate of the treatment, in comparison to nonliposomal conventional doxorubicin. [6, 7, 10, 13, 22, 24] Nevertheless, it is clinically significant that PLD decreases the risk of fatal cardiac events such as acute myocardial infarction and congestive heart failure. [6, 7, 18] As a result, the utilization of PLD increases the survival rate of patients with high cardiac risks compared to nonliposomal conventional doxorubicin. [13, 14]
Despite the efficacy of doxorubicin in the treatment of glioma in vitro, its utilization is limited by the efflux effect of the blood-brain barrier (BBB). [15, 22] Fortunately, the development of liposomal doxorubicin allows penetration of doxorubicin into the malignant glioma cells in the brain.  In spite of the fact that PLD shows high potency in the treatment of glioma, its dosing regimen in children remains unclear. Hence, further studies are necessary to balance the toxicology profile and efficacy of PLD in the treatment of glioma.
Moreover, there are some discrepancies regarding the potency between two formulations (Lipo-Dox and Doxil) of PLD.  An observational study indicates that Lipo-Dox is inferior to Doxil in terms of potency.  However, this observation might not be clinically significant as a larger sample size is needed to confirm the finding.
In addition, laboratory data have showed the efficacy of PLD in the treatment of intracranial model of breast cancer in mice.  In this model of breast cancer, PLD promotes higher survival rate and efficacy with reduced toxicity than nonliposomal doxorubicin in mice.  Clinical data regarding the utilization of PLD in this model of metastasis breast cancer is eagerly awaiting.
In comparison to nonliposomal conventional doxorubicin, it is certain that the liposomal formulations of doxorubicin promote better cardiac safety. [7, 9-14, 19, 21] The reduced cardiac toxicity had also been observed in comparison to other anthracycline-based chemotherapy.  Therefore, it is recommended that the liposomal formulations of doxorubicin should be used in the patients with high risk of cardiac events such as arrhythmia, congestive heart failure, and myocardial infarction. [13, 21]
Furthermore, the reduced toxicity has also been observed in terms of myelosuppression and infection in comparison to nonliposomal conventional doxorubicin.  However, the myelotoxicity of liposomal doxorubicin is not uncommon. [7, 12] The myelotoxic effects in association with liposomal doxorubicin include leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia. [7, 9-14, 19]
In terms of extra-myelotoxicity other than cardiotoxicity, the occurrence of Palmar-Plantar Erythrodysesthesia (commonly known as a hand-foot syndrome) is similar in both liposomal and nonliposomal formulations of doxorubicin. [9, 11, 21] Nausea and vomiting are moderate to severe in patients treated with nonliposomal doxorubicin but are usually mild in patients treated with liposomal doxorubicin. [3, 19]
As the liposomal formulations of doxorubicin undergo viability in relation to PKs, dose-dependent myelotoxicity cannot be effectively predicted. [7, 9-14] Factors affecting the PKs of liposomal doxorubicin are likely to affect the toxicology profile of such formulations. In general, higher risk of toxicity is expected to be seen in elderly patient, immunosuppressive" and female individuals.  Patients with high body fat composition, particularly intraabdominal fat, are also more susceptible to experience doxorubicin-associated myelotoxicity if they are treated with liposomal doxorubicin. 
Under the extremely rare scenario, acute peculiar mucous reaction following administration of PLD had been reported.  No study had been conducted in this area as the occurrence of this reaction had not been observed prior to the case report. Hence, further study has to be carried out in this area.
QUALITY OF LIFE AND COST-EFFECTIVENESS ANALYSIS
Although the improved survival rate with the use of liposomal doxorubicin has not been proven, it is observed that the patients receiving liposomal doxorubicin have a higher quality of life than the patients treated with nonliposomal doxorubicin in terms of pain, cognitive functioning, social functioning, and health distress. [21, 25] The improved quality of life is believed to be associated with the decreased adverse drug effects and the elevated selectivity promoted by the liposome in the liposomal formulation of doxorubicin.
However, the improved quality of life other than nausea and vomiting related to liposomal doxorubicin has not been detected in elderly patients with metastatic breast cancer.  This phenomenon can be explained by the deteriorated immune system of the elderly patients, resulting in a significant decrease in the CL of liposomal doxorubicin.  Consequently, a significant increase in AUC accounts for the dose-dependent toxicity following the administration of liposomal doxorubicin. 
Since the utilization of liposomal doxorubicin reduces the severity of chemotherapy-induced nausea and vomiting (CINV) in conjunction with the treatment of nonliposomal conventional doxorubicin, it is deemed to reduce the direct cost related to the CINV. As the CINV had been highlighted to be a significant cost to the National Health Service in European countries, the possibility of cost reduction is clinically significant.  Nonetheless, further investigation is needed to confirm the actuality of this extrapolation.
Regarding the routine cardiac surveillance prior to PLD treatment, it is believed to be unnecessary as selective cardiac surveillance will save more than 180, 000 USD in 184 patients received PLD.  However, as PLD is 100-times more costly than conventional nonliposomal doxorubicin, it is debatable that an opportunity of saving more than 4, 400, 000 USD will be ignored if practicing selective cardiac surveillance. 
As there is a lack of updated primary sources comparing the cost-effectiveness of liposomal doxorubicin and nonliposomal conventional doxorubicin, the cost-effectiveness studies comparing liposomal doxorubicin with other nonliposomal anticancer drugs have been included. The assumption being made is that similar result will be expected in nonliposomal conventional doxorubicin in comparison to other nonliposomal anticancer drugs as they belong to the class of chemotherapy whereas liposomal doxorubicin belongs to the class of nanotherapy.
In comparison to anticancer drugs other than doxorubicin, PLD has a higher efficacy and cost than gemcitabine, the incremental cost-effectiveness ratio (ICER) observed for PLD was between 170 [euro] and 318 [euro] per QALW, which is between 8864 [euro] and 16581 [euro] per quality-adjusted life year (QALY) gained.  In terms of paclitaxel, PLD possesses higher efficacy and cost, with an ICER of 21, 658 USD per QALY gained.  Overall, PLD is deemed to be cost-effective in some most countries, referring to the willingness-to-pay (WTP) threshold recommended by World Health Organization (WHO).'311 However, based on the gross domestic product stated by WHO, PLD may not be cost-effectiveness in some developing countries. 
DISCUSSION AND CLINICAL IMPLICATION
This review highlights the clinical significance of the interpatient variability associated with the use of liposomal doxorubicin. It is impacted by age, gender, race, immune status, and body fat composition of an individual treated with liposomal doxorubicin. [8, 9, 12] An important clinical concern is that most cancer patients are middle-aged or elderly, indicating a need for dose adjustment in the treatment of liposomal doxorubicin. Otherwise, the dose-dependent toxicity associated with liposomal doxorubicin cannot be extrapolated and managed. However, the effective way of individualizing the dose of liposomal doxorubicin has not been identified.
In the near future, the liposomal doxorubicin will be prescribed in more conditions such as pediatric glioma and intracranial model of breast cancer as the utilization of the liposome brings about the penetration across BBB. [15, 22] As the PK model of the liposomal doxorubicin in children remains unclear, more comprehensive precautions will be required to prevent or manage the adverse drug reaction of the liposomal doxorubicin in this population. Concerning the intracranial model of breast cancer, further studies are needed to investigate how the liposomal doxorubicin behaves in human settings. 
In terms of efficacy, there is limited evidence base to support the superiority of the liposomal doxorubicin compared to the nonliposomal conventional doxorubicin. [6, 7, 10, 13, 22, 24] Nevertheless, stringent precautions are recommended before choosing a formulation of doxorubicin for high-risk patients to protect against fatal cardiac events, as the reduced cardiotoxicity promoted by the liposomal doxorubicin has been confirmed. Subsequently, the clinical concern aroused is the cost-effectiveness of the routine cardiac surveillance prior to the introduction of liposomal doxorubicin. Overall, there remains a considerable controversy over the relative importance of routine cardiac surveillance in the patients accepting doxorubicin-based therapy.
Although the updated cost-effectiveness of the liposomal doxorubicin compared to nonliposomal doxorubicin remains unclear, the cost-effectiveness of liposomal doxorubicin in comparison to other chemotherapy is within the Willingness to Pay (WTP) threshold in most developed countries, so that the use of liposomal doxorubicin is deemed to be cost-effective only in this particular countries. [20, 23, 31] In healthcare settings, liposomal doxorubicin is considered to be more tolerable than nonliposomal conventional doxorubicin as regards of cardiotoxicity, myelotoxicity, nausea and vomiting with an estimation of 100 times the additional cost. Therefore, further pharmacoeconomic studies comparing liposomal and nonliposomal formulations of doxorubicin will be required to confirm the cost-effectiveness of liposomal doxorubicin.
In addition, this review reveals some limitations and weaknesses in relation to the updated evidence. The lack of blinding and allocation concealment in the randomized control trials could probably lead to a bias toward the superiority of liposomal formulation of doxorubicin compared to nonliposomal conventional doxorubicin. Another common weakness in most of the literature is the underpowered sample size. Therefore, it is identified that the sample present in the studies may not represent the whole population. Hence, larger studies are required to confirm the actuality of the results. Notwithstanding, the contamination, and co-intervention in most of the studies are well controlled, indicating that the results could be statistically and clinically significant. Further, our review did not compare the efficacy and toxicology of liposomal doxorubicin with other marketed chemotherapy, which is thought to be closely related to the current healthcare settings.
In summary, there remains a substantial gap in the scientific literature on the superiority of liposomal doxorubicin in relation to efficacy. While there is some experimental evidence that liposomal doxorubicin is able to increase survival rate in mice having an intracranial model of breast cancer, there is less evidence on its efficacy in healthcare settings. Current research has several limitations including the possibility of selection bias and performance bias as well as underpowered samples. However, it is confirmed that PLD and non-PLD encompass better safety profile compared to nonliposomal conventional doxorubicin in terms of cardiotoxicity and myelosuppression. However, larger interpatient variability in terms of PK is common in liposomal doxorubicin resulting in the difficulty in dose standardization. Moreover, the utilization of liposomal doxorubicin in the treatment of brain tumor will be developed in the near future. Large intervention studies in this area are likely to provide the best evidence of the efficacy of liposomal doxorubicin in increasing the survival rate in comparison to nonliposomal conventional doxorubicin. Finally, dose standardization is an urgent priority to manage the doxorubicin-induced toxicity following the administration of liposomal doxorubicin.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[1.] National Cancer Institute. Cancer Statistics. United States: National Institute of Health; 2015. Available from: http://www.cancer.gov/about-cancer/what-is-cancer/statistics. [Last updated on 2015 Mar 02; Last cited on 2015 Oct 15].
[2.] Aulton M, Taylor K. Aulton's Pharmaceutics: The Design and Manufacture of Medicines. Edinburgh: Churchill Livingstone/Elsevier; 2013. p. 790-5.
[3.] Rang HP, Maureen DM. Rang & Dale's Pharmacology. Edinburgh: Churchill Livingstone; 2012. p. 673-88.
[4.] Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Adv Drug Deliv Rev 2013; 65:36-48.
[5.] Duggan ST, Keating GM. Pegylated liposomal doxorubicin: A review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma. Drugs 2011; 71:2531-58.
[6.] Berger JL, Smith A, Zorn KK, Sukumvanich P, Olawaiye AB, Kelley J, et al. Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era. Onco Targets Ther 2014; 7:1409-13.
[7.] Wasle I, Gamerith G, Kocher F, Mondello P, Jaeger T, Walder A, et al. Non-pegylated liposomal doxorubicin in lymphoma: Patterns of toxicity and outcome in a large observational trial. Ann Hematol 2015; 94:593-601.
[8.] La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, et al. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol 2012; 69:43-50.
[9.] Boers-Sonderen MJ, van Herpen CM, van der Graaf WT, Desar IM, van der Logt MG, de Beer YM, et al. Correlation of toxicity and efficacy with pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) (Caelyx[R]). Cancer Chemother Pharmacol 2014; 74:457-63.
[10.] Hunault-Berger M, Leguay T, Thomas X, Legrand O, Huguet F, Bonmati C, et al. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: The GRAALL-SA1 study. Haematologica 2011; 96:245-52.
[11.] Fiegl M, Mlineritsch B, Hubalek M, Bartsch R, Pluschnig U, Steger GG. Single-agent pegylated liposomal doxorubicin (PLD) in the treatment of metastatic breast cancer: Results of an Austrian observational trial. BMC Cancer 2011; 11:373.
[12.] Wong AL, Seng KY, Ong EM, Wang LZ, Oscar H, Cordero MT, et al. Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients. Breast Cancer Res Treat 2014; 144:143-52.
[13.] Jurczak W, Szmit S, Sobocinski M, Machaczka M, Drozd-Sokolowska J, Joks M, et al. Premature cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen - A national multicenter study. Int J Cardiol 2013; 168:5212-7.
[14.] Lotrionte M, Palazzoni G, Abbate A, De Marco E, Mezzaroma E, Di Persio S, et al. Cardiotoxicity of a non-pegylated liposomal doxorubicin-based regimen versus an epirubicin-based regimen for breast cancer: The LITE (Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation) randomized pilot study. Int J Cardiol 2013; 167:1055-7.
[15.] Chastagner P, Devictor B, Geoerger B, Aerts I, Leblond P, Frappaz D, et al. Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma. Cancer Chemother Pharmacol 2015; 76:425-32.
[16.] Xu L, Wang W, Sheng YC, Zheng QS. Pharmacokinetics and its relation to toxicity of pegylated-liposomal doxorubicin in Chinese patients with breast tumours. J Clin Pharm Ther 2010; 35:593-601.
[17.] Turini M, Piovesana V, Ruffo P, Ripellino C, Cataldo N. An assessment of chemotherapy-induced nausea and vomiting direct costs in three EU countries. Drugs Context 2015; 4:212285.
[18.] Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010; 28:3107-14.
[19.] Crivellari D, Gray KP, Dellapasqua S, Puglisi F, Ribi K, Price KN, et al. Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a "standard chemotherapy regimen": The CASA randomized trial. Breast 2013; 22:130-7.
[20.] Lee HY, Yang BM, Hong JM, Lee TJ, Kim BG, Kim JW, et al. Cost-utility analysis for platinum-sensitive recurrent ovarian cancer therapy in South Korea: Results of the polyethylene glycolated liposomal doxorubicin/carboplatin sequencing model. Clinicoecon Outcomes Res 2013; 5:297-307.
[21.] Staropoli N, Ciliberto D, Botta C, Fiorillo L, Gualtieri S, Salvino A, et al. A retrospective analysis of pegylated liposomal doxorubicin in ovarian cancer: Do we still need it? J Ovarian Res 2013; 6:10.
[22.] Anders CK, Adamo B, Karginova O, Deal AM, Rawal S, Darr D, et al. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. PLoS One 2013; 8:e61359.
[23.] Bosetti R, Ferrandina G, Marneffe W, Scambia G, Vereeck L. Cost-effectiveness of gemcitabine versus PEGylated liposomal doxorubicin for recurrent or progressive ovarian cancer: Comparing chemotherapy with nanotherapy. Nanomedicine (Lond) 2014; 9:2175-86.
[24.] Vici P, Colucci G, Giotta F, Sergi D, Filippelli G, Perri P, et al. A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study. J Exp Clin Cancer Res 2011; 30:39.
[25.] Osoba D, Northfelt DW, Budd DW, Himmelberger D. Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma: A randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine. Cancer Invest 2001; 19:573-80.
[26.] Kushnir CL, Angarita AM, Havrilesky LJ, Thompson S, Spahlinger D, Sinno AK, et al. Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD). Gynecol Oncol 2015; 137:503-7.
[27.] Lal S, Mahajan A, Chen WN, Chowbay B. Pharmacogenetics of target genes across doxorubicin disposition pathway: A review. Curr Drug Metab 2010; 11:115-28.
[28.] Larbi A, Rymkiewicz P, Vasudev A, Low I, Shadan NB, Mustafah S, et al. The immune system in the elderly: A fair fight against diseases? Aging Health 2013; 9:35-47.
[29.] Ma H, Chen M, Liu J, Li Y, Li J. Serious stomatitis and esophagitis: A peculiar mucous reaction induced by pegylated liposomal doxorubicin. An Bras Dermatol 2015; 90 3 Suppl 1:209-11.
[30.] Cohn DE, Shimp WS. The cost implications of the use of pegylated liposomal doxorubicin when choosing an anthracycline for the treatment of platinum-resistant ovarian cancer: A low-value intervention? Gynecol Oncol Rep 2015; 13:47-8.
[31.] Cost Effectiveness and Strategic Planning (WHO-CHOICE). United States: World Health Organization; 2005. Available from: http://www.who.int/choice/costs/CER_levels/en/. [Last cited on 2015 Oct 17].
Yik Hoe Ngan, Manish Gupta
School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
Address for correspondence:
Dr. Manish Gupta,
School of Pharmacy, Monash University
Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia.
Table 1: Synopsis of original articles related to liposomal formulation of doxorubicin present in the market Participants and Study Setting follow-up Berger et al. (6) Magee-Women 18 patients treated Hospital, with liposomal University of doxorubicin Pittsburgh Medical Center. 2012 Wasle et al. (7) 11 Austrian 326 patients with and 1 Italian lymphoproliferative cancer center. disease received, at March 2008- least, one dose of December Myocet, which is a 2013 nonpegylated form of liposomal doxorubicin La-Beck et al. (8) Unknown 70 patients settings >18 years of age with histologically or cytologically confirmed solid tumors or Kaposi's sarcoma and adequate organ function without prior cumulative treatment of doxorubicin Boers-Sonderen Single center 20 patients with et al. (9) in Finland. histological proven Unknown advanced breast, timeline endometrial or ovarian cancers, who are more than 18 years old and have life expectancy of more than 12 weeks Hunault-Berger 26 centers 60 untreated patients et al. (10) in Finland. aged 55 years or more March 2002- with nonBurkitt's, October 2006. Philadelphia Outcome chromosome-negative data was or BCR-ABL negative updated on 1 acute lymphoblastic April 2009 leukemia without severe arrhythmia, coronary artery disease, acute heart failure, left ventricular ejection fraction <50%, renal or liver dysfunction, positivity for human immunodeficiency virus, or psychiatric disease Fiegl et al. (11) Australia. 129 consecutive 2003-2009 patients with advanced breast cancer, who received PLD as monotherapy within licensed approval Wong et al. (12) A single 84 Asians who are institution in newly diagnosed with Singapore. locally advanced or Unknown metastatic breast timeline cancer Jurczak et al. (13) Data collected 610 newly diagnosed in Polish NHL Caucasians Lymphoma Research Group. Timeline unknown Lotrionte Unknown 52 patients with et al. (14) settings nonmetastatic cancer Chastagner Unknown 13 children aged et al. (15) location. 6-17 years old October with histologically 2010-January documented 2013 malignant glioma Xu et al. (16) China. 2006 22 Chinese patients with histologically or cytologically confirmed breast cancer Turini et al. (17) Italian, Oncologists and German, oncology nurses and French. 2013-2014 Monk et al (18) 124 centers in 672 patients with 21 countries. histologically April 2005- confirmed pithelial May 2007 ovarian, fallopian tube, or primary peritoneal carcinoma Crivellari Multinational. 77 multinational et al. (19) Recruitment elderly (>66 years from old) patients November with endocrine 2005 and nonresponsive December (ER <10%; and 2007. PgR <10%) Follow-up breast cancer 42 months Lee et al. (20) South Korea. A Markov model with 2013 a 10-year time horizon Staropoli Clinical 108 patients with et al. (21) Data of Italy. histologically 2001-2011 confirmed ovarian cancer Anders et al. (22) Unknown 46 tumor-bearing mice settings following inoculated intracerebrally with MDA-MB-231-BR- luciferase- expressing cells Bosetti et al. (23) European 153 patients countries with recurrent or progressive ovarian cancer Vici et al. (24) 4 oncologic 104 patients with centers of histologically the Gruppo confirmed advanced Oncologico breast cancer who Italia are not previously Meridionale. treated with adjuvant March 2003- anthracyclines November 2005 Osoba et al. (25) 25 centers in 258 male patients Canada.2001 with biopsy-proven AIDS-related Kaposi's sarcoma Kushnir et al. (26) Johns Hopkins 184 patients Hospital with gynecologic and Duke malignancy University Medical Center. 2002-2014 Intervention Study Study design evaluated Berger et al. (6) Retrospective study Liposomal doxorubicin Wasle et al. (7) Observational study Myocet La-Beck et al. (8) There are 3 studies PLD being conducted. study 1 and 2 are observational studies whereas study 3 is a randomized controlled trial Boers-Sonderen Phase lb clinical trial Caelyx in et al. (9) combination with temsirolimus Hunault-Berger RCT Continuous- et al. (10) infusion doxorubicin in combination with vincristine on one arm or PLD (Caelyx) and standard vincristine on the other arm Fiegl et al. (11) Observational PLD phase IV study Wong et al. (12) Clinical trial Nonliposomal doxorubicin Jurczak et al. (13) Retrospective Nonliposomal analysis doxorubicin, non-PLD and PLD Lotrionte RCT Non-PLD-based et al. (14) regimen and EPI-based treatment Chastagner Phase I clinical study Myocet et al. (15) Xu et al. (16) Cross-over RCT 2 PLD product with 4-week wash-out time Turini et al. (17) Cross-sectional Chemotherapy study (an online survey) Monk et al (18) Phase III RCT Trabectedin plus PLD and PLD Crivellari Phase III RCT PLD regimen et al. (19) and metronomic cyclophosphamide plus methotrexate Lee et al. (20) Cost-utility analysis PLD/carboplatin versus paclitaxel/ carboplatin Staropoli Retrospective On the exposure et al. (21) cohort study arm, the patients are treated with PLD. On the control arm, the patients are treated with other drugs such as topotecan, gemcitabine, etoposide. Patients underwent PLD had high platinum-sensitivity Anders et al. (22) Laboratory study PLD versus nonliposomal doxorubicin Bosetti et al. (23) Cost-effectiveness PLD versus analysis based on gemcitabine the data of an RCT Vici et al. (24) RCT EPI/Vand PLD/V Osoba et al. (25) RCT PLD or doxorubicin plus bleomycin plus Plus vincristine Kushnir et al. (26) Retrospective chart PLD review Main outcomes Findings Study Berger et al. (6) RRs and toxicity No patients had a associated complete or partial with lipodox response to lipodox. Disease control rate of 11% Wasle et al. (7) Evaluation of toxicity The most common grade graded according 3/4 toxicities were to NCI CTCAE, hematologic toxicity, version 4.0 including leukopenia, neutropenia, thrombocytopenia and febrile neutropenia La-Beck et al. (8) The relationship The factors affecting between age as the CL of PLD are well as gender and different in the CLof PLD comparison to nonliposomal doxorubicin. Female patient has lower CL of PLD than male (P<0.0001). Apart from that, patients <60 years old have higher CL than patients >60 years old (P<0.0001) Boers-Sonderen To assess the factors The caelyx exposure et al. (9) affecting the PK/PD (log AUC) was higher of Caelyx in patients who experienced rash (P = 0.002) and mucositis (P = 0.001) compared to patients who did not experience these adverse events. Additionally, there is no relationship between Caelyx exposure and the occurrence of common side effects of Caelyx such as leukocytopenia, stomatitis, and hand-foot syndrome Hunault-Berger Primary Outcome: Despite the fact that et al. (10) composite efficacy more patients in and toxicity conventional doxorubicin consisting of arm dead, conventional continuous doxorubicin (90%) gave complete remission rise to higher rate, hematologic and complete remission extra-hematologic rate after two toxicity. Secondary induction cycles in Outcome: complete comparison to PLD remission rate, safety, (72%). Apart from cumulative incidence that, pegylated of relapse and failure, liposomal doxorubicin cumulative incidence decreased the toxicity of death in first of doxorubicin in complete remission terms of and treatment-related myelosuppression (P = death, event-free 0.005-0.9), infections survival and OS (P = 0.04-0.12) and cardiotoxicity (P = 0.12). Despite the reduced toxicity, pegylated doxorubicin does not promote better survival rate Fiegl et al. (11) Response to PLD There were encouraging which includes results with PLD as a toxicity and efficacy mono-therapeutic agent associated with PLD I the treatment of metastasized breast cancer. The most common side effect observed was dose-dependent PPE Wong et al. (12) PKand hematologic Increased body fat toxicities of composition, doxorubicin especially intra-abdominal fat content, is associated with increased doxorubicin exposure and rate of grade 4 leukopenia (P<0.0001). Therefore, individuals with excessive body fat in relative to LBM will have a high risk of doxorubicin -associated toxicity, in regardless of BMI. Furthermore, body surface area does not determine the PK and toxicity of doxorubicin Jurczak et al. (13) Response to Response to treatment treatment according according to Cheson to Cheson criteria, criteria in patients cardiotoxicity, and OS treated with liposomal doxorubicin is noninferior compared to nonliposomal doxorubicin. Moreover, the OS of patients with high risk of fatal cardiac events is comparable to those patients with low risk of cardiac fatal event, indicating that liposomal doxorubicin increases the OS in patients with high-risk fatal cardiac events Lotrionte TDI examined Lower cardiotoxicity et al. (14) systolic function is observed in the arm with nonpegylated liposomal doxorubicin-based regimen (P = 0.006) Chastagner Maximum RD and PK Despite the acceptable et al. (15) safety promoted by Myocet, PK differences between the adult and the pediatric population remain unclear. Large interpatient variability in terms of PK was highlighted in this study Xu et al. (16) Das software The PK demonstrated by calculated PK profile the 2 products was similar. In comparison to European study regarding the PK profile, The CLand VD of the Chinese patients are higher than European patients. Therapeutic efficacy was not observed in this study Turini et al. (17) To assess the It highlighted the chemotherapy- significant cost of induced nausea and chemotherapy-induced vomiting direct cost nausea and vomiting on the NHS in European Countries Monk et al (18) To assess the safety It confirmed the and efficacy of the superiority of the two intervention combination treatment compared to single treatment. (P< 0.05) Crivellari The primary The occurrence of BCFI et al. (19) endpoint is BCFI. was similar in two Secondary outcomes arms. No cardiac included tolerability, toxicity had been adverse events, observed. Patients on and quality of life PLD reported worse QL scores than those on non-PLD for all measures except for nausea and vomiting. The measures consist of physical well-being, functional performance, overall disease/treatment burden, mucosa inflammation of the mouth PLD/carboplatin Lee et al. (20) QALY combination is more effective and costly than paclitaxel/carboplatin combination, with an additional USD 21,658 QALY Staropoli Primary outcome: OS and PFS of the et al. (21) OS. Secondary control arm are higher outcome: PFS, than exposure arm RR, and toxicity (P<0.08). Common PLD-associated toxicity observed are neutropenia (14%), thrombocytopenia (7%), anemia (1%), hand-foot syndrome (5%), mucositis Anders et al. (22) PKand efficacy In comparison to nonliposomal doxorubicin, PLD promotes better efficacy and PK profile in terms of OS and AUC in the treatment of intracranial breast cancer Bosetti et al. (23) Costs and QALWs PLD has a higher drug cost than gemcitabine. (2814.13 [euro] vs. 1528.85 [euro]; P<0.0005). The hospitalization cost of gemcitabine is higher than PLD. (4008.80 [euro] vs. 1394.38 [euro]; P<0.0005). The OS is comparable for both groups (56 weeks for PLD vs. 51 weeks for gemcitabine; P = 0.048). The cost-effectiveness of PLD was 170 [euro] and 318 [euro] per QALW while the cost-effectiveness of gemcitabine was between 317 [euro] and 589 [euro] per quality-adjusted life week Vici et al. (24) Efficacy according 3 complete response to RECIST criteria (5.6%) and 20 partial and toxicity responses (37%), for according to National an overall RR of 42.6% Cancer Institute (95% CI, 29.3-55.9) in Common Toxicity EPI/V and 8 complete Criteria (version 3.0) responses (16%) and 18 partial responses (36%), for an overall RR of 52% (95% CI, 38.2-65.8) in PLD/V. In terms of toxicology, both arms showed a tolerable adverse effect Osoba et al. (25) Change in HRQL The patients treated from baseline to with PLD had high end of treatment statistically related to general significant health, pain, social improvement on 4 of functioning, mental the 9 domains health, cognitive (P<0.01), which functioning, includes pain, energy/fatigue, cognitive functioning, health distress, social functioning and health transition, and health distress. The overall QL patients treated with doxorubicin plus bleomycin plus vincristine had deteriorated energy and experienced fatigue Kushnir et al. (26) Cost savings There were no following selective significant difference cardiac surveillance in relation to cardiotoxicity between the selective cardiac surveillance and routine cardiac surveillance. More than 182,000 USD in 184 patients will be saved for not performing cardiac imaging prior to PLD treatment Study Limitations Berger et al. (6) Underpowered sample size and no statistical data provided, indicating the lack of statistical significance. High contamination due to pretreatment prior to liposomal doxorubicin Wasle et al. (7) Contaminations during the study period were not taken into account as some patients received not only Myocet but also other cytotoxic drugs such as cyclophosphamide, vincristine, prednisone, and rituximab. Additionally, baseline characteristic of the patients such as organ function had not been taken into consideration of the study La-Beck et al. (8) The detailed co-intervention had not been reported. Unknown settings limit the clinical applicability of the results Boers-Sonderen Underpowered sample size et al. (9) indicates the questionable significance in clinical settings Hunault-Berger Some results interpreted et al. (10) by the article can be due to chance (P>0.05) Fiegl et al. (11) The article is deemed to be a cross-sectional study, indicating that large performance bias is almost inevitable Wong et al. (12) Baseline characteristics such as patient age are not taken into consideration Jurczak et al. (13) In relation to OS, the observed noninferiority of liposomal doxorubicin in comparison to nonliposomal doxorubicin can due to chance (P = 0.9) Lotrionte Unknown settings limit et al. (14) the clinical applicability of the data Chastagner Underpowered sample size et al. (15) indicates the questionable significance in clinical settings Xu et al. (16) Underpowered sample size indicates the questionable significance in clinical settings. The name of the PLD product had not been mentioned. Unknown randomization procedure indicates the possibility of selection bias. Unknown blinding indicates the possibility of performance bias Turini et al. (17) It is questionable that the finding may not be applicable to Asian countries Monk et al (18) No blinding indicates the risk of performance bias Crivellari No allocation concealment et al. (19) indicates the risk of selection bias. No blinding indicates the risk of performance bias Lee et al. (20) There is a variation in PLD cost and PLD administration cost. Additionally, patients are assumed to accept six doses of chemotherapy on average from the diagnosis of ovarian cancer until death Staropoli The patient had been et al. (21) treated by drugs other than doxorubicin. Hence, it is important to underline that co-intervention might interfere the results. Other limitations mentioned in the article include small sample size, long enrollment time and selection bias Anders et al. (22) Further examination is required in human setting Bosetti et al. (23) It is uncertain that the same cost will apply to other countries Vici et al. (24) No allocation concealment indicates the risk of selection bias. No blinding indicates the risk of performance bias Osoba et al. (25) No allocation concealment indicates the risk of selection bias. No blinding indicates the risk of performance bias. Additionally, he study was conducted on 2001, which may not represent the latest actuality Kushnir et al. (26) The investigators did not consider that the cost of PLD is more than 100 times higher than nonliposomal conventional doxorubicin (27). Hence, the opportunity of saving more than 4,400,000 USD will be missed if not performing routine cardiac surveillance [euro] = Euro, RCT = Randomized controlled trial, PLD = Pegylated liposomal doxorubicin, CL = Clearance, VD = Volume of distribution, NHS = National Health Service, BCFI = Breast cancer-free interval, BMI = Body mass index, LBM = Lean body mass, HRQL = Health Related Quality of Life, QALWs = Quality-adjusted life weeks, RR = Response rate, PPE = Palmar-plantar erythrodysesthesia, TDI = Tissue Dropper Imaging, RD = Recommended dose, PK = Pharmacokinetics, NHL = NonHodgkin lymphoma, QALY = Quality adjusted life year, OS = Overall survival, CTCAE = Common Terminology Criteria for adverse events, PFS = Progression-free survival, EPI/V = Epirubicin/vinorelbine, PLDA/V = Pegylated liposomal doxorubicin/vinorelbine, AUC = Area under the curve, RECIST = Response evaluation criteria in solid tumors
|Printer friendly Cite/link Email Feedback|
|Author:||Ngan, Yik Hoe; Gupta, Manish|
|Publication:||Archives of Pharmacy Practice|
|Date:||Jan 1, 2016|
|Previous Article:||Pharmacovigilance and pharmacists: need for enhancing role as active health professionals.|
|Next Article:||Knowledge of warfarin therapy among patients attending Warfarin Clinic at a Public Hospital in Northern part of Malaysian Peninsular.|