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A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: an updated review.

INTRODUCTION

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. [1] 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. [2]

Doxorubicin is a very potent cytotoxic anticancer that directly inhibits topoisomerase II and nucleic acid synthesis. [3] 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. [3] 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. [2] 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. [2] 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. [2] 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. [5]

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. [2] 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. [6] Since DSPC has a higher transition temperature than HSPC, Lipo-Dox offers higher stability and longer half-life compared to Caelyx/Doxil. [6]

Liposomal Doxorubicin SUN contains a liposome coated with sodium methoxy PEG-40-carbonyl-DPSE. [4] Although its coating material is different to Caelyx/Doxil, it is proven to be therapeutically equivalent to Caelyx/Doxil. [5]

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]

LITERATURE REVIEW

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].

PHARMACOKINETIC

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. [7] 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. [5]

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. [27] 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. [27] 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. [27] 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. [27]

In comparison to conventional nonliposomal doxorubicin, PLD and non-PLD undertake a more complicated metabolizing pathway. [9] 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. [28] 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. [8] 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. [28] 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. [12] 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. [16]

EFFICACY

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. [15] 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. [6] An observational study indicates that Lipo-Dox is inferior to Doxil in terms of potency. [6] 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. [22] In this model of breast cancer, PLD promotes higher survival rate and efficacy with reduced toxicity than nonliposomal doxorubicin in mice. [22] Clinical data regarding the utilization of PLD in this model of metastasis breast cancer is eagerly awaiting.

TOXICOLOGY

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. [14] 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. [10] 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. [8] 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. [12]

Under the extremely rare scenario, acute peculiar mucous reaction following administration of PLD had been reported. [29] 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. [19] 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. [28] Consequently, a significant increase in AUC accounts for the dose-dependent toxicity following the administration of liposomal doxorubicin. [11]

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. [17] 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. [26] 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. [30]

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. [23] In terms of paclitaxel, PLD possesses higher efficacy and cost, with an ICER of 21, 658 USD per QALY gained. [20] 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. [31]

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. [22]

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.

CONCLUSION

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.

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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[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.

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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.

E-mail: manish.gupta@monash.edu

DOI: 10.4103/2045-080X.174930
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
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Author:Ngan, Yik Hoe; Gupta, Manish
Publication:Archives of Pharmacy Practice
Article Type:Report
Date:Jan 1, 2016
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