A comparison between liposomal and nonliposomal formulations of … · 2019. 10. 28. · Yik Hoe...

1© 2016 Archives of Pharmacy Practice | Published by Wolters Kluwer - Medknow

ABSTRACT

Cancer remains a major cause of hospitalization and death every year. From time to time, new formulations of anticancer drugs are available in the market and draw the concern of healthcare professionals in terms of the superiority, toxicology, and cost‑effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, which is a highly potent chemotherapeutic agent, comes with three formulations (pegylated liposomal, nonpegylated liposomal and nonliposomal conventional formulations). English‑language literature in relation to the three formulations has been reviewed to inform the healthcare professionals regarding the differences between these formulations. In terms of efficacy, there is only one study supporting the superiority of liposomal doxorubicin, but there are more data which supports the non‑inferiority of liposomal doxorubicin in comparison to conventional non‑liposomal doxorubicin. It is emphasized that liposomal doxorubicin promotes better toxicology profile than nonliposomal conventional doxorubicin with an increased cost. The cost‑effectiveness of liposomal doxorubicin is not well defined as there are very limited studies in this area. Apart from that, this review highlights the interpatient variability in regards to the clearance and volume of distribution following the administration of liposomal doxorubicin. In conclusion, further studies will be required to better define the superiority of liposomal formulation of doxorubicin regarding the efficacy and dose standardization of liposomal doxorubicin should be sought in the near future.

A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated reviewYik 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: [email protected]

Key words: Cancer, doxorubicin, liposome

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

Review Article

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

Access this article onlineQuick Response Code: Website:

www.archivepp.com

DOI:

10.4103/2045‑080X.174930

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.

For reprints contact: [email protected]

How to cite this article: Ngan YH, Gupta M. A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review. Arch Pharma Pract 2016;7:1‑13.

Ngan and Gupta: Liposomal and nonliposomal formulations of doxorubicin

2 Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016

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]

L IPOSOMAL 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 ( H S P C / P E G - D P S E ) w h e r e a s t h e m e m b r a n e o f L i p o - D o x i s m a d e o f distearoylphosphatidylcholine (DSPC) coated with the same coating material PEG-DSPE.[6] Since DSPC has a higher transition temperature than HSPC,


3Archives of Pharmacy Practice Vol. 7 Issue 1 Jan‑Mar 2016

Lipo-Dox offers higher stability and longer half-life compared to Caelyx/Doxil.[6]

Liposomal Doxorubicin SUN contains a l iposome 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 selectionIn 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 (t½) 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 t½ for conventional doxorubicin is about 20–25 h.[8,9]

Non-PLD has a shorter t½ than PLD but a longer t½ 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 t½ 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



Tabl

e 1:

Syn

opsi

s of

orig

inal

art

icle

s re

late

d to

lipo

som

al fo

rmul

atio

n of

dox

orub

icin

pre

sent

in th

e m

arke

tSt

udy

Setti

ngPa

rtic

ipan

ts a

nd

follo

w‑u

pSt

udy

desi

gnIn

terv

entio

n ev

alua

ted

Mai

n ou

tcom

esFi

ndin

gsLi

mita

tions

Ber

ger e

t al.[6

]M

agee

‑Wom

en

Hos

pita

l, U

nive

rsity

of

Pitt

sbur

gh

Med

ical

C

ente

r. 20

12

18 p

atie

nts

treat

ed

with

lipo

som

al

doxo

rubi

cin

Ret

rosp

ectiv

e st

udy

Lipo

som

al

doxo

rubi

cin

RR

s an

d to

xici

ty

asso

ciat

ed

with

lipo

dox

No

patie

nts

had

a co

mpl

ete

or p

artia

l res

pons

e to

lipo

dox.

D

isea

se c

ontro

l rat

e of

11%

Und

erpo

wer

ed s

ampl

e si

ze a

nd n

o st

atis

tical

dat

a pr

ovid

ed, i

ndic

atin

g th

e la

ck

of s

tatis

tical

sig

nific

ance

. H

igh

cont

amin

atio

n du

e to

pre

treat

men

t prio

r to

lipos

omal

dox

orub

icin

Was

le e

t al.[7

]11

Aus

trian

an

d 1

Italia

n ca

ncer

cen

ter.

Mar

ch 2

008‑

D

ecem

ber

2013

326

patie

nts

with

ly

mph

opro

lifer

ativ

e di

seas

e re

ceiv

ed, a

t le

ast,

one

dose

of

Myo

cet,

whi

ch is

a

nonp

egyl

ated

form

of

lipos

omal

dox

orub

icin

Obs

erva

tiona

l stu

dyM

yoce

tE

valu

atio

n of

toxi

city

gr

aded

acc

ordi

ng

to N

CI C

TCA

E,

vers

ion

4.0

The

mos

t com

mon

gr

ade

3/4

toxi

citie

s w

ere

hem

atol

ogic

toxi

city

, inc

ludi

ng

leuk

open

ia, n

eutro

peni

a,

thro

mbo

cyto

peni

a an

d fe

brile

neu

trope

nia

Con

tam

inat

ions

dur

ing

the

stud

y pe

riod

wer

e no

t tak

en

into

acc

ount

as

som

e pa

tient

s re

ceiv

ed n

ot o

nly

Myo

cet b

ut

also

oth

er c

ytot

oxic

dru

gs

such

as

cycl

opho

spha

mid

e,

vinc

ristin

e, p

redn

ison

e,

and

ritux

imab

. Add

ition

ally,

ba

selin

e ch

arac

teris

tic o

f th

e pa

tient

s su

ch a

s or

gan

func

tion

had

not b

een

take

n in

to c

onsi

dera

tion

of th

e st

udy

La‑B

eck

et a

l.[8]

Unk

now

n se

tting

s70

pat

ient

s >1

8 ye

ars

of a

ge

with

his

tolo

gica

lly

or c

ytol

ogic

ally

co

nfirm

ed s

olid

tum

ors

or K

apos

i’s s

arco

ma

and

adeq

uate

org

an

func

tion

with

out p

rior

cum

ulat

ive

treat

men

t of

dox

orub

icin

Ther

e ar

e 3

stud

ies

bein

g co

nduc

ted.

st

udy

1 an

d 2

are

obse

rvat

iona

l stu

dies

w

here

as s

tudy

3

is a

rand

omiz

ed

cont

rolle

d tri

al

PLD

The

rela

tions

hip

betw

een

age

as

wel

l as

gend

er a

nd

the

CL

of P

LD

The

fact

ors

affe

ctin

g th

e C

L of

PLD

are

diff

eren

t in

com

paris

on to

non

lipos

omal

do

xoru

bici

n. F

emal

e pa

tient

ha

s lo

wer

CL

of P

LD th

an

mal

e (P

<0.0

001)

. Apa

rt fro

m

that

, pat

ient

s <6

0 ye

ars

old

have

hig

her C

L th

an p

atie

nts

>60

year

s ol

d (P

<0.0

001)

The

deta

iled

co‑in

terv

entio

n ha

d no

t bee

n re

porte

d.

Unk

now

n se

tting

s lim

it th

e cl

inic

al a

pplic

abili

ty

of th

e re

sults

Boe

rs‑S

onde

ren

et a

l.[9]

Sin

gle

cent

er

in F

inla

nd.

Unk

now

n tim

elin

e

20 p

atie

nts

with

hi

stol

ogic

al p

rove

n ad

vanc

ed b

reas

t, en

dom

etria

l or o

varia

n ca

ncer

s, w

ho a

re

mor

e th

an 1

8 ye

ars

old

and

have

life

ex

pect

ancy

of m

ore

than

12

wee

ks

Pha

se Ib

clin

ical

tria

lC

aely

x in

co

mbi

natio

n w

ith

tem

siro

limus

To a

sses

s th

e fa

ctor

s af

fect

ing

the

PK

/PD

of

Cae

lyx

The

cael

yx e

xpos

ure

(log

AU

C) w

as h

ighe

r in

patie

nts

who

exp

erie

nced

rash

(P

=0.0

02) a

nd m

ucos

itis

(P=0

.001

) com

pare

d to

pat

ient

s w

ho d

id n

ot

expe

rienc

e th

ese

adve

rse

even

ts. A

dditi

onal

ly, th

ere

is n

o re

latio

nshi

p be

twee

n C

aely

x ex

posu

re a

nd th

e oc

curr

ence

of c

omm

on s

ide

effe

cts

of C

aely

x su

ch a

s le

ukoc

ytop

enia

, sto

mat

itis,

an

d ha

nd‑fo

ot s

yndr

ome

Und

erpo

wer

ed s

ampl

e si

ze

indi

cate

s th

e qu

estio

nabl

e si

gnifi

canc

e in

clin

ical

set

tings

Cont

d...



Tabl

e 1:

Con

td...

Stud

ySe

tting

Part

icip

ants

and

fo

llow

‑up

Stud

y de

sign

Inte

rven

tion

eval

uate

dM

ain

outc

omes

Find

ings

Lim

itatio

ns

Hun

ault‑

Ber

ger

et a

l.[10]

26 c

ente

rs

in F

inla

nd.

Mar

ch 2

002‑

O

ctob

er 2

006.

O

utco

me

data

was

up

date

d on

1

Apr

il 20

09

60 u

ntre

ated

pat

ient

s ag

ed 5

5 ye

ars

or m

ore

with

non

Bur

kitt’

s,

Phi

lade

lphi

a ch

rom

osom

e‑ne

gativ

e or

BC

R‑A

BL

nega

tive

acut

e ly

mph

obla

stic

le

ukem

ia w

ithou

t se

vere

arr

hyth

mia

, co

rona

ry a

rtery

di

seas

e, a

cute

he

art f

ailu

re, l

eft

vent

ricul

ar e

ject

ion

fract

ion

<50%

, ren

al

or li

ver d

ysfu

nctio

n,

posi

tivity

for h

uman

im

mun

odefi

cien

cy

viru

s, o

r psy

chia

tric

dise

ase

RC

TC

ontin

uous

‑ in

fusi

on d

oxor

ubic

in

in c

ombi

natio

n w

ith v

incr

istin

e on

one

arm

or

PLD

(Cae

lyx)

and

st

anda

rd v

incr

istin

e on

the

othe

r arm

Prim

ary

Out

com

e:

com

posi

te e

ffica

cy

and

toxi

city

con

sist

ing

of c

ontin

uous

co

mpl

ete

rem

issi

on

rate

, hem

atol

ogic

and

ex

tra‑h

emat

olog

ic

toxi

city

. Sec

onda

ry

Out

com

e: c

ompl

ete

rem

issi

on ra

te, s

afet

y,

cum

ulat

ive

inci

denc

e of

rela

pse

and

failu

re,

cum

ulat

ive

inci

denc

e of

dea

th in

firs

t co

mpl

ete

rem

issi

on

and

treat

men

t‑rel

ated

de

ath,

eve

nt‑fr

ee

surv

ival

and

OS

Des

pite

the

fact

that

m

ore

patie

nts

in

conv

entio

nal d

oxor

ubic

in

arm

dea

d, c

onve

ntio

nal

doxo

rubi

cin

(90%

) gav

e ris

e to

hig

her c

ompl

ete

rem

issi

on

rate

afte

r tw

o in

duct

ion

cycl

es

in c

ompa

rison

to P

LD (7

2%).

Apa

rt fro

m th

at, p

egyl

ated

lip

osom

al d

oxor

ubic

in

decr

ease

d th

e to

xici

ty o

f do

xoru

bici

n in

term

s of

m

yelo

supp

ress

ion

(P=0

.005

‑0.

9), i

nfec

tions

(P=0

.04‑

0.12

) and

car

diot

oxic

ity

(P=0

.12)

. Des

pite

the

redu

ced

toxi

city

, peg

ylat

ed

doxo

rubi

cin

does

not

pr

omot

e be

tter s

urvi

val r

ate

Som

e re

sults

inte

rpre

ted

by th

e ar

ticle

can

be

due

to c

hanc

e (P

>0.0

5)

Fieg

l et a

l.[11]

Aus

tralia

. 20

03‑2

009

129

cons

ecut

ive

patie

nts

with

ad

vanc

ed b

reas

t ca

ncer

, who

re

ceiv

ed P

LD a

s m

onot

hera

py w

ithin

lic

ense

d ap

prov

al

Obs

erva

tiona

l ph

ase

IV s

tudy

PLD

Res

pons

e to

PLD

w

hich

incl

udes

to

xici

ty a

nd e

ffica

cy

asso

ciat

ed w

ith P

LD

Ther

e w

ere

enco

urag

ing

resu

lts w

ith P

LD a

s a

mon

o‑th

erap

eutic

age

nt I

the

treat

men

t of m

etas

tasi

zed

brea

st c

ance

r. Th

e m

ost

com

mon

sid

e ef

fect

obs

erve

d w

as d

ose‑

depe

nden

t PP

E

The

artic

le is

dee

med

to

be

a cr

oss‑

sect

iona

l st

udy,

indi

catin

g th

at

larg

e pe

rform

ance

bia

s is

alm

ost i

nevi

tabl

e

Won

g et

al.[1

2]A

sing

le

inst

itutio

n in

S

inga

pore

. U

nkno

wn

timel

ine

84 A

sian

s w

ho a

re

new

ly d

iagn

osed

with

lo

cally

adv

ance

d or

m

etas

tatic

bre

ast

canc

er

Clin

ical

tria

lN

onlip

osom

al

doxo

rubi

cin

PK

and

hem

atol

ogic

to

xici

ties

of

doxo

rubi

cin

Incr

ease

d bo

dy fa

t co

mpo

sitio

n, e

spec

ially

in

tra‑a

bdom

inal

fat

cont

ent,

is a

ssoc

iate

d w

ith

incr

ease

d do

xoru

bici

n ex

posu

re a

nd ra

te o

f gra

de

4 le

ukop

enia

(P<0

.000

1).

Ther

efor

e, in

divi

dual

s w

ith

exce

ssiv

e bo

dy fa

t in

rela

tive

to L

BM

will

hav

e a

high

risk

of

dox

orub

icin

‑ass

ocia

ted

toxi

city

, in

rega

rdle

ss o

f BM

I. Fu

rther

mor

e, b

ody

surfa

ce

area

doe

s no

t det

erm

ine

the

PK

and

toxi

city

of d

oxor

ubic

in

Bas

elin

e ch

arac

teris

tics

such

as

pat

ient

age

are

not

take

n in

to c

onsi

dera

tion

Cont

d...



Tabl

e 1:

Con

td...

Stud

ySe

tting

Part

icip

ants

and

fo

llow

‑up

Stud

y de

sign

Inte

rven

tion

eval

uate

dM

ain

outc

omes

Find

ings

Lim

itatio

ns

Jurc

zak

et a

l.[13]

Dat

a co

llect

ed

in P

olis

h Ly

mph

oma

Res

earc

h G

roup

. Ti

mel

ine

unkn

own

610

new

ly d

iagn

osed

N

HL

Cau

casi

ans

Ret

rosp

ectiv

e an

alys

isN

onlip

osom

al

doxo

rubi

cin,

no

n‑P

LD a

nd P

LD

Res

pons

e to

tre

atm

ent a

ccor

ding

to

Che

son

crite

ria,

card

ioto

xici

ty, a

nd O

S

Res

pons

e to

trea

tmen

t ac

cord

ing

to C

heso

n cr

iteria

in

patie

nts

treat

ed w

ith li

poso

mal

do

xoru

bici

n is

non

infe

rior

com

pare

d to

non

lipos

omal

do

xoru

bici

n. M

oreo

ver,

the

OS

of p

atie

nts

with

hig

h ris

k of

fata

l car

diac

eve

nts

is

com

para

ble

to th

ose

patie

nts

with

low

risk

of c

ardi

ac fa

tal

even

t, in

dica

ting

that

lipo

som

al

doxo

rubi

cin

incr

ease

s th

e O

S in

pat

ient

s w

ith h

igh‑

risk

fata

l car

diac

eve

nts

In re

latio

n to

OS

, the

ob

serv

ed n

onin

ferio

rity

of

lipos

omal

dox

orub

icin

in

com

paris

on to

non

lipos

omal

do

xoru

bici

n ca

n du

e to

cha

nce

(P=0

.9)

Lotri

onte

et

al.[1

4]U

nkno

wn

setti

ngs

52 p

atie

nts

with

no

nmet

asta

tic c

ance

rR

CT

Non

‑PLD

‑bas

ed

regi

men

and

E

PI‑b

ased

trea

tmen

t

TDI e

xam

ined

sy

stol

ic fu

nctio

nLo

wer

car

diot

oxic

ity is

ob

serv

ed in

the

arm

with

no

npeg

ylat

ed li

poso

mal

do

xoru

bici

n‑ba

sed

regi

men

(P=0

.006

)

Unk

now

n se

tting

s lim

it th

e cl

inic

al a

pplic

abili

ty

of th

e da

ta

Cha

stag

ner

et a

l.[15]

Unk

now

n lo

catio

n.

Oct

ober

20

10‑J

anua

ry

2013

13 c

hild

ren

aged

6‑

17 y

ears

old

w

ith h

isto

logi

cally

do

cum

ente

d m

alig

nant

glio

ma

Pha

se I

clin

ical

stu

dyM

yoce

tM

axim

um R

D a

nd P

KD

espi

te th

e ac

cept

able

sa

fety

pro

mot

ed b

y M

yoce

t, P

K d

iffer

ence

s be

twee

n th

e ad

ult a

nd th

e pe

diat

ric

popu

latio

n re

mai

n un

clea

r. La

rge

inte

rpat

ient

var

iabi

lity

in te

rms

of P

K w

as

high

light

ed in

this

stu

dy

Und

erpo

wer

ed s

ampl

e si

ze

indi

cate

s th

e qu

estio

nabl

e si

gnifi

canc

e in

clin

ical

set

tings

Xu

et a

l.[16]

Chi

na. 2

006

22 C

hine

se p

atie

nts

with

his

tolo

gica

lly o

r cy

tolo

gica

lly c

onfir

med

br

east

can

cer

Cro

ss‑o

ver R

CT

with

4‑w

eek

was

h‑ou

t tim

e

2 P

LD p

rodu

ctD

as s

oftw

are

calc

ulat

ed P

K p

rofil

eTh

e P

K d

emon

stra

ted

by

the

2 pr

oduc

ts w

as s

imila

r. In

com

paris

on to

Eur

opea

n st

udy

rega

rdin

g th

e P

K

profi

le, T

he C

L an

d V

D o

f the

C

hine

se p

atie

nts

are

high

er

than

Eur

opea

n pa

tient

s.

Ther

apeu

tic e

ffica

cy w

as

not o

bser

ved

in th

is s

tudy

Und

erpo

wer

ed s

ampl

e si

ze

indi

cate

s th

e qu

estio

nabl

e si

gnifi

canc

e in

clin

ical

set

tings

. Th

e na

me

of th

e PL

D p

rodu

ct

had

not b

een

men

tione

d.

Unk

now

n ra

ndom

izat

ion

proc

edur

e in

dica

tes

the

poss

ibilit

y of

sel

ectio

n bi

as.

Unk

now

n bl

indi

ng in

dica

tes

the

poss

ibilit

y of

per

form

ance

bia

sTu

rini e

t al.[1

7]Ita

lian,

G

erm

an,

and

Fren

ch.

2013

‑201

4

Onc

olog

ists

and

on

colo

gy n

urse

sC

ross

‑sec

tiona

l st

udy

(an

onlin

e su

rvey

)

Che

mot

hera

pyTo

ass

ess

the

chem

othe

rapy

‑ in

duce

d na

usea

and

vo

miti

ng d

irect

cos

t

It hi

ghlig

hted

the

sign

ifica

nt

cost

of c

hem

othe

rapy

‑indu

ced

naus

ea a

nd v

omiti

ng o

n th

e N

HS

in E

urop

ean

Cou

ntrie

s

It is

que

stio

nabl

e th

at th

e fin

ding

may

not

be

appl

icab

le

to A

sian

cou

ntrie

s

Mon

k et

al.[1

8]12

4 ce

nter

s in

21

cou

ntrie

s.

Apr

il 20

05‑

May

200

7

672

patie

nts

with

hi

stol

ogic

ally

co

nfirm

ed p

ithel

ial

ovar

ian,

fallo

pian

tu

be, o

r prim

ary

perit

onea

l car

cino

ma

Pha

se II

I RC

TTr

abec

tedi

n pl

us

PLD

and

PLD

To a

sses

s th

e sa

fety

an

d ef

ficac

y of

the

two

inte

rven

tion

It co

nfirm

ed th

e su

perio

rity

of th

e co

mbi

natio

n tre

atm

ent

com

pare

d to

sin

gle

treat

men

t. (P

<0.0

5)

No

blin

ding

indi

cate

s th

e ris

k of

per

form

ance

bia

s

Cont

d...



Tabl

e 1:

Con

td...

Stud

ySe

tting

Part

icip

ants

and

fo

llow

‑up

Stud

y de

sign

Inte

rven

tion

eval

uate

dM

ain

outc

omes

Find

ings

Lim

itatio

ns

Criv

ella

ri et

al.[1

9]M

ultin

atio

nal.

Rec

ruitm

ent

from

N

ovem

ber

2005

and

D

ecem

ber

2007

. Fo

llow

‑up

42 m

onth

s

77 m

ultin

atio

nal

elde

rly (>

66 y

ears

ol

d) p

atie

nts

with

end

ocrin

e no

nres

pons

ive

(ER

<10

%; a

nd

PgR

<10

%)

brea

st c

ance

r

Pha

se II

I RC

TP

LD re

gim

en

and

met

rono

mic

cy

clop

hosp

ham

ide

plus

met

hotre

xate

The

prim

ary

endp

oint

is B

CFI

. S

econ

dary

out

com

es

incl

uded

tole

rabi

lity,

ad

vers

e ev

ents

, an

d qu

ality

of l

ife

The

occu

rren

ce o

f BC

FI

was

sim

ilar i

n tw

o ar

ms.

No

card

iac

toxi

city

had

bee

n ob

serv

ed. P

atie

nts

on P

LD

repo

rted

wor

se Q

L sc

ores

th

an th

ose

on n

on‑P

LD

for a

ll m

easu

res

exce

pt

for n

ause

a an

d vo

miti

ng.

The

mea

sure

s co

nsis

t of

phys

ical

wel

l‑bei

ng, f

unct

iona

l pe

rform

ance

, ove

rall

dise

ase/

treat

men

t bur

den,

muc

osa

infla

mm

atio

n of

the

mou

th

No

allo

catio

n co

ncea

lmen

t in

dica

tes

the

risk

of s

elec

tion

bias

. No

blin

ding

indi

cate

s th

e ris

k of

per

form

ance

bia

s

Lee

et a

l.[20]

Sou

th K

orea

. 20

13A

Mar

kov

mod

el w

ith

a 10

‑yea

r tim

e ho

rizon

Cos

t‑util

ity a

naly

sis

PLD

/car

bopl

atin

ve

rsus

pac

litax

el/

carb

opla

tin

QA

LYP

LD/c

arbo

plat

in c

ombi

natio

n is

mor

e ef

fect

ive

and

cost

ly

than

pac

litax

el/c

arbo

plat

in

com

bina

tion,

with

an

addi

tiona

l US

D 2

1,65

8 Q

ALY

Ther

e is

a v

aria

tion

in P

LD

cost

and

PLD

adm

inis

tratio

n co

st. A

dditi

onal

ly, p

atie

nts

are

assu

med

to a

ccep

t six

do

ses

of c

hem

othe

rapy

on

aver

age

from

the

diag

nosi

s of

ova

rian

canc

er u

ntil

deat

hS

taro

poli

et a

l.[21]

Clin

ical

D

ata

of It

aly.

20

01‑2

011

108

patie

nts

with

hi

stol

ogic

ally

co

nfirm

ed o

varia

n ca

ncer

Ret

rosp

ectiv

e co

hort

stud

yO

n th

e ex

posu

re

arm

, the

pat

ient

s ar

e tre

ated

with

PLD

. On

the

cont

rol a

rm, t

he

patie

nts

are

treat

ed

with

oth

er d

rugs

su

ch a

s to

pote

can,

ge

mci

tabi

ne,

etop

osid

e. P

atie

nts

unde

rwen

t P

LD h

ad h

igh

plat

inum

‑sen

sitiv

ity

Prim

ary

outc

ome:

O

S. S

econ

dary

ou

tcom

e: P

FS,

RR

, and

toxi

city

OS

and

PFS

of t

he c

ontro

l ar

m a

re h

ighe

r tha

n ex

posu

re a

rm (P

<0.0

8).

Com

mon

PLD

‑ass

ocia

ted

toxi

city

obs

erve

d ar

e ne

utro

peni

a (1

4%),

thro

mbo

cyto

peni

a (7

%),

anem

ia (1

%),

hand

‑foot

sy

ndro

me

(5%

), m

ucos

itis

The

patie

nt h

ad b

een

treat

ed b

y dr

ugs

othe

r th

an d

oxor

ubic

in. H

ence

, it

is im

porta

nt to

und

erlin

e th

at c

o‑in

terv

entio

n m

ight

in

terfe

re th

e re

sults

. Oth

er

limita

tions

men

tione

d in

th

e ar

ticle

incl

ude

smal

l sa

mpl

e si

ze, l

ong

enro

llmen

t tim

e an

d se

lect

ion

bias

And

ers

et a

l.[22]

Unk

now

n se

tting

s46

tum

or‑b

earin

g m

ice

follo

win

g in

ocul

ated

in

trace

rebr

ally

with

M

DA

‑MB

‑231

‑BR

‑ lu

cife

rase

‑ ex

pres

sing

cel

ls

Labo

rato

ry s

tudy

PLD

ver

sus

nonl

ipos

omal

do

xoru

bici

n

PK

and

effi

cacy

In c

ompa

rison

to

nonl

ipos

omal

dox

orub

icin

, P

LD p

rom

otes

bet

ter e

ffica

cy

and

PK

pro

file

in te

rms

of O

S

and

AU

C in

the

treat

men

t of

intra

cran

ial b

reas

t can

cer

Furth

er e

xam

inat

ion

is

requ

ired

in h

uman

set

ting

Cont

d...



Tabl

e 1:

Con

td...

Stud

ySe

tting

Part

icip

ants

and

fo

llow

‑up

Stud

y de

sign

Inte

rven

tion

eval

uate

dM

ain

outc

omes

Find

ings

Lim

itatio

ns

Bos

etti

et a

l.[23]

Eur

opea

n co

untri

es15

3 pa

tient

s w

ith re

curr

ent

or p

rogr

essi

ve

ovar

ian

canc

er

Cos

t‑effe

ctiv

enes

s an

alys

is b

ased

on

the

data

of a

n R

CT

PLD

ver

sus

gem

cita

bine

Cos

ts a

nd Q

ALW

sPL

D h

as a

hig

her d

rug

cost

than

gem

cita

bine

. (€

2814

.13

vs. €

1528

.85;

P<

0.00

05).

The

hosp

italiz

atio

n co

st o

f gem

cita

bine

is h

ighe

r th

an P

LD. (

€400

8.80

vs.

€1

394.

38; P

<0.0

005)

. Th

e O

S is

com

para

ble

for

both

gro

ups

(56

wee

ks

for P

LD v

s. 5

1 w

eeks

for

gem

cita

bine

; P=0

.048

). Th

e co

st‑e

ffect

iven

ess

of P

LD w

as

€170

and

€31

8 pe

r QAL

W

whi

le th

e co

st‑e

ffect

iven

ess

of g

emci

tabi

ne w

as

betw

een

€317

and

€58

9 pe

r qu

ality

‑adj

uste

d lif

e w

eek

It is

unc

erta

in th

at th

e sa

me

cost

will

app

ly

to o

ther

cou

ntrie

s

Vici

et a

l.[24]

4 on

colo

gic

cent

ers

of

the

Gru

ppo

Onc

olog

ico

Italia

M

erid

iona

le.

Mar

ch 2

003‑

N

ovem

ber

2005

104

patie

nts

with

hi

stol

ogic

ally

co

nfirm

ed a

dvan

ced

brea

st c

ance

r who

ar

e no

t pre

viou

sly

treat

ed w

ith a

djuv

ant

anth

racy

clin

es

RC

TE

PI/V

and

PLD

/VE

ffica

cy a

ccor

ding

to

RE

CIS

T cr

iteria

an

d to

xici

ty

acco

rdin

g to

Nat

iona

l C

ance

r Ins

titut

e C

omm

on T

oxic

ity

Crit

eria

(ver

sion

3.0

)

3 co

mpl

ete

resp

onse

(5.6

%)

and

20 p

artia

l re

spon

ses

(37%

), fo

r an

over

all R

R o

f 42

.6%

(95%

CI,

29.3

‑55.

9)

in E

PI/V

and

8 c

ompl

ete

resp

onse

s (1

6%) a

nd 1

8 pa

rtial

resp

onse

s (3

6%),

for

an o

vera

ll R

R o

f 52%

(95%

C

I, 38

.2‑6

5.8)

in P

LD/V

. In

term

s of

toxi

colo

gy,

both

arm

s sh

owed

a

tole

rabl

e ad

vers

e ef

fect

No

allo

catio

n co

ncea

lmen

t in

dica

tes

the

risk

of s

elec

tion

bias

. No

blin

ding

indi

cate

s th

e ris

k of

per

form

ance

bia

s

Oso

ba e

t al.[2

5]25

cen

ters

in

Can

ada.

200

125

8 m

ale

patie

nts

with

bio

psy‑

prov

en

AID

S‑r

elat

ed K

apos

i’s

sarc

oma

RC

TP

LD o

r dox

orub

icin

pl

us b

leom

ycin

plu

sP

lus

vinc

ristin

e

Cha

nge

in H

RQ

L fro

m b

asel

ine

to

end

of tr

eatm

ent

rela

ted

to g

ener

al

heal

th, p

ain,

soc

ial

func

tioni

ng, m

enta

l he

alth

, cog

nitiv

e fu

nctio

ning

, en

ergy

/fatig

ue,

heal

th d

istre

ss,

heal

th tr

ansi

tion,

and

ov

eral

l QL

The

patie

nts

treat

ed w

ith

PLD

had

hig

h st

atis

tical

ly

sign

ifica

nt im

prov

emen

t on

4 of

the

9 do

mai

ns (P

<0.0

1),

whi

ch in

clud

es p

ain,

co

gniti

ve fu

nctio

ning

, soc

ial

func

tioni

ng a

nd h

ealth

di

stre

ss. T

he p

atie

nts

treat

ed w

ith d

oxor

ubic

in p

lus

bleo

myc

in p

lus

vinc

ristin

e ha

d de

terio

rate

d en

ergy

and

ex

perie

nced

fatig

ue

No

allo

catio

n co

ncea

lmen

t in

dica

tes

the

risk

of s

elec

tion

bias

. No

blin

ding

indi

cate

s th

e ris

k of

per

form

ance

bia

s.

Add

ition

ally,

he

stud

y w

as

cond

ucte

d on

200

1, w

hich

m

ay n

ot re

pres

ent t

he la

test

ac

tual

ity

Cont

d...



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.[6,7,10,13,22,24]

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 Ta

ble

1: C

ontd

...St

udy

Setti

ngPa

rtic

ipan

ts a

nd

follo

w‑u

pSt

udy

desi

gnIn

terv

entio

n ev

alua

ted

Mai

n ou

tcom

esFi

ndin

gsLi

mita

tions

Kus

hnir

et a

l.[26]

John

s H

opki

ns

Hos

pita

l an

d D

uke

Uni

vers

ity

Med

ical

C

ente

r. 20

02‑

2014

184

patie

nts

with

gyn

ecol

ogic

m

alig

nanc

y

Ret

rosp

ectiv

e ch

art

revi

ewP

LDC

ost s

avin

gs

follo

win

g se

lect

ive

card

iac

surv

eilla

nce

Ther

e w

ere

no s

igni

fican

t di

ffere

nce

in re

latio

n to

ca

rdio

toxi

city

bet

wee

n th

e se

lect

ive

card

iac

surv

eilla

nce

and

rout

ine

card

iac

surv

eilla

nce.

Mor

e th

an

182,

000

US

D in

184

pat

ient

s w

ill b

e sa

ved

for n

ot

perfo

rmin

g ca

rdia

c im

agin

g pr

ior t

o P

LD tr

eatm

ent

The

inve

stig

ator

s di

d no

t co

nsid

er th

at th

e co

st o

f P

LD is

mor

e th

an 1

00 ti

mes

hi

gher

than

non

lipos

omal

co

nven

tiona

l dox

orub

icin

[27].

Hen

ce, t

he o

ppor

tuni

ty o

f sa

ving

mor

e th

an 4

,400

,000

U

SD

will

be

mis

sed

if no

t pe

rform

ing

rout

ine

card

iac

surv

eilla

nce

€=E

uro,

RC

T=R

ando

miz

ed c

ontro

lled

trial

, PLD

=Peg

ylat

ed li

poso

mal

dox

orub

icin

, CL=

Cle

aran

ce, V

D=V

olum

e of

dis

tribu

tion,

NH

S=N

atio

nal H

ealth

Ser

vice

, BC

FI=B

reas

t can

cer‑

free

inte

rval

, BM

I=B

ody

mas

s in

dex,

LB

M=L

ean

body

mas

s, H

RQ

L=H

ealth

Rel

ated

Qua

lity

of L

ife, Q

ALW

s=Q

ualit

y‑ad

just

ed li

fe w

eeks

, RR

=Res

pons

e ra

te, P

PE

=Pal

mar

‑pla

ntar

ery

thro

dyse

sthe

sia,

TD

I=Ti

ssue

Dro

pper

Imag

ing,

RD

=Rec

omm

ende

d do

se, P

K=P

harm

acok

inet

ics,

NH

L=N

onH

odgk

in ly

mph

oma,

QA

LY=Q

ualit

y ad

just

ed li

fe y

ear,

OS

=Ove

rall

surv

ival

, CTC

AE

=Com

mon

Ter

min

olog

y C

riter

ia fo

r adv

erse

eve

nts,

PFS

=Pro

gres

sion

‑free

sur

viva

l, E

PI/V

=Epi

rubi

cin/

vino

relb

ine,

PLD

/V=P

egyl

ated

lipo

som

al d

oxor

ubic

in/v

inor

elbi

ne, A

UC

=Are

a un

der t

he c

urve

, RE

CIS

T=R

espo

nse

eval

uatio

n cr

iteria

in s

olid

tum

ors



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 and €318 per QALW, which is between €8864 and €16581 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).[31] 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.

Financial support and sponsorshipNil.

Conflicts of interestThere are no conflicts of interest.

REFERENCES

1. National Cancer Institute. Cancer Statistics. UnitedStates: 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 on2015 Oct 15].

2. Aulton M, Taylor K. Aulton’s Pharmaceutics: The Designand 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®). 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. Pharmacokineticsand 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. Effectof 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. Pharmacogeneticsof 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 andesophagitis: 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 useof 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].

Reproduced with permission of the copyright owner. Further reproduction prohibited withoutpermission.

A comparison between liposomal and nonliposomal formulations of … · 2019. 10. 28. · Yik Hoe...

Documents

Transcript of A comparison between liposomal and nonliposomal formulations of … · 2019. 10. 28. · Yik Hoe...