1 3

J Cancer Res Clin OncolDOI 10.1007/s00432-013-1564-4

RevIew

A systematic review on the safety and efficacy of yttrium‑90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases

Akshat Saxena · Lourens Bester · Leonard Shan · Marlon Perera · Peter Gibbs · Baerbel Meteling · David L. Morris

Received: 24 October 2013 / Accepted: 28 November 2013 © Springer-verlag Berlin Heidelberg 2013

ranged from 11 to 100 % (median 40.5 %). Most cases of acute toxicity were mild (Grade I or II) (median 39 %; range 7–100 %) which resolved without intervention. The number of previous lines of chemotherapy (≥3), poor radi-ological response to treatment, extra-hepatic disease and extensive liver disease (≥25 %) were the factors most com-monly associated with poorer overall survival.Conclusion Y90 radioembolization is a safe and effective treatment of CRCLM in the salvage setting and should be more widely utilized.

Keywords Colorectal cancer · Liver metastases · Unresectable · Radioembolization · Yttrium-90 · Survival · Toxicity · Chemorefractory

Introduction

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. In 2011, over 141,000 patients were diagnosed with CRC in the United States, and 49,000 died from this disease (Colorectal Cancer Facts and Fig-ures 2011). The liver is the most common site of metasta-ses from CRC; up to 80 % of patients develop colorectal cancer liver metastases (CRCLM) throughout the natural course of their disease (Kemeny and Fata 1999). Surgi-cal extirpation of CRCLM offers the only opportunity for cure, but is only feasible in a minority of patients (<25 %) (Khatri et al. 2007). even when surgery is performed, the majority of patients will develop recurrence and die from this disease (Tomlinson et al. 2007; Nordlinger et al. 2008).

Patients with unresectable CRCLM have a poor out-come. Advances in chemotherapy and biological agents have improved median survival in the metastatic setting and ren-dered an increasing number of patients resectable (Khatri

Abstract Introduction The management of unresectable, chemore-fractory colorectal cancer liver metastases (CRCLM) is a clinical dilemma. Yttrium-90 (Y90) radioembolization is a potentially safe and effective treatment for patients with CRCLM who have failed conventional chemotherapy regimens.Methods A systematic review of clinical studies before November 2012 was performed to examine the radiologi-cal response, overall survival and progression-free sur-vival of patients who underwent Y90 radioembolization of unresectable CRCLM refractory to systemic therapy. The secondary objectives were to evaluate the safety profile of this treatment and identify prognostic factors for overall survival.Results Twenty studies comprising 979 patients were examined. Patients had failed a median of 3 lines of chemo-therapy (range 2–5). After treatment, the average reported value of patients with complete radiological response, par-tial response and stable disease was 0 % (range 0–6 %), 31 % (range 0–73 %) and 40.5 % (range 17–76 %), respec-tively. The median time to intra-hepatic progression was 9 months (range 6–16). The median overall survival was 12 months (range 8.3–36). The overall acute toxicity rate

A. Saxena (*) · L. Shan · M. Perera · D. L. Morris UNSw Department of Surgery, St George Hospital, Kogarah, NSw 2217, Australiae-mail: akshat16187@gmail.com

L. Bester · B. Meteling Department of Interventional Radiology, St vincent’s Hospital Sydney, Darlinghurst, Sydney, NSw 2010, Australia

P. Gibbs Department of Medical Oncology, Royal Melbourne Hospital, Parkville, vIC 3050, Australia

J Cancer Res Clin Oncol

1 3

et al. 2007; Falcone et al. 2007). Current tumour manage-ment is increasingly reliant on multimodal approaches to consolidate regional response from systemic chemotherapies and increase the number of patients who are candidates for surgery (Khatri et al. 2007). Unfortunately, a significant pro-portion of patients have chemorefractory disease.

The management of chemorefractory CRCLM is a clini-cal dilemma. There is an urgent medical need for effec-tive treatments of patients with CRCLM who have failed conventional chemotherapy regimens. Radioembolization using yttrium-90 (Y90) microspheres delivers targeted radiation therapy to unresectable primary and secondary hepatic malignancies. It has recently emerged as a useful treatment option in the armamentarium against chemore-fractory CRCLM. Several studies have shown that Y90 radioembolization is both safe and effective in the chem-orefractory setting (Chua et al. 2011; Hendlisz et al. 2010; Seidensticker et al. 2012). There is still a need, however, to systematically evaluate the outcomes of this treatment modality in the chemorefractory setting. The primary aim of this study was to comprehensively review the radiologi-cal response and survival outcomes after Y-90 radioemboli-zation of unresectable CRCLM. As a secondary outcome, prognostic factors for overall survival and short-term mor-bidity were evaluated.

Methods

Objective of literature search

The primary objectives of this study were to determine the clinical toxicity, radiological response, overall survival (OS) and progression-free survival (PFS) outcomes of patients who underwent yttrium-90 radioembolization of unresectable and chemorefractory CRCLM. The secondary objectives were to identify prognostic factors for overall survival.

Literature search strategy

Original published studies on the use of yttrium-90 radi-oembolization for the treatment of colorectal cancer hepatic metastases were identified by searching the MeDLINe database (1966–November 2012) and PubMed (January 1980–November 2012) using the key words; (“colorec-tal cancer” or “CRC”) and (“liver metastases” or “hepatic metastases”) and (“radioembolization” or “microspheres”) and “unresectable” and “yttrium-90”. The reference lists of all retrieved articles were manually reviewed to further identify potentially relevant studies. All relevant articles identified were assessed with application of a predeter-mined selection criterion.

Selection criteria

experimental and observational studies that used yttrium-90 radioembolization as a therapeutic option for patients with unresectable, chemorefractory CRCLM were identified for inclusion. Studies were classified into three levels of evidence as follows: level I, randomized controlled trials; level II, non-randomized controlled clinical trials or well-designed cohort studies; and level III, observational studies, as described by the US Preven-tive Services Task Force. Specific inclusion criteria were studies published after year 2000, with ≥10 patients, human articles and papers published in the english lan-guage. Abstracts, letters, editorials and expert opinions were excluded. Conference abstracts were also excluded due to a lack of detail regarding trial design. when cen-tres have published studies with accumulating numbers of patients or increased lengths of follow-up, only the most recent and complete reports were included for qual-itative appraisal and efficacy assessment. It is acknowl-edged that all of the studies included in the present review aimed to demonstrate the efficacy of yttrium-90 radioembolization for the treatment of unresectable colo-rectal cancer liver metastases. A few studies, however, also used chemotherapy in the adjuvant or neo-adjuvant setting. It is acknowledged that it is impossible to isolate the data on just yttrium-90 radioembolization in these studies.

Data extraction and critical appraisal

Three reviewers (A.S., L.S. and M.P.) independently appraised each article using a standard protocol. Data extracted include the methodology, quality criteria, patient characteristics, treatment toxicity, radiological response, overall survival (median, 1, 2, 3 year) and progression-free survival (median) and prognostic factors. Overall survival and progression-free survival were determined from the time of yttrium-90 radioembolization. A meta-analysis was not appropriate because most studies lacked a comparator. All data were extracted from the relevant articles, texts, tables and figures. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies.

Results

Quantity and quality of evidence

Literature search using the above-mentioned search strategy through both MeDLINe and PubMed data-bases identified 220 studies. A flow chart of publication

J Cancer Res Clin Oncol

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identification and quality appraisal is demonstrated in Fig. 1. Overall, 20 studies comprising 979 patients were individually reviewed through careful analysis of the study methodology with reference to fulfilment of the systematic review’s primary and secondary end-points (Chua et al. 2011; Hendlisz et al. 2010; Seidensticker et al. 2012; Gray et al. 2001; Lewandowski et al. 2005; Murthy et al. 2005; Kennedy et al. 2006; Lim et al. 2005; Stubbs et al. 2006; Murthy et al. 2007; Jakobs et al. 2008; Mulcahy et al. 2009; van Hazel et al. 2009; Cianni et al. 2009; Cosimelli et al. 2010; Martin et al. 2012; Nace et al. 2011; Hong et al. 2009; Stuart et al. 2008; Mancini et al. 2006). There were 2 phase III randomized controlled tri-als (level I evidence) (Hendlisz et al. 2010; Gray et al. 2001), 5 phase II studies (level II evidence) (Lewan-dowski et al. 2005; Lim et al. 2005; Mulcahy et al. 2009; van Hazel et al. 2009; Cosimelli et al. 2010) and 13 obser-vational studies (level III evidence) (Chua et al. 2011; Seidensticker et al. 2012; Murthy et al. 2005; Kennedy et al. 2006; Stubbs et al. 2006; Murthy et al. 2007; Jakobs et al. 2008; Cianni et al. 2009; Martin et al. 2012; Nace et al. 2011; Hong et al. 2009; Stuart et al. 2008; Mancini et al. 2006). No prior systematic review or meta-analysis on this topic was identified. A quality assessment of each study was performed, and the data are summarized in Table 1.

Assessment of patient characteristics

Table 2 summarizes the patient demographics and tumour characteristics of each included study. The median value of the reported average age was 62 years ranging from 58 to 64. The median value of the percentage of male patients was 72.5 % ranging from 48 to 90 %. The majority of patients had bilobar disease (median 83 %; range 67–95 %). Most patients had <25 % replacement of the liver by tumour (median 60 %; range 33–81 %). extra-hepatic metastases were present in a median of 33 % of patients (range 0–58 %). The median number of previous lines of chemotherapy was 3 (range 2–5.1). A median of 20 % of patients had undergone previous liver resection (range 0–92 %). The median value of the mean radioactivity deliv-ered was 1.80 Gigabecquerels (range 1.70–2.37). Post-procedure chemotherapy was delivered to 70 % of patients (range 28–100).

Assessment of outcomes

Table 3 summarizes the effectiveness of yttrium-90 radi-oembolization with respect to response, overall survival and progression-free survival outcomes. The average length of follow-up after Y90 radioembolization of CRCLM as reported in 10 studies was 10 months (range 4–26).

Fig. 1 Flowchart of publica-tion identification and quality appraisal

Studies identified through literature search

n = 379

Human and English studies n = 144

Non-human and Non-English excluded n = 159

Studies within publication years n = 135

Studies involving Y90 radioembolization of CRCLM

n = 28

Studies included for review n = 20

Studies outside years 1990 to 2009 excluded n = 11

Studies included following extraction from manual review of reference lists n = 2

Did not fulfil primary or secondary end points n = 3

More updated study from authors published n = 2

Discussed different aspects in management of same cohort n = 3

Case reports, review articles, editorials, series < 10 patients excluded n = 107

J Cancer Res Clin Oncol

1 3

Tabl

e 1

Res

ults

of

qual

ity a

sses

smen

t in

20 s

tudi

es w

ith m

ore

than

10

patie

nts

unde

rgoi

ng Y

90 r

adio

embo

lizat

ion

for

CR

CL

M

Ref

eren

ces

Num

ber

of

patie

nts

Loc

atio

n (c

ity,

coun

try)

Stud

y pe

riod

Lev

el o

f ev

iden

ceSt

udy

obje

ctiv

ese

xplic

it in

clus

ion

crite

ria

Patie

nt c

hara

c-te

rist

ics

Prin

cipa

l co

nfou

nder

sTa

rget

po

pula

tion

Stag

e of

di

seas

eO

bjec

tive

outc

omes

Len

gth

of

follo

w-u

pA

dditi

onal

pr

oced

ures

Mar

tin e

t al.

(201

2)24

Ohi

o, U

SA20

05–2

008

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

NR

Seid

enst

icke

r et

al.

(201

2)20

Mia

mi,

USA

2005

–200

8II

IY

esY

esY

esY

esY

esY

esY

esN

oY

es

Nac

e et

al.

(201

1)29

Pitts

burg

, USA

2002

–200

8II

IY

esY

esY

esY

esY

esY

esY

esN

oN

R

Chu

a et

al.

(201

1)14

0Sy

dney

, Aus

tral

ia20

06–2

009

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Hen

dlis

z et

al.

(201

0)21

Bru

ssel

s, B

elgi

um20

04–2

007

IY

esY

esY

esY

esY

esY

esY

esY

esY

es

Cos

imel

li et

al.

(201

0)50

Rom

e, I

taly

NR

IIY

esY

esY

esY

esY

esY

esY

esY

esY

es

Cia

nni e

t al.

(200

9)41

Lat

ina,

Ita

ly20

05–2

008

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

NR

van

Haz

el e

t al.

(200

9)25

Pert

h, A

ustr

alia

2001

–200

4II

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Mul

cahy

et a

l. (2

009)

72C

hica

go, U

SA20

03–2

007

IIY

esY

esY

esY

esY

esY

esY

esY

esN

R

Hon

g et

al.

(200

9)15

Bal

timor

e, U

SA20

01–2

006

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NR

Jako

bs e

t al.

(200

8)41

Mun

ich,

Ger

man

yII

IY

esY

esY

esY

esY

esY

esY

esY

esN

R

Stua

rt e

t al.

(200

8)13

Mis

sour

i, U

SA20

05–2

007

III

Yes

Yes

No

No

Yes

Yes

Yes

No

NR

Mur

thy

et a

l. (2

007)

10H

oust

on, U

SAN

RII

IY

esN

oY

esY

esY

esY

esY

esY

esY

es

Stub

bs e

t al.

(200

6)10

0w

ellin

gton

, New

Z

eala

nd19

97–2

003

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Ken

nedy

et a

l. (2

006)

208

Mis

siss

ippi

, USA

2002

–200

5II

IY

esY

esY

esY

esY

esY

esY

esN

oN

R

Man

cini

et a

l. (2

006)

35R

ome,

Ita

ly20

05–2

006

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NR

Lim

et a

l. (2

005)

30M

elbo

urne

, Aus

-tr

alia

2002

–200

4II

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NR

Lew

ando

wsk

i et a

l. (2

005)

27C

hica

go, U

SA20

01–2

003

IIY

esY

esY

esY

esY

esY

esY

esN

oY

es

Mur

thy

et a

l. (2

005)

12H

oust

on, U

SA20

02–2

003

III

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

NR

Gra

y et

al.

(200

1)35

Pert

h, A

ustr

alia

1991

–199

7I

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

J Cancer Res Clin Oncol

1 3

Tabl

e 2

Sum

mar

y of

pat

ient

cha

ract

eris

tics

in p

atie

nts

unde

rgoi

ng Y

90 r

adio

embo

lizat

ion

of C

RC

LM

Ref

eren

ces

Num

ber

of

pat

ient

sM

ale

(%)

Age

(m

ean)

Bilo

bar

dise

ase

(%)

Rep

lace

men

t by

tum

our

(%)

ext

ra-h

epat

ic

met

asta

ses

(%)

Num

ber o

f pr

evio

us li

nes

of

chem

othe

rapy

(m

ean)

Prev

ious

live

r-di

rect

ed th

erap

yM

ean

ac

tivity

(G

bq)

Post

-yttr

ium

ch

emot

hera

py

(%)

<25

%25

–50

%>

50 %

Hep

atic

re

sect

ion

(%)

Abl

atio

n

(%)

Oth

er (

%)

Mar

tin e

t al.

(201

2)24

6763

67N

RN

RN

R54

3 (m

edia

n)N

RN

RN

R1.

72N

R

Seid

enst

icke

r et

al.

(201

2)29

7662

NR

4555

048

3 (m

edia

n)N

RN

RN

R1.

7631

Nac

e et

al.

(201

1)51

6864

NR

NR

NR

NR

58N

R24

2210

(TA

e o

r TA

Ce

)1.

89N

R

Chu

a et

al.

(201

1)14

063

6490

5636

936

NR

276

NR

1.80

34

Hen

dlis

z et

al.

(2

010)

2148

62 (

med

ian)

NR

NR

NR

NR

0N

R0

NR

NR

1.79

100

Cos

imel

li et

al.

(201

0)50

7464

7040

600

NR

424

NR

NR

1.70

28

Cia

nni e

t al.

(200

9)41

7361

9561

1524

10N

RN

RN

RN

R1.

82N

R

van

Haz

el e

t al.

(200

9)25

7259

NR

Med

ian

20 %

NR

1.4

0N

RN

R1.

8N

R

Mul

cahy

et a

l.

(200

9)72

6561

8381

154

402.

3N

RN

RN

R2.

37N

R

Hon

g et

al.

(200

9)15

7364

NR

NR

NR

NR

33N

R20

20N

RN

RN

R

Jako

bs e

t al.

(200

8)41

7361

NR

6634

172.

854

205

1.90

NR

Stua

rt e

t al.

(200

8)13

NR

NR

NR

NR

NR

NR

38N

RN

RN

RN

RN

RN

R

Mur

thy

et a

l. (2

007)

1090

60N

RN

RN

RN

R30

5.1

2010

NR

30.1

(m

Ci)

70

Stub

bs e

t al.

(200

6)10

062

61N

R60

2119

25N

RN

RN

RN

RN

R80

(H

AC

)

Ken

nedy

et a

l.

(200

6)20

862

62N

RN

RN

RN

RN

RN

R9

436

(TA

e o

r TA

Ce

)1.

75N

R

Man

cini

et a

l. (2

006)

35N

RN

RN

R38

620

NR

NR

NR

NR

NR

1.70

NR

Lim

et a

l. (2

005)

3073

62N

RN

RN

RN

R23

2.2

NR

NR

NR

NR

70

Lew

ando

wsk

i et a

l. (2

005)

2756

6878

78N

RN

RN

R2

(med

ian)

NR

NR

NR

2.37

89

Mur

thy

et a

l. (2

005)

1283

5892

3325

42N

R4.

892

017

NR

NR

Gra

y et

al.

(200

1)35

7759

NR

6626

90

NR

0N

RN

R2.

1610

0

Med

ian

–72

.562

8360

269

333

2010

13.5

1.80

70

Ran

ge–

48–9

058

–64

67–9

533

–81

15–6

20–

420–

582–

5.1

0–92

0–22

5–36

1.70

–2.3

728

–100

J Cancer Res Clin Oncol

1 3

Tabl

e 3

Sum

mar

y of

res

pons

e an

d su

rviv

al o

utco

mes

of

patie

nts

with

CR

CL

M u

nder

goin

g Y

90 r

adio

embo

lizat

ion

Ref

eren

ces

Num

ber

of

patie

nts

Res

pons

e (R

eC

IST

)C

eA

red

uctio

n po

st-p

roce

dure

Med

ian

follo

w-u

p (m

onth

s)

Med

ian

time

to

intr

a-he

patic

pr

ogre

ssio

n

(mon

ths)

Prog

ress

ion-

fr

ee s

urvi

val

(mon

ths)

Ove

rall

surv

ival

CR

(%

)PR

(%

)SD

(%

)PD

(%

)%

Pat

ient

s w

ith

redu

ced

Ce

A%

Tum

our

redu

ctio

n (m

edia

n)

Med

ian

(mon

ths)

6 m

onth

s (%

)12

m

onth

s (%

)

24

mon

ths

(%)

36

mon

ths

(%)

60

mon

ths

(%)

Mar

tin e

t al.

(201

2)24

NR

NR

NR

NR

21N

RN

RN

R3.

98.

960

5026

NR

NR

Seid

enst

icke

r

et a

l. (2

012)

200

4117

38N

RN

RN

RN

R5.

58.

364

24N

RN

RN

R

Nac

e et

al.

(201

1)29

013

6423

41 %

had

>50

% r

educ

tion

in

Ce

AN

RN

RN

R10

.259

4420

14N

R

Chu

a et

al.

(201

1)14

01

3131

36N

RN

R9

NR

NR

9N

R44

2220

NR

Hen

dlis

z et

al.

(201

0)21

010

7610

NR

NR

256

4.5

8.7

NR

NR

NR

NR

NR

Cos

imel

li et

al.

(201

0)50

222

2444

NR

NR

11N

R3.

712

.685

5013

NR

NR

Cia

nni e

t al.

(200

9)41

541

3420

100

50N

R9

9.3

1290

440

00

van

Haz

el e

t al.

(200

9)25

048

3913

NR

82N

R9

6.0

12.2

NR

NR

NR

NR

NR

Mul

cahy

et a

l. (2

009)

720

4045

15N

RN

R26

15N

R14

.5N

RN

RN

RN

RN

R

Hon

g et

al.

(200

9)15

NR

NR

NR

NR

NR

NR

6N

RN

R32

.8N

RN

RN

RN

RN

R

Jako

bs e

t al.

(200

8)41

017

6110

5428

87

NR

10.5

6840

2114

NR

Stua

rt e

t al.

(200

8)13

NR

NR

NR

NR

NR

NR

NR

NR

3.4

12N

RN

RN

RN

RN

R

Mur

thy

et a

l. (2

007)

100

050

5060

NR

5N

RN

R36

NR

NR

NR

NR

NR

Stub

bs e

t al.

(200

6)10

01

7320

696

2111

NR

NR

1176

4818

114

Ken

nedy

et a

l. (2

006)

208

036

5510

50N

RN

RN

RN

R10

.5 (

R);

4.

5 (N

R)

70 (

R)

0 (N

R)

46 (

R)

0 (N

R)

00

0

Man

cini

et a

l. (2

006)

350

12.5

7512

.5N

RN

R4

NR

NR

NR

NR

NR

NR

NR

NR

Lim

et a

l. (2

005)

300

3327

40N

RN

R18

NR

5.3

NR

6637

NR

NR

NR

Lew

ando

wsk

i et a

l. (2

005)

27N

R29

NR

NR

NR

NR

NR

NR

NR

9.4

NR

NR

NR

NR

NR

Mur

thy

et a

l. (2

005)

120

042

3333

NR

NR

NR

NR

24.6

NR

NR

NR

NR

NR

Gra

y et

al.

(200

1)35

640

379

74N

RN

R16

NR

15.9

8672

3917

4

Med

ian

–0

3140

.517

.557

3910

94.

912

6844

20.5

142

Ran

ge–

0–6

0–73

17–7

66–

5021

–100

21–8

24–

266–

163.

4–9.

38.

3–36

59–9

024

–72

0–39

0–20

0–4

J Cancer Res Clin Oncol

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Radiological response data were reported in 16 studies; the average reported value of patients with complete response and partial response was 0 % (range 0–6 %) and 31 % (range 0–73 %), respectively. The median time to intra-hepatic progression was 9 months (range 6–16). Overall survival results were reported in 11 studies; median sur-vival was 12 months (range 8.3–3.6).

Assessment of acute and delayed toxicity

Table 4 presents a thorough overview of acute and delayed toxicity associated with Y90 radioembolization. The over-all acute toxicity rate ranged from 11 % to 100 % (median 40.5 %). Most cases of acute toxicity were mild (Grade I or II) (median 39 %; range 7–100 %) which resolved without intervention. The most common acute toxicities were fatigue (median 38.5 %; range 0–100 %), abdominal pain (median 16 %; range 0–48 %) and nausea/vomiting (median 19 %; range 5–56 %). Delayed toxicity was less prevalent (median 5 %; range 4–10 %).

Significant prognostic factors

A detailed evaluation of significant and non-significant prognostic factors for overall survival is presented in Table 5.

Discussion

Continuous refinements of existing chemotherapeutic regimens and the introduction of new systemic and bio-logical agents have significantly improved survival out-comes in patients with unresectable CRCLM undergoing first-line chemotherapy. Combined with 5-fluorouracil, irinotecan (FOLFIRI) and oxaliplatin (FOLFOX) have yielded objective response rates of 50–56 % and a median survival of 6.4–12.9 months in patients with metastatic, liver-dominant colorectal cancer (Saltz et al. 2000; Gold-berg et al. 2004; Hurwitz et al. 2004). Between 4 and 37 % of patients are downstaged such that they may undergo a potentially curative surgical procedure (Beppu et al. 2010; Adam et al. 2004). The addition of an epidermal growth factor inhibitor in patients with KRAS wild type tumours improves response rates and survival in the first-line set-ting (van Cutsem et al. 2011) and may increase the number of patients able to undergo liver resection (Folprecht et al. 2010) (ref). Single agent epidermal growth factor inhibi-tors also provide a survival benefit in patients who have failed chemotherapy (Karapetis et al. 2008). The addition of bevacizumab in the first-line (Bennouna et al. 2013) and second-line settings further improves survival (Bennouna et al. 2013). Most recently a phase III study of regorafenib

compared with best supportive care demonstrated a modest survival advantage (Grothey et al. 2013).

Studies have consistently suggested the therapeu-tic potential of radioembolization in heavily pre-treated patients with chemoresistant CRC liver metastases (van Hazel et al. 2009; Martin et al. 2012). The widespread adoption of this treatment, however, has been precluded by the small sample size of many published series and the lack of robust clinical data. we critically appraised 20 studies with 979 patients in order to ascertain the objective response rates and overall survival outcomes reported after Y90 radioembolization of chemorefractory CRCLM.

Our review confirmed that the majority of patients were heavily pretreated. Many patients underwent prior liver-directed therapy in the form of hepatic resection and/or ablation. Moreover, patients had failed a median of 3 (range 2–5.1) lines of chemotherapy prior to radioembolization. In this group of salvage patients, the natural history of disease portends a poor prognosis. Our study showed that Y90 radi-oembolization achieved an objective tumour response in a median of 31 % of patients and stable disease in 40.5 %. Median progression-free survival, whilst only assessed in 8 studies, was 4.9 months (range 3.4–9.3), whereas median overall survival was 12 months (range 8.3–36). Median 2-year survival was 20.5 % (range 0–39). Y90 radioem-bolization was also associated with a significant reduction in cancer embryonic antigen (CeA), a biological marker in cancer. Overall, a median of 57 % (range 21–100) of patients had reduced CeA on follow-up; the median CeA reduction was 39 % (range 21–82). These data, in the con-text of patient with advanced, chemorefractory disease is excellent.

In analysing the outcomes of individual studies on Y90 radioembolization for CRCLM, there is a need to refer to studies from high-volume centres. Kennedy et al. (2006) published the largest dedicated series on Y90 radioemboli-zation for chemorefractory CRCLM. A total of 208 patients underwent Y90 radioembolization between 2002 and 2005 across 7 institutions in the USA. The authors demonstrated a median survival of 10.5 months in patients who responded to treatment. Objective tumour response was 35.5 %; a fur-ther 55 % of patients had disease stabilization. These find-ings are consistent with those reported in the current study. Cosimelli et al. (2010) in a prospective, multi-centre phase II Italian trial evaluated the outcomes of 50 patients treated with resin-based microspheres. The majority of patients had failed ≥4 lines of chemotherapy (76 %) and had exten-sive replacement (25–50 %) of liver by tumour (60 %). In this group of salvage patients, median survival was 12.6 months with an objective tumour response observed in 24 % of patients. Stubbs et al. (2006) reported a 73 % objective response rate and 11 month median survival in 100 patients with unresectable, chemorefractory CRCLM.

J Cancer Res Clin Oncol

1 3

Tabl

e 4

Sum

mar

y of

acu

te a

nd d

elay

ed to

xici

ty in

pat

ient

s un

derg

oing

Y90

rad

ioem

boliz

atio

n of

CR

CL

M

Ref

eren

ces

Num

ber

of

patie

nts

Acu

te to

xici

ty (

<30

day

s)Se

veri

ty o

f ac

ute

toxi

city

Del

ayed

toxi

city

All

(%)

Fatig

ue

(%)

Abd

omin

al

pain

(%

)N

ause

a/vo

mit-

ing

(%)

Gas

triti

s (%

)O

ther

(%

)G

rade

1

or 2

(%

)G

rade

3

or 4

(%

)In

cide

nce

(%)

Type

(%

)

Mar

tin e

t al.

(201

2)24

NR

NR

NR

NR

8N

R8

0N

RN

R

Seid

enst

icke

r et

al.

(201

2)29

9369

48N

R10

NR

930

NR

NR

Nac

e et

al.

(201

1)51

NR

2216

120

NR

NR

NR

108:

LFT

dys

func

tion

2: B

iliar

y st

rict

ure

Chu

a et

al.

(201

1)14

026

NR

146

2N

RN

RN

R5

2: L

iver

dys

func

tion

3: I

nter

stin

al u

lcer

atio

n1:

Gal

l bla

dder

com

plic

atio

n

Hen

dlis

z et

al.

(201

0)21

100

3819

330

19 (

anor

exia

)95

5N

RN

R

Cos

imel

li et

al.

(201

0)50

38N

R16

NR

014

(fe

ver)

380

84:

Dea

th (

rena

l and

live

r fa

ilure

)4:

Gas

troi

ntes

tinal

ulc

erat

ion

Cia

nni e

t al.

(200

9)41

150

120

2 (c

hole

cyst

itis)

NR

NR

55:

Gas

triti

s

van

Haz

el e

t al.

(200

9)25

NR

NR

4456

4N

RN

RN

RN

RN

R

Mul

cahy

et a

l. (2

009)

72N

R61

2521

16

(fev

er)

NR

NR

NR

NR

Hon

g et

al.

(200

9)15

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Jako

bs e

t al.

(200

8)41

71N

R41

55

2 (c

hole

cyst

itis)

665

NR

NR

Stua

rt e

t al.

(200

8)13

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Mur

thy

et a

l. (2

007)

1010

010

0N

RN

RN

RN

R10

010

NR

NR

Stub

bs e

t al.

(200

6)10

011

NR

NR

NR

8N

R7

4N

RN

R

Ken

nedy

et a

l. (2

006)

208

NR

3913

176

29 (

liver

dy

sfun

ctio

n)N

RN

RN

RN

R

Man

cini

et a

l. (2

006)

3543

03

NR

011

(fe

ver)

6

( le

ucoc

ytos

is)

All

even

ts g

rade

2–3

NR

NR

Lim

et a

l. (2

005)

3023

NR

NR

1013

010

13N

RN

R

Lew

ando

wsk

i et a

l. (2

005)

27N

R48

NR

333

7 (a

scite

s)N

RN

R4

4: P

leur

al e

ffus

ion

Mur

thy

et a

l. (2

005)

12N

RN

R40

00

4033

NR

NR

Gra

y et

al.

(200

1)35

NR

NR

NR

31N

RN

RN

R66

NR

NR

Med

ian

–40

.538

.516

192

–39

55

–

Ran

ge–

11–1

000–

100

0–48

5–56

0–13

–7–

100

0–33

4–10

–

J Cancer Res Clin Oncol

1 3

whilst concerns have been raised about the reproducibility of these findings, the fact that the results of our systematic review are commensurate with those of large, published series also suggest that Y90 radioembolization is an effica-cious treatment in the salvage setting.

Identifying prognostic factors is imperative to optimize patient selection and improve outcomes. This review iden-tified that the presence of extra-hepatic disease, extensive pre-treatment chemotherapy (≥3 lines) and extensive liver disease (≥26 %) were the factors most likely to be associ-ated with a poor outcome. Limited extra-hepatic disease is not deemed a contraindication to treatment with Y90 radi-oembolization. Despite this, further research is required to establish which sites of extra-hepatic disease are most likely associated with a poor outcome and what burden of extra-hepatic disease can be accepted.

Y90 radioembolization has acceptable toxicity. Our review showed that studies reported a median acute mor-bidity rate of 40.5 %. The majority of post-procedure com-plications were transient which resolved without active

intervention. Fatigue, abdominal pain and nausea/vomit-ing were the most common complications. Gastric ulcer developed in a median of 2 % of patients. The incidence of delayed complications was low (median 5 %). One issue raised by the systematic review was the discrepancy in reporting of adverse events between studies. Several stud-ies documented that fatigue and abdominal pain were com-plications; others, however, did not. A consistent approach to the reporting of adverse outcomes is imperative to allow a standardized comparison of safety data.

Apart from systemic agents and Y90 radioemboliza-tion, other interventions have been evaluated as poten-tial treatment options for unresectable, chemorefractory CRCLM. Bland transarterial embolization has showed no improvement in survival compared with best support-ive care (Riemsma et al. 2012). The role of hepatic artery chemoinfusion has been investigated in at least 10 pro-spective randomized trials since 1987. These studies have shown improved response rates with chemoperfusion (42–62 % vs. 5–20 %) but only a few have showed an actual

Table 5 Clinicopathologic factors of patients undergoing Y90 radioembolization for CRCLM associated with poorer overall survival on univari-ate analysis

Association with poorer overall survival

Significant (positive association) Non-significant (no association)

Female gender Chua et al. (2011)1 study

Nace et al. (2011), Martin et al. (2012)2 studies

Number of previous chemotherapy lines Chua et al. (2011) (≥3), Mulcahy et al. (2009) (p = 0.05) (≥3)2 studies

Treatment response unfavourable Chua et al. (2011), Jakobs et al. (2008), Mulcahy et al. (2009)2 studies

Nace et al. (2011)1 study

extra-hepatic disease Chua et al. (2011), Stubbs et al. (2006), Nace et al. (2011)3 studies

Martin et al. (2012)1 study

Lymph node involvement Stubbs et al. (2006)1 study

extent of liver disease Chua et al. (2011) (≥26 %), Mulcahy et al. (2009) (≥26 %)2 studies

Stubbs et al. (2006) (>25 %)1 study

Decrease in CeA after treatment Jakobs et al. (2008)1 study

Nace et al. (2011)1 study

eCOG status Mulcahy et al. (2009) (0 vs. 1 vs. 2)1 study

Chua et al. (2011) (≥1)1 study

Rectal primary site Chua et al. (2011)1 study

Number of radioembolization treatments Chua et al. (2011) (≤1)1 study

Radioembolization without concomitant chemotherapy

Chua et al. (2011)1 study

Nace et al. (2011)1 study

Radioembolization without subsequent hepatic artery chemotherapy

Stubbs et al. (2006)1 study

CRC stage at diagnosis Mulcahy et al. (2009) (2/3 vs. 4)1 study

Karnofsky score ≤70 Stubbs et al. (2006)1 study

J Cancer Res Clin Oncol

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improvement in survival (Melichar 2012; Kemeny et al. 1987, 2006). Multiple phase II studies have shown con-sistently higher response rates with TACe but randomized studies are lacking, and the impact on survival is still unclear (Albert et al. 2011; vogl et al. 2007; Nishiofuku et al. 2013). Moreover, a recent Cochrane review concluded that there is minimal evidence to support TAe/TACe in the metastatic setting (Riemsma et al. 2012).

An emerging alternative to Y90 radioembolization is drug-eluding beads impregnated with irinotecan (DeBIRI). The unique properties of the beads allow for fixed dosing and the ability to release the chemotherapeutic agent in a sustained and controlled manner. This reduces systemic toxicity and theoretically improves tumour response. Ini-tial evaluations of DeBIRI have demonstrated that it has acceptable toxicity and has promising activity. Martin et al. (2011) and Fiorentini et al. (2012) reported a multi-institutional series of 55 patients who received DeBIRI after failing systemic chemotherapy between 2006 and 2008. Adverse events occurred in 28 % of patients with median grade of 2 (range 1–3) with no deaths at 30 days post-procedure. Response rates were 66 % at 6 months and 75 % at 12 months. Overall survival in these patients was 19 months. A small study that randomized patients to DeBIRI or FOLFIRI reported a progression-free and over-all survival advantage, along with quality of life gains, for the DeBIRI-treated patients (Fiorentini et al. 2012). A sig-nificant improvement in time to extra-hepatic progression was an unexplained finding. Further studies are required to determine the safety and efficacy of DeBIRI in the man-agement of unresectable, chemorefractory CRCLM.

This systematic review has several shortcomings. Firstly, the majority of included studies were observational studies. Secondly, there were significant differences between the included studies. Some employed resin-based microspheres whilst others used glass-based microspheres. The propor-tion of patients with extra-hepatic disease, poor perfor-mance status and other negative prognostic indicators var-ied between the studies. Moreover, the use of concomitant chemotherapy varied between the studies. These discrep-ancies may account in part for the variation in outcomes reported across the studies. Many studies were also limited by a small sample size. evaluation of objective outcomes, in particular morbidity, was complicated by variation in the methods used across different centres. Despite these limita-tions, our systematic review shows that Y90 radioemboliza-tion is a safe and effective treatment.

In conclusion, this systematic review demonstrates that Y90 radioembolization is a safe and effective treatment for unresectable, chemorefractory CRCLM. There exists a need, however, to conduct prospective, adequately powered studies to further evaluate this treatment modality. Further research is necessary to identify prognostic factors and to

adopt a consistent approach to the reporting of objective outcomes.

Conflict of interest The authors have no conflicts of interest to declare.

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