ORIGINAL ARTICLE – COLORECTAL CANCER
Neoadjuvant Radiotherapy for Rectal Cancer: Meta-analysisof Randomized Controlled Trials
Nuh N. Rahbari, MD1, Heike Elbers, MD1, Vasileios Askoxylakis, MD2, Edith Motschall3, Ulrich Bork, MD4,
Markus W. Buchler, MD1, Jurgen Weitz, MD4, and Moritz Koch, MD4
1Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany;2Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany; 3Institute of Medical Biometry and
Medical Informatics, University of Freiburg, Freiburg, Germany; 4Department of Gastrointestinal, Thoracic and Vascular
Surgery, University of Dresden, Dresden, Germany
ABSTRACT
Background. Although neoadjuvant radiotherapy may
improve local control of rectal cancer, its clinical value
requires further evaluation as a result of potential side
effects and advances in surgical technique. A meta-analysis
was performed to assess effectiveness and safety of neo-
adjuvant radiotherapy in the management of rectal cancer.
Methods. The following databases were searched: the
Cochrane Library, Biosis, Web of Science, Embase, ASCO
Abstracts and WHO International Clinical Trials Registry
Platform. Randomized controlled trials on the following
comparisons were included: (1) neoadjuvant therapy versus
surgery alone and (2) neoadjuvant chemoradiotherapy
versus neoadjuvant radiotherapy.
Results. We identified 17 and 5 relevant trials that enrol-
led 8,568 and 2,393 patients, respectively. Neoadjuvant
radiotherapy improved local control (hazard ratio 0.59;
95 % confidence interval 0.48–0.72) compared to surgery
alone even after total mesorectal excision, whereas its
benefit in overall survival just failed to reach statistical
significance (0.93; 0.85–1.00). However, it was associated
with increased perioperative mortality (1.48; 1.08–2.03), in
particular if a dose of 5 Gy per fraction was administered
(1.85; 1.23–2.78). Chemoradiotherapy improved local
control as opposed to radiotherapy (0.53; 0.39–0.72), with
no impact on perioperative outcome and long-term
survival.
Conclusions. Neoadjuvant radiotherapy improves local
control in patients with rectal cancer, particularly when
chemoradiotherapy is administered. The question if the use
of more effective chemotherapy protocols improves overall
survival warrants further investigation.
To date, several randomized controlled trials have evalu-
ated neoadjuvant radiotherapy in patients undergoing
resection for rectal cancer. These trials assessed the effec-
tiveness and safety of neoadjuvant radiotherapy per se as well
as in comparison to neoadjuvant chemoradiotherapy. Despite
the available evidence, several studies have demonstrated
marked variations in the treatment of rectal cancer patients,
even within different countries that might reflect uncertain-
ties of clinicians regarding the optimal treatment strategy.1–3
We critically reviewed the evidence for neoadjuvant
radiotherapy in patients with rectal cancer. Using a meta-
analytical approach to generate more precise effect esti-
mates, we evaluated effectiveness and safety of neoadjuvant
radiotherapy versus surgery alone and neoadjuvant radio-
therapy versus neoadjuvant chemoradiotherapy.
METHODS
Literature Search and Selection Criteria
The following databases were searched in October 2011
up to the latest issue available or to the date of searching:
Nuh N. Rahbari and Heike Elbers contributed equally to this work.
Electronic supplementary material The online version of thisarticle (doi:10.1245/s10434-013-3198-9) contains supplementarymaterial, which is available to authorized users.
� Society of Surgical Oncology 2013
First Received: 27 December 2012
N. N. Rahbari, MD
e-mail: [email protected]
Ann Surg Oncol
DOI 10.1245/s10434-013-3198-9
Medline, Medline In-Process and Other Non-Indexed
Citations (via OvidSP); Cochrane Library (via Wiley In-
terscience); Web of Science, Biosis Previews (via
Thomson Reuters); Embase and Embase Alert (via DIMDI,
Deutsches Institut fur Medizinische Dokumentation und
Information); Subset ‘‘Supplied by publisher’’ (via Pub-
Med), and ASCO Annual Meetings and ASCO
Gastrointestinal Cancers Symposium. For Medline, the
‘‘Cochrane Highly Sensitive Search Strategy for identify-
ing randomized trials—sensitivity- and precision-
maximizing version’’ was applied.4 In addition, ASCO
abstracts were searched, and reference lists of retrieved
relevant articles were screened for additional trials. No
language restrictions and time limits were applied. Detailed
search strategies for all databases used may be requested
from the authors. The search strategy and results of the
literature search are available upon request.
Two reviewers (N. N. R. and H. E.) independently
screened the search findings and obtained full articles in
case of potentially relevant references. Randomized con-
trolled trials that compared (1) neoadjuvant radiotherapy
followed by surgery to surgery alone and (2) neoadjuvant
chemoradiotherapy to neoadjuvant radiotherapy in the
initial management of operable rectal cancer were eligible
for inclusion. To be eligible for inclusion, studies had to
report comparable data on either short or long-term out-
comes after the examined treatments. In case of multiple
publications on the same study, the most recent information
was used.
Data Extraction and Risk of Bias Assessment
A set of a priori defined data from each study were
extracted independently by two reviewers (N. N. R. and
H. E.). To enable valid comparisons of trials using different
radiotherapy schedules, the biological effective dose
(BED) was calculated for the individual trials using the
following formula considering tissue repopulation during
treatment 5:
½BED ¼ nd ð1 þ d=a=bÞ � c=a=ðT � TkÞ�
where n is the number of fractions; d is the dose per
fraction (in Gy); a/b is the linear quadratic quotient, set at
10 Gy; c/a is the repair rate, set at 0.6 Gy; T the total
treatment time (in days); and Tk is the delay time (in days),
set at 7.
Risk of bias for all studies was assessed by the modified
risk of bias tool recommended by the Cochrane Collabo-
ration and included the following items: sequence
generation, allocation concealment, handling of incomplete
data, outcome assessment, selective outcome reporting and
other sources of bias.4
Statistical Analysis
This meta-analysis was conducted in accordance with
the recommendations made by the Cochrane Collaboration
as well as the PRISMA statement.6 Hazard ratio (HR) was
used as effect measure for time-to-event outcomes [overall
survival (OS), cancer-specific survival (CCS), disease-free
survival (DFS), recurrence-free survival (RFS), metastasis-
free survival (MFS), local recurrence-free survival
(LRFS)]. If the HR and associated variance was not
reported in the original trial publication, we calculated the
HR as described by Parmar et al.7,8 using a generic Excel
sheet and the statistical data provided by the authors (e.g.,
individual patient data, duration of follow-up, number of
events, p-values or survival plots). A HR value of [1
implied a worse prognosis in the neoadjuvant therapy arm
compared to the surgery-alone arm and in the neoadjuvant
chemoradiotherapy arm compared to the radiotherapy arm.
The pooled HR was calculated using the inverse-variance-
weighted average of the individual studies.9,10 Odds ratio
(OR) together with the 95 % confidence interval (CI) were
used as summary statistics for dichotomous data. Meta-
analyses were conducted using a random effects model.11
We assessed statistical heterogeneity with I2 statistics. This
method describes the proportion of total variation between
included studies that are attributable to differences between
studies rather than sampling error (chance). Statistical
heterogeneity between groups was considered relevant for
comparisons with I2 statistics of [50 %. Sensitivity anal-
yses were carried out to explore reasons for heterogeneity.
Furthermore, we performed a priori subgroup analyses. We
used funnel plot analyses to evaluate publication bias.12 All
analyses were performed by Review Manager version 5.0
software (Nordic Cochrane Centre, Copenhagen; Cochrane
Collaboration, 2008).
RESULTS
Figure 1 summarizes the selection of studies.
Neoadjuvant Therapy Versus Surgery Alone
The literature search revealed a total of 20 potentially
relevant randomized controlled trials. One trial compared
neoadjuvant chemoradiotherapy to surgery alone.13 In
total, 17 trials with a cumulative sample size of 8,568
patients (median 351 patients; range 31–1,805 patients)
were included.14–30 Table 1 summarizes the baseline
characteristics of the identified studies. The clinicopatho-
logic data of the study populations and the results of the
identified studies are summarized in Table 2.
N. N. Rahbari et al.
Meta-analyses demonstrated a significant association of
neoadjuvant therapy with perioperative mortality (HR 1.48;
95 % CI 1.08–2.03; p = 0.01; I2 = 32 %) and morbidity
(HR 1.25; 95 % CI 1.02–1.54; p = 0.03; I2 = 63 %).
Subgroup analyses revealed the increased risk of periop-
erative mortality (HR 1.85; 95 % CI 1.23–2.78; p = 0.003;
I2 = 37 %) and morbidity (HR 1.42; 95 % CI 1.23–1.64;
p \ 0.001; I2 = 15 %) of being associated with a high
dose per fraction (5 Gy) rather than the total dose of
radiation (Fig. 2). Despite the increase in perioperative
morbidity and mortality, there was no significant difference
in the incidence of anastomotic leakage (HR 0.96; 95 % CI
0.58–1.60; p = 0.87; I2 = 65 %). Because of patient
overlap between the Swedish Rectal Cancer Trial and the
Stockholm II Trial, sensitivity analyses were performed
excluding the Stockholm II data. These analyses confirmed
the adverse impact of neoadjuvant therapy on perioperative
mortality in the analyses of all studies (HR 1.45; 95 % CI
1.04–2.03; p = 0.03; I2 = 36 %) and those with dose per
fraction of 5 Gy (HR 1.83; 95 % 1.16–2.89; p = 0.009;
I2 = 46 %).
There was no significant impact of neoadjuvant therapy
on overall resectability, curative resection rates and
sphincter preservation (Table 3).
On meta-analysis, the benefit of neoadjuvant therapy for
OS failed to reach statistical significance in the analyses of
all patients (HR 0.93; 95 % CI 0.85–1.00; p = 0.06;
I2 = 35 %) and the subgroup that underwent a curative
resection (HR 0.88; 95 % CI 0.78–1.00; p = 0.05;
I2 = 42 %). However, meta-analyses on CSS favored
neoadjuvant therapy in the cohort of all patients (HR 0.80;
95 % CI 0.72–0.88; p \ 0.001; I2 = 14 %) as well as those
who underwent curative resection (HR 0.71; 95 % CI 0.62–
0.80; p \ 0.001; I2 = 0 %) with a low degree of hetero-
geneity. Neoadjuvant therapy had a favorable impact on
DFS (HR 0.85; 95 % CI 0.75–0.97; p = 0.02; I2 = 24 %)
and RFS (HR 0.74; 95 % CI 0.64–0.84; p \ 0.001;
I2 = 0 %) in meta-analyses including four and five studies,
respectively. As indicated in the analysis of LRFS, this
effect was primarily caused by improved local control (HR
0.59; 0.48–0.72; p \ 0.001; I2 = 66 %) (Fig. 3). Sensi-
tivity analyses revealed heterogeneity of being caused by
the MRC1 trial that did not show a benefit of neoadjuvant
radiation on LRFS. Removal of this study resolved heter-
ogeneity entirely (HR 0.55; 95 % CI 0.49–0.63; p \ 0.001;
I2 = 0 %). Subgroup analysis showed the advantage of
neoadjuvant therapy on LRFS also for the cohort of
patients with a curative resection (HR 0.50; 95 % CI 0.43–
0.59; p \ 0.001; I2 = 0 %). Moreover, further subgroup
analyses confirmed the beneficial effect of neoadjuvant
therapy on LRFS of being independent of the radiation
scheme, stage of disease, adherence to the total mesorectal
excision (TME) technique and study quality (Table 4).
Sensitivity analyses excluding the Stockholm II data to
control for patient overlap with the Swedish Rectal Cancer
Trial did not alter the results substantially (data not shown).
Neoadjuvant Chemoradiotherapy Versus Neoadjuvant
Radiotherapy
Five studies including 2,393 patients (median 312
patients; range 83–1,011 patients) were identified that
compared neoadjuvant chemoradiotherapy and radiother-
apy in patients undergoing surgical resection for rectal
cancer.31–35 For one study the short-term outcomes were
available only.35 The radiotherapy protocols in the neoad-
juvant chemoradiotherapy and radiotherapy arms were
similar in three of these studies.31,33,34 In two studies,
neoadjuvant short-term radiation was compared to che-
moradiotherapy.32,35 Grade III and IV acute toxicity was
significantly increased in patients who received neoadju-
vant chemoradiotherapy (OR 4.10; 95 % CI 1.68–10.00;
p = 0.002; I2 = 81 %). The analyses of perioperative
outcomes did, however, not indicate a significant differ-
ence between neoadjuvant chemoradiotherapy and
radiotherapy regarding perioperative mortality (OR 1.47;
95 % CI 0.83–2.61; p = 0.19; I2 = 0 %). Although peri-
operative morbidity was increased in the radiotherapy
group (OR 0.82; 95 % CI 0.67–1.00; p = 0.05; I2 = 0 %),
there was no difference regarding the risk of anastomotic
Articles screened (n = 2324)
Articles assessed fordetailed information (n = 308)
Potentially relevant randomizedcontrolled trials (n = 25)
Included randomized controlled trials (n = 22)Neoadjuvant therapy vs. suergery alone (n = 17)Neoadjuvant radiotherapy vs. neoadjuvant chemoradiationtherapy (n = 5)
Reasons for exclusion
Not meeting inclusion criteria (n = 1278)Abstract or response/comment (n = 315)Review article (n = 423)
Reasons for exclusion
Study design (n = 185)Redundancy (n = 98)
Reasons for exclusion
Language (n = 1)Design (n = 1)Outcome reporting (n = 1)
FIG. 1 Study flow
Neoadjuvant Radiotherapy for Rectal Cancer
TA
BL
E1
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N. N. Rahbari et al.
TA
BL
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con
tin
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Tri
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Ris
k
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Ran
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miz
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RT
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1–
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bef
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Po
ster
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(3/4
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Yes
81
Lo
w
Bo
uli
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assi
fet
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G)3
41
97
2–
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CR
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d)
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rst
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6h
bef
ore
RT
;R
T:
34
.5G
y,
15
frac
tio
ns,
18
d;
surg
ery
wit
hin
2w
eek
afte
rR
T
CR
T:
1.8
;
RT
:1
.8
CR
T:
34
.1;
RT
:3
4.1
NR
(2fi
eld
s)N
o6
2.4
Hig
h
Bo
sset
etal
.(E
OR
TC
22
92
1)3
11
99
3–
20
03
CR
T:
45
Gy
,2
5fr
acti
on
s,3
5d
5-F
U
(35
0m
g/m
2;/
d),
LV
(20
mg
/m2/d
)
wit
hin
20
min
infi
rst
and
fift
hw
eek
of
RT
;R
T:
45
Gy
,2
5fr
acti
on
s,3
5d
ays;
inb
oth
arm
ssu
rger
y3
–1
0w
eek
afte
r
Tx
CR
T:
1.8
;
RT
:1
.8
CR
T:
36
.3;
RT
:3
6.3
5cm
abo
ve
and
5cm
bel
ow
the
tum
or,
per
irec
tal
LN
bel
ow
S2
/3(3
/4fi
eld
s)
No
64
.8L
ow
Lat
kau
skas
etal
.35
20
07
–2
01
0C
RT
:5
0G
y,
25
frac
tio
ns,
35
d5
-FU
(40
0m
g/m
2;/
d),
LV
(20
mg
/m2/d
)
du
rin
gfi
rst
and
last
wee
ko
fR
T;
RT
:
25
Gy
,5
frac
tio
ns,
35
day
s;in
bo
th
arm
ssu
rger
y6
wee
kaf
ter
Tx
CR
T:
1.8
—2
;
RT
:5
CR
T:
43
.2;
RT
:3
7.5
NR
NR
–a
Hig
h
TM
Eto
tal
mes
ore
ctal
exci
sio
n,
BE
Db
iolo
gic
alef
fect
ive
do
se,
LN
lym
ph
no
de,
RT
rad
ioth
erap
y,
CR
Tch
emo
rad
ioth
erap
y,
Tx
ther
apy
,5-F
U5
-flu
oro
ura
cil,
LV
leu
cov
ori
n,
NR
no
tre
po
rted
aF
oll
ow
-up
on
go
ing
Neoadjuvant Radiotherapy for Rectal Cancer
TA
BL
E2
Pat
ien
tch
arac
teri
stic
san
dsu
mm
ary
of
resu
lts
of
iden
tifi
edra
nd
om
ized
con
tro
lled
tria
ls
Ch
arac
teri
stic
nA
ge,
yea
rsG
end
erS
tag
eo
fd
isea
se,
%R
esec
tio
nra
te,
%
M,
%F
,%
0I
IIII
IIV
MR
C1
14
S2
75
64
.56
33
70
25
.13
0.3
44
.60
92
SF
RT
?S
27
70
20
.83
3.6
45
.60
93
.1
MF
RT
?S
27
20
22
.44
1.8
35
.90
90
.8
MR
C2
15
S1
40
\8
06
93
10
73
45
90
98
RT
?S
13
96
83
20
16
54
30
08
9
SR
CT
16
S5
74
B7
90
26
.83
0.1
40
.10
97
.0
RT
?S
57
30
31
.63
43
0.9
09
6.7
Sto
ckh
olm
I17
S4
25
67
47
43
02
22
92
71
19
5
RT
?S
42
46
96
04
00
21
25
26
14
91
Sto
ckh
olm
II18
S2
85
66
61
.43
8.6
02
82
93
58
10
0
RT
?S
27
20
36
28
25
10
TM
ET
rial
19
S9
08
66
64
36
22
72
73
67
97
RT
?S
89
76
56
43
61
30
28
33
79
8
Dah
let
al.2
0S
14
56
85
7.9
42
.10
28
.33
5.2
17
.92
.19
0.3
RT
?S
15
56
65
8.1
41
.93
.93
1.6
34
.21
5.5
3.9
88
.4
NW
RC
T21
S1
41
89
.4
RT
?S
14
39
3.0
Rei
set
al.2
2S
34
58
.84
1.2
01
1.8
41
.24
70
10
0
RT
?S
34
50
50
08
.86
4.7
26
.40
10
0
Go
ldb
erg
etal
.23
S2
39
68
58
.24
1.8
02
5.9
28
.94
2.3
09
7.1
RT
?S
22
86
70
24
.13
0.3
40
.80
96
.5
Pet
erse
net
al.2
4S
46
67
01
35
2.2
28
.36
.51
00
RT
?S
47
65
01
74
6.8
27
.78
.51
00
VA
SA
GI2
5S
35
36
5.8
10
08
8.2
RT
?S
34
76
5.8
10
08
7
VA
SO
GII
26
S1
81
10
09
2.8
RT
?S
18
01
00
94
.4
GT
CC
Go
fth
eE
OR
TC
27
S2
21
62
M/F
=1
.30
8.1
44
.32
6.7
01
00
RT
?S
21
65
8M
/F=
1.8
08
.34
0.7
25
.50
10
0
Kli
ger
man
etal
.28
S1
60
12
.51
8.8
68
.80
93
.75
RT
?S
15
04
6.7
20
20
08
6.7
To
ron
toT
rial
29
S6
50
37
.02
4.6
24
.61
3.8
RT
?S
60
02
52
1.7
36
.61
6.7
Ille
ny
iet
al.3
0S
15
86
0.6
58
42
N. N. Rahbari et al.
TA
BL
E2
con
tin
ued
Ch
arac
teri
stic
nA
ge,
yea
rsG
end
erS
tag
eo
fd
isea
se,
%R
esec
tio
nra
te,
%
M,
%F
,%
0I
IIII
IIV
RT
?S
14
9
Po
sto
p.
CR
T1
13
63
37
00
33
67
01
00
Ran
do
miz
edco
ntr
oll
edtr
ials
of
neo
adju
van
tch
emo
rad
ioth
erap
yv
ersu
sn
eoad
juv
ant
rad
ioth
erap
y
Bu
jko
etal
.32
Pre
op
RT
15
56
06
53
59
4
Pre
op
CR
T1
57
59
66
34
94
FF
CD
92
03
33
Pre
op
RT
36
76
3M
/F=
1.9
89
8.1
Pre
op
CR
T3
75
64
M/F
=1
.95
95
.7
Bo
uli
s-W
assi
fet
al.
(GT
CC
G)3
4P
reo
pR
T1
21
2.5
23
.15
0.4
24
01
00
Pre
op
CR
T1
24
4.8
18
.54
63
0.6
01
00
Bo
sset
etal
.(E
OR
TC
22
92
1)3
1P
reo
pR
T5
05
63
72
.92
7.1
95
.6
Pre
op
CR
T5
06
62
73
.32
6.7
95
.6
Lat
kau
skas
etal
.35
Pre
op
RT
37
67
64
.93
5.1
Pre
op
CR
T4
66
37
1.8
28
.2
Ch
arac
teri
stic
Cu
rati
ve
rese
ctio
nra
te,
%S
ph
inct
erp
rese
rvat
ion
,%
5y
ear,
%
OS
CS
SD
FS
MF
SL
RF
S
MR
C1
14
S7
3.1
27
.63
8.0
46
.65
6.7
49
.85
6.8
SF
RT
?S
69
.72
24
1.7
49
.95
5.2
52
.55
5.4
MF
RT
?S
67
.62
14
0.0
46
.25
2.9
50
.55
2.9
MR
C2
15
S4
03
71
8.6
73
.67
7.1
47
.94
6.4
RT
?S
47
36
25
.96
1.2
69
.13
5.3
36
.0
SR
CT
16
S7
9.1
42
.34
86
21
4.0
27
.0
RT
?S
79
.24
0.0
58
72
19
.01
1.0
Sto
ckh
olm
I17
S8
23
64
8.9
39
.82
8.0
22
.8
RT
?S
78
36
50
.93
4.2
23
.61
0.8
Sto
ckh
olm
II18
S8
7.4
41
.34
4.6
38
.93
0.9
24
.6
RT
?S
84
.53
9.3
30
.92
9.0
12
.1
TM
ET
rial
19
S9
1.1
71
63
.57
2.4
28
.31
0.9
RT
?S
92
.17
16
4.2
75
.42
5.8
5.6
Dah
let
al.2
0S
88
.33
6.5
57
.52
0.6
20
.7
RT
?S
84
.53
4.8
56
.72
3.2
14
.8
NW
RC
T21
S5
3.2
30
.56
6.0
35
.53
2.6
RT
?S
47
.53
0.1
60
.84
2.7
11
.9
Rei
set
al.2
2S
64
.73
4.4
55
.93
2.3
47
.1
Neoadjuvant Radiotherapy for Rectal Cancer
TA
BL
E2
con
tin
ued
Ch
arac
teri
stic
Cu
rati
ve
rese
ctio
nra
te,
%S
ph
inct
erp
rese
rvat
ion
,%
5y
ear,
%
OS
CS
SD
FS
MF
SL
RF
S
RT
?S
52
.98
0.0
17
.61
4.7
14
.7
Go
ldb
erg
etal
.23
S5
6.1
57
.34
0.3
25
.32
4.3
RT
?S
64
.05
9.6
38
.81
6.8
Pet
erse
n24
S8
0.4
39
.12
8
RT
?S
85
.15
5.3
49
VA
SA
GI2
5S
78
.52
9.1
28
.95
96
3.0
40
.0
RT
?S
79
.52
7.6
35
.25
1a
47
.0a
29
.0
VA
SO
GII
26
S8
6.7
54
9.6
72
90
4p
erso
n-y
ears
of
recu
rren
ce-f
ree
exp
erie
nce
RT
?S
85
.05
50
.35
5b
GT
CC
Go
fth
eE
OR
TC
27
S7
9.2
18
.14
93
23
0.0
RT
?S
76
.81
1.1
51
.62
1.7
a1
5.0
a
Kli
ger
man
etal
.28
S2
55
0
RT
?S
46
.23
0.8
To
ron
toT
rial
29
S3
8.0
RT
?S
40
.0
Ille
ny
iet
al.3
0S
39
.2
RT
?S
33
.5
Po
sto
p.
CR
T9
97
2.5
85
74
24
6
Ran
do
miz
edco
ntr
oll
edtr
ials
of
neo
adju
van
tch
emo
rad
ioth
erap
yv
ersu
sn
eoad
juv
ant
rad
ioth
erap
y
Bu
jko
32
Pre
op
RT
86
.26
16
6.5
22
.65
8.4
31
.41
0.6
Pre
op
CR
T5
86
6.2
29
.35
5.6
34
.61
5.6
FF
CD
92
03
33
Pre
op
RT
93
.36
0.5
67
.91
9.3
16
.5
Pre
op
CR
T9
4.2
57
.16
7.4
24
.38
.1
Bo
uli
s-W
assi
fet
al.
(GT
CC
G)
34
Pre
op
RT
8.3
59
27
.33
0.0
85
.0
Pre
op
CR
T1
4.5
46
23
.4
Bo
sset
etal
.(E
OR
TC
22
92
1)3
1P
reo
pR
T5
0.5
64
.85
4.4
26
.7
Pre
op
CR
T5
2.8
65
.85
6.1
15
.4
Lat
kau
skas
etal
.35
Pre
op
RT
86
.58
4.8
Pre
op
CR
T9
1.3
75
.7
Ssu
rger
y,
RT
rad
ioth
erap
y,
OS
ov
eral
lsu
rviv
al,
CS
Sca
nce
r-sp
ecifi
csu
rviv
al,
DF
Sd
isea
se-f
ree
surv
ival
,M
FS
met
asta
sis-
free
surv
ival
,L
RF
Slo
cal
recu
rren
ce-f
ree
surv
ival
,T
ME
tota
l
mes
ore
ctal
exci
sio
na
Rel
ated
top
atie
nts
wit
hcu
rati
ve
rese
ctio
ns
on
lyb
Rel
ated
toal
ld
eath
s
N. N. Rahbari et al.
leakage (OR 1.07; 95 % CI 0.62–1.84; p = 0.81;
I2 = 0 %). Meta-analyses did, moreover, not indicate a
significant advantage of either neoadjuvant treatment
strategy with respect to overall resectability (OR 0.75;
95 % CI 0.48–1.16; p = 0.19; I2 = 0 %) and sphincter
preservation (OR 1.04 95 % CI 0.87–1.25; p = 0.65;
I2 = 7 %).
Data on OS and DFS were available for four studies.
Meta-analyses including the results of these studies
revealed no significant difference between neoadjuvant
chemoradiotherapy and radiotherapy with respect to OS
(HR 1.03; 95 % CI 0.89–1.19; p = 0.67; I2 = 0 %) and
DFS (HR 0.95; 0.84–1.07; p = 0.43; I2 = 0 %) The sim-
ilar OS and DFS were, moreover, confirmed in all
subgroups. Suitable data for the meta-analyses on LRFS
could be obtained for three studies. The pooled analysis
showed a strong advantage of neoadjuvant chemoradio-
therapy regarding LRFS (HR 0.53; 95 % CI 0.39–0.72;
p \ 0.001; I2 = 0 %). The more favorable LRFS after
neoadjuvant chemoradiotherapy was also observed in the
subgroup analyses including studies with adherence to the
TME technique (HR 0.55; 95 % CI 0.38–0.80; p = 0.002;
I2 = 0 %) and low risk of bias (HR 0.53; 95 % CI 0.39–
0.72; p \ 0.001; I2 = 0 %).
Funnel plot analyses did not indicate significant publi-
cation bias (Online Appendix 1).
DISCUSSION
In contrast to previous analyses our findings show a
significantly increased risk of perioperative mortality and
morbidity in patients who received neoadjuvant treat-
ment.36,37 Remarkably, the detrimental impact of
neoadjuvant therapy on perioperative outcome was driven
primarily by studies with a high dose per fraction (5 Gy)
and was not caused by a high cumulative dose of radio-
therapy. In patients undergoing rectal resection
anastomotic leakage presents the major perioperative
FIG. 2 Meta-analyses on perioperative mortality in studies compar-
ing neoadjuvant therapy to surgery alone. a Meta-analyses including
all studies with available data. b Subgroup analyses on studies with a
radiation dose per fraction C5 Gy. Sensitivity analyses excluding the
Stockholm II data (to control for patients overlap with the Swedish
Rectal Cancer Trial) confirmed the adverse impact of neoadjuvant
therapy on perioperative mortality in the analyses of all studies (HR
1.45; 95 % CI 1.04–2.03; p = 0.03; I2 = 36 %) and those with dose
per fraction [5 Gy (HR 1.83; 95 % 1.16–2.89; p = 0.009;
I2 = 46 %)
Neoadjuvant Radiotherapy for Rectal Cancer
TA
BL
E3
Met
a-an
alyse
sof
per
ioper
ativ
eoutc
om
es
Char
acte
rist
icV
aria
ble
Per
ioper
ativ
em
ort
alit
yP
erio
per
ativ
em
orb
idit
yA
nas
tom
oti
cle
akag
eO
ver
all
rese
ctab
ilit
yC
ura
tive
rese
ctab
ilit
yS
phin
cter
pre
serv
atio
n
Ran
dom
ized
contr
oll
edtr
ials
of
neo
adju
van
tth
erap
yver
sus
no
neo
adju
van
tth
erap
y
All
pat
ients
–1.4
8(1
.08,
2.0
3);
p=
0.0
1;
n=
15
1.2
5(1
.02,
1.5
4);
p=
0.0
3;
n=
7
0.9
6(0
.58,
1.6
0);
p=
0.8
7;
n=
9
1.0
1(0
.81,
1.2
5);
p=
0.9
5;
n=
12
0.9
9(0
.89,
1.1
1);
p=
0.9
2;
n=
13
0.9
1(0
.82,
1.0
1);
p=
0.0
7;
n=
13
BE
D\
35.2
Gy
1.4
3(1
.03,
1.9
9);
p=
0.0
4;
n=
7
0.9
0(0
.70,
1.1
4);
p=
0.3
8;
n=
3
0.7
0(0
.24,
2.0
2);
p=
0.5
1;
n=
4
0.9
7(0
.74,
1.2
6);
p=
0.8
0;
n=
7
0.9
9(0
.83,
1.1
9);
p=
0.9
2;
n=
7
0.9
9(0
.73,
1.3
4);
p=
0.9
6;
n=
4
C35.2
Gy
1.5
1(0
.88,
2.5
8);
p=
0.1
3;
n=
8
1.4
3(1
.23,
1.6
6);
p\
0.0
01;
n=
4
1.1
5(0
.64,
2.1
0);
p=
0.6
4;
n=
5
1.0
7(0
.66,
1.7
2);
p=
0.7
9;
n=
5
0.9
9(0
.85,
1.1
6);
p=
0.9
4;
n=
6
0.9
0(0
.80,
1.0
1);
p=
0.0
6;
n=
9
Tota
ldose
B25
Gy
1.7
0(1
.21,
2.4
0);
p=
0.0
02;
n=
9
1.3
5(1
.14,
1.6
0);
p\
0.0
01;
n=
6
0.9
0(0
.50,
1.6
3);
p=
0.7
2;
n=
7
1.1
1(0
.86,
1.4
5);
p=
41;
n=
7
1.0
0(0
.88,
1.1
4);
p=
1.0
;
n=
9
0.9
5(0
.85,
1.0
6);
p=
0.3
3;
n=
7
[25
Gy
0.8
6(0
.46,
1.6
0);
p=
0.6
3;
n=
6
–1.2
3(0
.48,
3.1
5);
p=
0.6
7;
n=
2
0.7
9(0
.53,
1.1
8);
p=
0.2
5;
n=
5
0.9
7(0
.75,
1.2
6);
p=
0.8
2;
n=
4
0.7
8(0
.62,
0.9
8);
p=
0.0
4;
n=
6
No.
of
frac
tions
B5
1.8
2(1
.25,
2.6
6);
p=
0.0
02;
n=
9
1.4
2(1
.23,
1.6
4);
p\
0.0
01;
n=
5
0.9
0(0
.50,
1.6
3);
p=
0.7
2;
n=
7
1.2
2(0
.89,
1.6
7);
p=
0.2
3;
n=
7
0.9
9(0
.86,
1.1
4);
p=
0.8
9;
n=
8
0.9
5(0
.84,
1.0
7);
p=
0.3
7;
n=
7
[5
0.9
5(0
.62,
1.4
4);
p=
0.8
0;
n=
7
0.8
9(0
.65,
1.2
0);
p=
0.4
40.7
9(0
.32,
1.9
4);
p=
0.6
1;
n=
3
0.8
5(0
.65,
1.1
1);
p=
0.2
4;
n=
6
0.9
4(0
.78,
1.1
3);
p=
0.5
;
n=
6
0.8
0(0
.67,
0.9
5);
p=
0.0
1;
n=
7
Dose
per
frac
tion
\5
Gy
1.0
0(0
.70,
1.4
3);
p=
0.9
8;
n=
8
0.8
9(0
.65,
1.2
0);
p=
0.4
4;
n=
2
0.6
8(0
.34,
1.3
7);
p=
0.2
8;
n=
4
0.9
3(0
.69,
1.2
4);
p=
0.6
1;
n=
6
0.9
5(0
.79,
1.1
4);
p=
0.5
7;
n=
7
0.8
4(0
.68,
1.0
3);
p=
0.0
9;
n=
7
5G
y1.8
5(1
.23,
2.7
8);
p=
0.0
03;
n=
8
1.4
2(1
.23,
1.6
4);
p\
0.0
01;
n=
5
0.9
6(0
.51,
1.8
1);
p=
0.9
1;
n=
6
1.2
3(0
.90,
1.6
9);
p=
0.2
0;
n=
6
0.9
8(0
.85,
1.1
4);
p=
0.8
2;
n=
7
0.9
3(0
.83,
1.0
5);
p=
0.2
6;
n=
6
Onse
tof
study
\1980
1.2
7(0
.90,
1.8
0);
p=
0.1
8;
n=
8
0.9
0(0
.70,
1.1
4);
p=
0.3
8;
n=
3
0.6
1(0
.06,
6.5
2);
p=
0.6
8;
n=
2
0.9
2(0
.69,
1.2
3);
p=
0.5
7;
n=
6
0.9
0(0
.74,
1.1
0);
p=
0.3
2;
n=
5
0.8
0(0
.66,
0.9
5);
p=
0.0
1;
n=
7
C1980
1.7
0(0
.99,
2.9
0);
p=
0.0
5;
n=
7
1.4
3(1
.23,
1.6
6);
p\
0.0
01;
n=
4
1.1
0(0
.69,
1.7
5);
p=
0.6
9;
n=
7
1.1
0(0
.76,
1.6
0);
p=
0.5
8;
n=
6
1.0
4(0
.90,
1.2
1);
p=
0.5
9;
n=
8
0.9
7(0
.86,
1.0
9);
p=
0.6
1;
n=
6
TM
EY
es1.2
1(0
.71,
2.0
6);
p=
0.7
1;
n=
2
–0.7
2(0
.43,
1.2
2);
p=
0.2
;
n=
2
1.6
8(0
.83,
3.3
9);
p=
0.1
5;
n=
2
1.1
6(0
.84,
1.5
9);
p=
0.3
6;
n=
2
1.2
0(0
.62,
2.3
0);
p=
0.5
9;
n=
2
No
1.3
8(0
.94,
2.0
1);
p=
0.1
0;
n=
13
1.2
5(0
.95,
1.6
4);
p=
0.1
1;
n=
6
1.0
6(0
.56,
2.0
1);
p=
0.8
5;
n=
7
0.9
3(0
.74,
1.1
8);
p=
0.5
4;
n=
10
0.9
7(0
.86,
1.1
0);
p=
0.6
4;
n=
11
0.8
9(0
.79,
1.0
0);
p=
0.0
5;
n=
11
Ran
dom
ized
contr
oll
edtr
ials
of
neo
adju
van
tch
emora
dio
ther
apy
ver
sus
neo
adju
van
tra
dio
ther
apy
All
pat
ients
1.4
7(0
.83,
2.6
1);
p=
0.1
9;
n=
4
0.8
2(0
.67,
1.0
0);
p=
0.0
5;
n=
4
1.0
7(0
.62,
1.8
4);
p=
0.8
1;
n=
4
0.7
5(0
.48,
1.1
6);
p=
0.1
9;
n=
4
1.2
3(0
.77,
1.9
7);
p=
0.3
9;
n=
2
1.0
4(0
.87,
1.2
5);
p=
0.6
5;
n=
5
Stu
dy
des
ign
RT
regim
en
iden
tica
l
1.5
7(0
.87,
2.8
3);
p=
0.1
3;
n=
3
0.8
4(0
.63,
1.1
3);
p=
0.2
5;
n=
2
1.0
8(0
.51,
2.2
8);
p=
0.8
4;
n=
2
0.7
2(0
.38,
1.3
3);
p=
0.2
9;
n=
3
–1.0
7(0
.85,
1.3
5);
p=
0.5
8;
n=
3
RT
regim
en
dif
fere
nt
–0.6
8(0
.43,
1.0
9);
p=
0.2
5;
n=
2
1.0
6(0
.48,
2.3
4);
p=
0.8
9;
n=
2
––
1.0
4(0
.57,
1.9
2);
p=
0.9
;
n=
2
Onse
tof
study
B1993
1.5
7(0
.87,
2.8
3);
p=
0.1
3;
n=
3
0.8
4(0
.63,
1.1
3);
p=
0.2
5;
n=
2
1.0
8(0
.51,
2.2
8);
p=
0.8
4;
n=
2
0.9
7(0
.53,
1.7
5);
p=
0.9
1;
n=
2
–1.0
7(0
.85,
1.3
5);
p=
0.5
8;
n=
3
[1993
–0.6
8(0
.43,
1.0
9);
p=
0.1
1;
n=
2
1.0
6(0
.48,
2.3
4);
p=
0.8
9;
n=
2
0.5
4(0
.28,
1.0
5);
p=
0.0
7;
n=
2
–0.9
4(0
.74,
1.2
0);
p=
0.6
3;
n=
2
TM
EY
es0.8
8(0
.33,
2.3
1);
p=
0.7
9;
n=
2
0.7
2(0
.54,
0.9
7);
p=
0.0
3;
n=
2
0.9
4(0
.51,
1.7
3);
p=
0.8
4;
n=
2
0.5
4(0
.28,
1.0
5);
p=
0.0
7;
n=
2
–0.9
1(0
.72,
1.1
7);
p=
0.4
7;
n=
2
No
1.9
4(0
.95,
3.9
6);
p=
0.0
7;
n=
2
––
0.9
7(0
.53,
1.7
5);
p=
0.9
1;
n=
2
–1.2
4(0
.79,
1.9
5);
p=
0.3
4;
n=
2
Dat
aar
epre
sente
das
HR
(95
%C
I),
p-v
alue
and
num
ber
of
incl
uded
studie
s
Adas
hin
dic
ates
no
anal
yse
sfe
asib
ledue
tola
ckof
even
ts
BE
Dbio
logic
alef
fect
ive
dose
,R
Tra
dio
ther
apy,
CR
Tch
emora
dio
ther
apy,
TM
Eto
tal
mes
ore
ctal
exci
sion
N. N. Rahbari et al.
complication.38 However, its impact on long-term outcome
remains controversial.39,40 It is an interesting finding of this
study that perioperative mortality was increased in patients
with preoperative radiotherapy despite no difference in the
incidence of anastomotic leakage. These data should
prompt further effort to further investigate the reasons of
perioperative death.
The notion that the increased perioperative risk is pri-
marily caused by early studies with less advanced
perioperative care is rebutted by our subgroup analyses
showing no adverse impact of neoadjuvant therapy on
perioperative mortality (and morbidity) in studies with an
onset before 1980. Still, the toxicity results might be
influenced by treatment-related factors that are not inclu-
ded in the analysis. Target volume definition, radiation
field size, as well as the applied irradiation technique are
known to affect treatment toxicity. Previous analyses
revealed that the increased postoperative mortality and
higher incidence of late bowel obstruction reported in the
Stockholm I trial were associated with the large radiation
volume including paraaortic lymph node regions.41,42
However, analogous to surgical developments, major
advances in radiotherapy approaches have been achieved,
facilitating a more accurate target definition and precise
dose delivery. Therefore, actual trials using modern
radiotherapy strategies (e.g., intensity-modulated radio-
therapy) need to be evaluated in future trials.
One might argue that the increased perioperative risk of
neoadjuvant therapy may be justified by a strong prog-
nostic benefit. Indeed, the present meta-analyses revealed a
more favorable CSS and LRFS for patients receiving
neoadjuvant therapy. Current guidelines recommend neo-
adjuvant radiotherapy for patients with uT3/4 and/or node-
positive disease.43,44 However, it is still not completely
clear which patients benefit from preoperative treatment
and to what extent. In four studies stratified data on LRFS
were reported for patients’ stage of disease.16–19 Our
analyses showed a benefit of neoadjuvant therapy for
patients with stage I, II and III disease, though the effect
was more pronounced in patients with stage II and III
tumors. These data support current guidelines. The poten-
tial side effects of radiotherapy and the high proportion of
patients who might be cured by radical surgery alone still
do not justify neoadjuvant therapy in patients with stage I
disease.41,45,46 The value of neoadjuvant therapy in patients
with an adequate circumferential resection margin has been
particularly controversial. In accordance with previous
data, our subgroup analyses confirmed the favorable results
FIG. 3 Meta-analyses on a overall survival and b local recurrence-free survival in studies comparing neoadjuvant therapy to surgery alone
Neoadjuvant Radiotherapy for Rectal Cancer
TA
BL
E4
Met
a-an
alyse
sof
long-t
erm
outc
om
es
Char
acte
rist
icV
aria
ble
Over
all
surv
ival
Can
cer-
spec
ific
surv
ival
Dis
ease
-fre
esu
rviv
alM
etas
tasi
s-fr
eesu
rviv
alL
oca
lre
curr
ence
-fre
esu
rviv
al
Ran
dom
ized
contr
oll
edtr
ials
of
neo
adju
van
tth
erap
yver
sus
no
neo
adju
van
tth
erap
y
Cohort
All
pat
ients
0.9
3(0
.85,
1.0
0),
p=
0.0
6;
n=
12
0.8
0(0
.72,
0.8
8),
p\
0.0
01;
n=
70.8
5(0
.75,
0.9
7),
p=
0.0
2;
n=
40.9
1(0
.83,
1.0
0),
p=
0.0
5;
n=
80.5
9(0
.48,
0.7
2),
p\
0.0
01;
n=
10
Cura
tive
rese
ctio
n0.8
8(0
.78,
1.0
0),
p=
0.0
5;
n=
70.7
1(0
.62,
0.8
0),
p\
0.0
01;
n=
40.8
2(0
.68,
1.0
0),
p=
0.0
5;
n=
30.8
4(0
.73,
0.9
5),
p=
0.0
08;
n=
60.5
0(0
.43,
0.5
9),
p\
0.0
01;
n=
8
Sta
ge
of
dis
ease
UIC
CI
1.0
9(0
.87,
1.3
7),
p=
0.4
5;
n=
3–
0.8
7(0
.67,
1.1
5),
p=
0.3
3;
n=
21.0
5(0
.55,
1.9
9),
p=
0.8
9;
n=
20.4
2(0
.26,
0.6
8),
p\
0.0
01;
n=
4
UIC
CII
0.9
5(0
.75,
1.2
2),
p=
0.7
1;
n=
3–
–0.7
2(0
.47,
1.1
0),
p=
0.1
3;
n=
20.4
3(0
.31,
0.6
0),
p\
0.0
01;
n=
4
UIC
CII
I0.9
3(0
.71,
1.2
0),
p=
0.5
6;
n=
4–
–0.9
5(0
.74,
1.2
2),
p=
0.6
8;
n=
20.5
1(0
.41,
0.6
4),
p\
0.0
01;
n=
4
BE
D\
35.2
Gy
0.9
2(0
.79,
1.0
7),
p=
0.2
7;
n=
60.8
9(0
.72,
1.1
0),
p=
0.2
6;
n=
2–
1.0
0(0
.82,
1.2
2),
p=
0.9
9;
n=
20.6
0(0
.35,
1.0
4),
p=
0.0
7;
n=
4
C35.2
Gy
0.9
2(0
.83,
1.0
3),
p=
0.1
4;
n=
60.7
7(0
.69,
0.8
6),
p\
0.0
01;
n=
50.8
7(0
.75,
1.0
0),
p=
0.0
5;
n=
30.8
9(0
.80,
0.9
9),
p=
0.0
3;
n=
60.5
6(0
.49,
0.6
5),
p\
0.0
01;
n=
6
Tota
ldose
B25
Gy
0.9
3(0
.85,
1.0
3),
p=
0.1
5;
n=
90.8
1(0
.72,
0.9
0),
p\
0.0
01;
n=
60.9
0(0
.75,
1.0
7),
p=
0.2
2;
n=
20.9
3(0
.84,
1.0
3),
p=
0.1
6;
n=
60.5
7(0
.44,
0.7
4),
p\
0.0
01;
n=
8
[25
Gy
0.9
2(0
.81,
1.0
5),
p=
0.2
3;
n=
4–
0.7
5(0
.59,
0.9
4),
p=
0.0
1;
n=
20.7
8(0
.54,
1.1
2),
p=
0.1
8;
n=
20.6
6(0
.51,
0.8
6),
p=
0.0
02;
n=
2
No.
of
frac
tions
B5
0.9
3(0
.85,
1.0
3),
p=
0.1
5;
n=
90.8
1(0
.72,
0.9
0),
p\
0.0
01;
n=
60.9
0(0
.75,
1.0
7),
p=
0.2
2;
n=
20.9
3(0
.84,
1.0
3),
p=
0.1
6;
n=
60.5
7(0
.44,
0.7
4),
p\
0.0
01;
n=
8
[5
0.9
2(0
.81,
1.0
5),
p=
0.2
3;
n=
40.8
7(0
.60,
1.2
4),
p=
0.4
4;
n=
20.7
5(0
.59,
0.9
4),
p=
0.0
1;
n=
20.8
6(0
.68,
1.1
1),
p=
0.2
5;
n=
30.7
9(0
.57,
1.1
0),
p=
0.1
6;
n=
3
Dose
per
frac
tion
\5
0.8
8(0
.74,
1.0
5),
p=
0.1
5;
n=
50.8
7(0
.60,
1.2
4),
p=
0.4
4;
n=
20.7
5(0
.59,
0.9
4),
p=
0.0
1;
n=
20.8
6(0
.68,
1.1
1),
p=
0.2
5;
n=
30.7
4(0
.53,
1.0
4),
p=
0.0
8;
n=
4
50.9
5(0
.88,
1.0
3),
p=
0.2
3;
n=
80.8
1(0
.72,
0.9
0),
p\
0.0
01;
n=
60.9
0(0
.75,
1.0
7),
p=
0.2
2;
n=
20.9
3(0
.84,
1.0
3),
p=
0.1
6;
n=
60.5
8(0
.44,
0.7
6),
p\
0.0
01;
n=
7
Onse
tof
study
\1980
0.9
9(0
.85,
1.1
4),
p=
0.8
4;
n=
4–
–0.9
7(0
.79,
1.1
9),
p=
0.7
6;
n=
20.8
4(0
.53,
1.3
4),
p=
0.4
7;
n=
2
C1980
0.9
0(0
.81,
1.0
0),
p=
0.0
6;
n=
80.7
7(0
.69,
0.8
5),
p\
0.0
01;
n=
60.8
7(0
.75,
1.0
0),
p=
0.0
5;
n=
30.9
0(0
.81,
1.0
0),
p=
0.0
4;
n=
60.5
4(0
.47,
0.6
2),
p\
0.0
01;
n=
8
TM
EY
es0.7
7(0
.43,
1.3
8),
p=
0.3
8;
n=
2–
––
0.5
1(0
.37,
0.7
0),
p\
0.0
01;
n=
2
No
0.9
3(0
.86,
1.0
1),
p=
0.0
8;
n=
10
0.8
0(0
.71,
0.9
0),
p\
0.0
01;
n=
60.8
5(0
.69,
1.0
5),
p=
0.1
3;
n=
30.9
2(0
.82,
1.0
3),
p=
0.1
5;
n=
70.6
1(0
.48,
0.7
7),
p\
0.0
01;
n=
8
Ran
dom
ized
contr
oll
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ials
of
neo
adju
van
tch
emora
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ver
sus
neo
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van
tra
dio
ther
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All
pat
ients
–1.0
3(0
.89,
1.1
9),
p=
0.6
7;
n=
4–
0.9
5(0
.84,
1.0
7),
p=
0.4
3;
n=
4–
0.5
3(0
.39,
0.7
2),
p\
0.0
01;
n=
3
Stu
dy
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ign
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tica
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gim
en1.0
4(0
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6),
p=
0.6
8;
n=
3–
0.9
4(0
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1.0
7),
p=
0.3
5;
n=
2–
0.5
0(0
.36,
0.7
1),
p\
0.0
01;
n=
2
Dif
fere
nt
regim
en–
––
––
Onse
tof
study
B1993
1.0
4(0
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p=
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8;
n=
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4(0
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p=
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5;
n=
3–
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5(0
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0),
p=
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02;
n=
2
[1993
––
––
–
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es1.0
2(0
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p=
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5;
n=
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8(0
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8),
p=
0.8
6;
n=
2–
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5(0
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0.8
0),
p=
0.0
02;
n=
2
No
1.0
7(0
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1.3
9),
p=
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4;
n=
2–
0.9
3(0
.79,
1.0
9),
p=
0.3
7;
n=
2–
–
Dat
aar
epre
sente
das
HR
(95
%C
I),
p-v
alue
and
num
ber
of
incl
uded
studie
s
BE
Dbio
logic
alef
fect
ive
dose
,R
Tra
dio
ther
apy,
CR
Tch
emora
dio
ther
apy,
TM
Eto
tal
mes
ore
ctal
exci
sion
N. N. Rahbari et al.
of neoadjuvant radiotherapy in patients who received a
curative resection.47 Interestingly, neoadjuvant radiother-
apy was also associated with a benefit in OS in these
patients. Moreover, the analyses on patients with TME
further support the notion that neoadjuvant therapy
improves local control even after adequate surgical
resection.
In line with two recent Cochrane reviews our pooled
analyses demonstrated the advantage of chemoradiotherapy
for local control but failed to show a benefit in overall and
disease-free survival.48,49 However, in none of the trials
modern combination chemotherapy protocols were applied.
Despite the survival benefit of oxaliplatin and irinotecan in
combination with 5-fluorouracil/leucovorin in adjuvant
therapy of colon cancer, the results of recently published
studies on modern chemotherapy protocols in the neoad-
juvant setting of patients with primary rectal cancer are
controversial and not yet completed.50–54 On the basis of
the results of our analyses showing increased acute toxicity
with additional chemotherapy, a further adverse impact of
more effective combination therapy on toxicity must be
considered. However, the available data of standard 5-flu-
orouracil-based chemoradiotherapy did not indicate a
detrimental impact of chemoradiotherapy on perioperative
morbidity and mortality. Further controlled clinical trials
are required to identify agents that in combination with
radiotherapy improve systemic disease control in patients
with rectal cancer.
In conclusion, the present systematic review and meta-
analyses showed a favorable impact of neoadjuvant
radiotherapy on local recurrence in rectal cancer patients.
The increased perioperative mortality in patients with
short-course radiotherapy should prompt further strategies
to enhance the risk–benefit ratio. As neoadjuvant chemo-
radiotherapy improved LRFS compared to neoadjuvant
radiotherapy with no benefit in long-term survival the
results of further studies are required to evaluate, if more
active chemotherapy protocols or targeted therapy in the
neoadjuvant setting prolong survival after curative
resection.
DISCLOSURE The authors declare no conflict of interest.
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