Ann Surg Oncol
DOI 10.1245/s10434-014-3805-4
ORIGINAL ARTICLE – COLORECTAL CANCER
A Meta-Analysis to Determine the Effect of Primary Tumor
Resection for Stage IV Colorectal Cancer with Unresectable
Metastases on Patient Survival
Cillian Clancy, MB BCh, MRCSI1, John P. Burke, PhD MRCSI1, Mitchel Barry, MD, FRCSI3, Matthew F. Kalady,
MD FASCRS4, and J. Calvin Coffey, PhD FRCSI1,2
1
Department of Colorectal Surgery, University Hospital Limerick, Limerick, Ireland; 24i Centre for Interventions in
Infection, Inflammation and Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland;
3
Department of Surgery, Mater Misericordiae University Hospital, Dublin, Ireland; 4Department of Colorectal Surgery,
Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
ABSTRACT
Background. Approximately 20 % of patients diagnosed
with colorectal cancer will have distant metastases at first
presentation (stage IV disease). The effect of removing the
primary tumor on survival for patients with stage IV dis-
ease with unresectable metastases remains unclear. To
address this a meta-analysis of all studies comparing pri-
mary tumor resection with chemotherapy alone in cases of
stage IV colorectal cancer with unresectable metastases
was performed.
Methods. A comprehensive search for published studies
examining the effect of primary tumor resection in the
setting of colorectal cancer with unresectable metastases
was performed. Each study was reviewed and data
extracted. Random-effects methods were used to combine
data.
Results. There were 21 studies including a total of 44,226
patients that met the inclusion criteria. Resection of the
primary tumor in patients with unresectable metastases
compared with chemotherapy alone was associated with a
lower mortality risk (OR 0.28; 95 % CI 0.165–0.474;
P \ 0.001), translating into a difference in mean survival of
6.4 months in favor of resection (95 % CI 5.025–7.858,
This study was presented at the Association of Surgeons in Great
Britain and Ireland 2014.
Ó Society of Surgical Oncology 2014
First Received: 4 March 2014
C. Clancy, MB BCh, MRCSI
e-mail: clancyci@tcd.ie
P \ 0.001). Patients who underwent resection of the primary
tumor were more likely to have liver metastasis only (OR
1.551; 95 % CI 1.247–1.929; P \ 0.001), were less likely to
have C2 metastasis (OR 0.653; 95 % CI 0.508–0.839;
P = 0.001), and were less likely to have rectal cancer (OR
0.495; 95 % CI 0.390–0.629; P \ 0.001). There was sig-
nificant cross-study heterogeneity.
Conclusions. Resection of the primary tumor may confer
a survival advantage in stage IV colorectal cancer with
unresectable metastases but significant selection bias exists
in current studies. Randomized controlled trials are
essential to validate these findings.
Colorectal cancer is the fourth most common cause of
cancer-related mortality worldwide. Approximately
20–25 % of patients newly diagnosed with colorectal cancer
will have distant metastases at first presentation, termed
stage IV according to TNM criteria.1 In select cases surgical
resection of isolated metastases is possible. However, many
of these patients (75–90 %) have metastatic disease that is
not amenable to resection.2 Emergency presentation with
symptoms associated with the primary tumor such as
bleeding, obstruction, or perforation necessitates either
resection or palliative intervention. There are, however, a
large proportion of patients with stage IV colorectal cancer
who are asymptomatic. The potential morbidity and mor-
tality associated with surgery and the potential of developing
tumor-associated complications requiring emergency
resection must be considered. Elective resection of the pri-
mary tumor in this patient group remains controversial, and
survival benefit is unclear.

Metastatic colorectal cancer patients are a heteroge-
neous group, and many different management strategies are
available. Palliative surgery such as stoma formation and
bypass can be performed, but resection and chemotherapy
remain the mainstay of treatment where possible. In the
American Surveillance, Epidemiology, and End Results
database, 66 % of stage IV colorectal cancer patients
underwent resection of the primary tumor over a 12-year
period from 1988 to 2000.3 However, with continuous
improvement in the efficacy of chemotherapeutic regimens
there is an increasing trend toward nonoperative manage-
ment as this may spare significant surgery-related
morbidity. Some studies report the number of patients
undergoing chemotherapy without any surgical interven-
tion to be as high as 40 %.4,5 With the majority of
metastatic colorectal cancer patients undergoing resection
or chemotherapy alone, a clearer understanding of survival
benefit is required to achieve optimal outcomes. As there
are no randomized controlled trials, it is also important to
determine the patient demographics and tumor character-
istics of those undergoing resection compared with those
receiving only chemotherapy in order to adequately assess
differences in survival and preexisting selection bias in
currently available studies. To address this, a meta-analysis
of all studies comparing primary tumor resection with
chemotherapy alone in stage IV colorectal cancer was
performed.
MATERIALS AND METHODS
Literature Search and Study Selection
A systematic search of Pubmed and Embase was per-
formed for all studies published relating to stage IV
colorectal cancer with unresectable metastases and surgical
resection by using the following in the search algorithm:
(colon OR rectal OR colorectal) AND (cancer) AND (stage
IV OR metastatic) AND (surgery OR resection) AND
(primary). The Cochrane Central Register of Controlled
Trials was also searched for articles that investigated sur-
gical resection and stage IV colorectal cancer. The latest
search was performed on January 3, 2014. Two authors
(C.C. and J.P.B.) independently examined the title and
abstract of citations, and the full texts of potentially eligible
trials were obtained; disagreements were resolved by dis-
cussion. The reference lists of retrieved papers were further
screened for additional eligible publications. When data
were unclear or incomplete, the corresponding author was
contacted to clarify data extraction.
C. Clancy et al.
Eligibility Criteria
Studies including data on survival comparing resection
and chemotherapy in stage IV colorectal cancer with un-
resectable metastases were eligible for inclusion. The
primary end point of the study was the comparative median
survival of resection of the primary tumor and chemo-
therapy alone groups. The secondary end points included
patient demographics, tumor location, and metastatic bur-
den in patients undergoing resection of the primary tumor
compared with those receiving only chemotherapy. All
studies relating to nonstage IV colorectal cancer were
excluded. All studies with no comparative data for resec-
tion and chemotherapy were excluded. Studies that
included patients undergoing nonresection surgery or me-
tastectomy were excluded. There were no language
restrictions.
Data Extraction and Outcomes
The following information regarding each eligible trial
was recorded: author’s names, journal, year of publication,
study type, enrollment dates, median follow-up, patient
demographics, American Society of Anesthesiology (ASA)
grade, tumor location, number and location of metastases,
and total number of patients included. Timing and type of
chemotherapeutic regimens were recorded for each study
where available. In addition, the proportion of symptomatic
patients included in each study was recorded. From each
eligible study the overall survival in the number of patients
with stage IV colorectal cancer undergoing resection and
undergoing chemotherapy alone was recorded.
Statistical Analysis
All pooled outcome measures were determined using a
random-effects model as described by DerSimonian and
Laird, and the odds ratio (OR) was estimated with its
variance and 95 % confidence interval (95 % CI).6 The
random-effects analysis weighted the natural logarithm of
each study’s OR by the inverse of its variance plus an
estimate of the between-study variance in the presence of
between-study heterogeneity. As previously described,
heterogeneity between ORs for the same outcome between
different studies was assessed.7,8 This was through the use
of the I2 inconsistency test and Chi square-based Cochran’s
Q statistic test in which P \ 0.05 is taken to indicate the
presence of significant heterogeneity.9 Analyses were
conducted using Comprehensive Meta-analysis version 2
(Biostat Inc., Englewood, NJ).
TABLE 1 Characteristics of included trials
First author Year Study type Enrollment Total N of patients N, resection N, no resection Median survival Median survival,
interval resection (months) no resection (months)
15
Scoggins 1999 Retrospective review 1985–1997 89 66 23 14.5 16.6
Surgery in Stage IV Colorectal Cancer

16
Tebbutt 2003 Retrospective review 1990–2000 362 280 82 14 8.2
Ruo 5 2003 Retrospective review 1996–1999 422 127 103 16 9
17
Michel 2004 Retrospective review 1996–1999 77 31 23 21 14
18
Cummins 2004 Retrospective review 1989–2003 74 36 25 11.5 4.8
3
Cook 2005 Retrospective review 1988–2000 26,754 17657 9097 11 2
13
Benoist 2005 Retrospective review 1997–2002 59 32 27 22 23
14
Galizia 2008 Retrospective review 1995–2005 65 42 23 36 17
19
Kaufman 2008 Retrospective review 1998–2003 185 115 70 30 15
20
Chan 2010 Retrospective review 2000–2002 411 286 125 14 6
4
Aslam 2010 Retrospective review 1998–2007 647 366 281 14.5 5.8
10
Cellini 2010 Retrospective review 2002–2008 74 22 9 32 37
21
Seo 2010 Retrospective review 2001–2008 227 144 83 22 14
22
Karoui 2011 Retrospective review 1998–2007 208 85 123 30.7 21.9
23
Venderbosch 2011 Cohort study 2003–2004 399 258 141 16.7 11.4
2011 Cohort study 2005–2006 448 289 159 20.7 13.4
26
Kim 2012 Retrospective review 2000–2009 201 105 96 14 8
Verberne 11 2012 Retrospective review 2002–2006 88 26 21 26 17
Ferrand 27 2013 Cohort study 1997–2001 294 156 60 16.3 19.5
12
Boselli 2013 Retrospective review 2010–2011 48 17 31 4 5
28
Tsang 2014 Retrospective review 1996–2007 11,716 8,599 3,117 21 10
29
Ahmed 2014 Retrospective review 1992–2005 1,180 761 419 15.2 8.3
 C. Clancy et al.

Records identified through no resection, 79.8 versus 93.3 %; OR 0.280; 95 % CI

database searching 0.165–0.474; P \ 0.001), but significant heterogeneity
n = 9,404
Pubmed (4,861) existed (Fig. 2). Also, 20 studies describing 43,720 patients
Cochrane (11) included assessable data on stage IV colorectal cancer and
Embase (4,535)
mean survival times according to treatment.3–5,10,11,13–16,
18–29
Resection of the primary tumor was associated with
longer survival when compared with chemotherapy only
Records after duplicates
removed
(standard mean difference 6.441 months; 95 % CI
(n = 6,514) 5.025–7.858; P \ 0.001)
Articles excluded by title & abstract
(n = 6,471). Reasons:
-Management of metastases (1,259)
-Irrelevant (5,190) Metastatic Burden
-No comparative data (22)
Full-text articles
assessed for There were 7 studies with a total of 1749 patients that
eligibility included data on treatment type and patients with metastatic
(n = 43) Full text articles excluded (n =22) disease located only in the liver.5,11,22–27 Patients undergoing
Reasons:
-Resection vs Palliative Surgery (7) resection of the primary tumor were more likely to have
-Metastectomy included (3) metastatic disease confined to the liver (resection vs no
-Systematic Review (4)
Publications included in -No comparative data (8) resection, 60.5 versus 50.6 %; OR 1.551; 95 % CI
meta-analysis 1.247–1.929; P \ 0.001) (Fig. 3a). Also, 7 studies with a
(n = 21) total of 2132 patients included data on treatment type and the
n = 44,226 patients
number of metastases present.5,20,21,23–27 Patients undergo-
FIG. 1 PRISMA diagram. Preferred reporting items in systematic ing resection were less likely to have 2 or more metastases
reviews and meta-analyses (resection vs no resection, 37.1 versus 47.5 %; OR 0.653;
95 % CI 0.508–0.839; P = 0.001) (Fig. 3b).
RESULTS
Patient Characteristics
Eligible Studies
There were 6 studies describing a total of 27,915 patients
A total of 21 published studies containing data comparing that included data on treatment type and patient
resection of the primary tumor to chemotherapy alone were age.3,11,20,21,26,27 There was no association between age over
identified describing 22 patient cohorts (Table 1).3–5,10–29 The 65 and treatment type (resection vs no resection, 59.2 versus
initial search identified 6,514 articles. There were 43 full- 67.2 %; OR 0.846; 95 % CI 0.529–1.353; P = 0.48).
text studies assessed for eligibility, 22 of which were Also, 3 studies describing a total of 896 patients inclu-
excluded (Fig. 1). Some studies included symptomatic ded data on treatment type and ASA grade.4,12,26 There was
patients and those undergoing emergency surgery no association between ASA grade [ 2 and treatment type
(Table 2).4,10,17,18,20,26,29 Studies differed in chemotherapeu- (resection vs no resection, 18.6 versus 27.0 %; OR 0.868;
tic regimens and timing of treatment (Table 2). There were 4 95 % CI 0.223–3.384; P = 0.84).
studies that included only patients with hepatic metasta-
ses.10,12–14 All studies were published within the last 15 years,
and the spectrum of patients was reflective of modern clinical Tumor Location
practice. Overall, a total of 44,226 patients were included in
the final analysis; 66.7 % of patients underwent resection of There were 15 studies with a total of 42,079 patients that
the primary tumor, and 33.3 % received only chemotherapy. included data on treatment type and rectal tumors.3–5,13–16,20–28
Patients undergoing resection of the primary tumor were less
Survival likely to have rectal tumors (resection vs no resection, 12.7
versus 28.5 %; OR 0.495; 95 % CI 0.390–0.629; P \ 0.001).
A total of 19 studies describing 16,295 patients included Also, 13 studies describing a total of 41,185 patients included
assessable data on stage IV colorectal cancer and mortality data on treatment type and colon tumors.3–5,13–16,20–22,26–28
risk according to treatment with a mean patient follow-up of Patients undergoing resection of the primary tumor were more
31.6 ± 15.4 months.4,5,10–15,17–20, 22–29 Resection of the likely to have colon tumors (resection vs no resection, 85.2
primary tumor resulted in a lower mortality risk (resection vs versus 58.1 %; OR 1.728; 95 % CI 1.231–2.424; P = 0.002).
TABLE 2 Treatment regimens of included trials
First author Rectal Emergency Symptomatic No resection, chemotherapy type Resection, Resection, chemotherapy type
cancer surgery (%) resections (%) chemotherapy timing
(%)
15
Scoggins 28 0 0 NA NA NA
Surgery in Stage IV Colorectal Cancer

16
Tebbutt 36 NA NA 5-FU/raltitrexed ? capecitabine ? uracil tegafur Adjuvant 5-FU/raltitrexed ? capecitabine
5
Ruo 32 0 0 5-FU ± leucovorin NA NA
17
Michel 20 21.7 0 Oxaliplatin/irinotecan Adjuvant Oxaliplatin/irinotecan
18
Cummins 2.7 0 98.4 NA NA NA
3
Cook 15.6 NA NA NA NA NA
13
Benoist 22 0 0 5-FU ± leucovorin ± irinotecan Adjuvant 5-FU ± leucovorin ± irinotecan
14
Galizia 18.5 0 0 5-FU ± oxaliplatin/irinotecan Adjuvant 5-FU ± oxaliplatin/irinotecan
19
Kaufman 28 NA NA NA Neoadj/adjuvant/none NA
20
Chan 24 NA 47 5-FU ± irinotecan Adjuvant/none 5-FU ± irinotecan
4
Aslam 35 30.6 NA NA Adjuvant/none NA
10
Cellini 100 27 27 5-FU ? leucovorin oxaliplatin/irinotecan Neoadj ? adjuvant 5-FU ? leucovorin oxaliplatin/irinotecan
21
Seo 44 0 0 5-FU ± oxaliplatin/irinotecan Adjuvant 5-FU ± oxaliplatin/irinotecan
22
Karoui 0 NA NA 5-FU ? leucovorin oxaliplatin/irinotecan Adjuvant 5-FU ? leucovorin oxaliplatin/irinotecan
23
Venderbosch 26 NA NA Capecitabine ? irinotecan ? oxaliplatin Adjuvant Capecitabine ? irinotecan ? oxaliplatin
18.7 NA NA Capecitabine ? oxaliplatin ? becacizumab ± cetuximab Adjuvant Capecitabine ? oxaliplatin ? becacizumab ± cetuximab
26
Kim 39.8 0 93.7 NA Adjuvant/none NA
11
Verberne 100 1 7 NA Adjuvant NA
27
Ferrand 19.9 NA NA 5-FU ? leucovorin ± raltitrexed Adjuvant 5-FU ? leucovorin ± raltitrexed
12
Boselli 0 0 0 5-FU ? leucovorin ? oxaliplatin/ Adjuvant 5-FU ? leucovorin ? oxaliplatin/
irinotecan ± bevacizumab irinotecan ± bevacizumab
28
Tsang 19.6 NA NA NA NA NA
29
Ahmed 20.1 NA 39.5 5-FU ± oxaliplatin/irinotecan Adjuvant 5-FU ± oxaliplatin/irinotecan

neoadj neoadjuvant, 5-FU 5-fluorouracil

 C. Clancy et al.

FIG. 2 Meta-analysis of Study name Statistics for each study Odds ratio and 95% Cl
resection vs nonresection and Odds Lower Upper
overall survival. Each study is ratio limit limit Z-value p-value
shown by the point estimate of
the odds ratio (OR; square Scoggins C 1.012 0.339 3.020 0.021 0.983
proportional to the weight of Ruo L 0.038 0.005 0.286 -3.177 0.001
each study) and 95 % Tsang W 0.369 0.310 0.438 -11.288 0.000
confidence interval (95 % CI) Michel P 0.667 0.224 1.986 -0.728 0.467
for the OR (extending lines); the Cummins E 0.444 0.095 2.075 -1.032 0.302
combined ORs and 95 % CIs by Benoist P 1.000 0.352 2.845 0.000 1.000
random-effects calculations are Galizia G 0.375 0.114 1.237 -1.610 0.107
shown by diamonds. Resection Kaufman M 0.167 0.070 0.396 -4.058 0.000
vs nonresection and risk of Chan T 0.259 0.137 0.490 -4.155 0.000
mortality (n = 16,295; Aslam M 0.007 0.000 0.113 -3.493 0.000
P \ 0.001; test for Cellini C 1.000 0.205 4.870 -0.000 1.000
heterogeneity, Cochran Karoui M 0.645 0.361 1.153 -1.479 0.139
Q = 152.6 (df = 18); Venderbosch S1 0.094 0.017 0.524 -2.698 0.007
P \ 0.001; I2 Venderbosch S2 0.504 0.328 0.774 -3.131 0.002
(inconsistency) = 88.2 %) Kim S 1.000 0.398 2.516 -0.000 1.000
Verberne C 0.296 0.056 1.566 -1.433 0.152
Ferrand F 0.250 0.123 0.507 -3.848 0.000
Boselli C 1.000 0.275 3.636 0.000 1.000
Ahmed S 0.002 0.001 0.005 -12.443 0.000
0.280 0.165 0.474 -4.737 0.000
0.01 0.1 1 10 100
Resection No Resection

FIG. 3 a Resection vs A
nonresection and only liver Study name Statistics for each study Odds ratio and 95% Cl
metastasis (n = 1749;
P \ 0.001; test for Odds Lower Upper
heterogeneity, Cochran Q = 6.3 ratio limit limit Z-Value p-Value
(df = 6); P = 0.394;
Ruo L 1.841 1.088 3.117 2.273 0.023
I2 = 4.3 %). b Resection vs
nonresection and C 2 Karoui M 0.928 0.527 1.634 -0.260 0.795
metastasis (n = 2132; Venderbosch S1 2.309 1.288 4.142 2.808 0.005
P = 0.001; test for Venderbosch S2 1.379 0.917 2.075 1.545 0.122
heterogeneity, Cochran Q = 9.4 Kim S 1.818 1.027 3.220 2.050 0.040
(df = 6); P = 0.160;
Verberne C 2.078 0.640 6.744 1.217 0.223
I2 = 35.0 %)
Ferrand F 1.439 0.788 2.625 1.185 0.236
1.551 1.247 1.929 3.946 0.000
0.01 0.1 1 10 100
No Resection Resection
B
Study name Statistics for each study Odds ratio and 95% Cl
Odds Lower Upper
ratio ratio ratio Z-Value p-Value
Ruo L 0.527 0.307 0.903 -2.332 0.020
Seo G 0.563 0.326 0.971 -2.064 0.039
Chan T 0.337 0.136 0.834 -2.351 0.019
Venderbosch S1 0.642 0.421 0.978 -2.063 0.039
Venderbosch S2 0.629 0.422 0.936 -2.286 0.022
Kim S 1.329 0.760 2.324 0.996 0.319
Ferrand F 0.704 0.385 1.287 -1.140 0.254
0.653 0.508 0.839 -3.329 0.001
0.01 0.1 1 10 100
Resection No Resection
Surgery in Stage IV Colorectal Cancer
DISCUSSION
In this study, resection of the primary tumor in stage IV
colorectal cancer was associated with longer survival when
compared with chemotherapy only. There is a difference of
6.4 months in survival of patients undergoing resection.
Palliative chemotherapy alone compared with supportive
care has previously shown an increase in survival of
3.7 months.30 Further assessment according to treatment
type, however, reveals those undergoing resection have
lower metastatic burden that may significantly influence
survival. To date this is the largest meta-analysis of studies
comparing resection to chemotherapy alone in stage IV
disease.
Previous systematic reviews have questioned selection
bias in patients undergoing resection compared with those
receiving chemotherapy alone.2,31 In this study we have
identified some of the factors influencing the decision to
resect the primary tumor. Patients undergoing resection
were more likely to have metastatic disease confined to the
liver, single metastases, and tumors located in the colon.
As would be expected, those with multiple metastases in
locations other than the liver are more likely to receive
only chemotherapy. It is likely those with advanced rectal
tumors more commonly undergo palliative surgical pro-
cedures such as stoma formation rather than resection.
There was no association with surgery and age or ASA
grade, which suggests selection bias may be confined to
metastatic burden.
It is noteworthy that the 2 studies including data from
patients enrolled in arms of prospective, randomized con-
trolled trials both published in the last 3 years show a
difference in survival of 5–7 months associated with
resection compared with palliative chemotherapy
alone.11,27 Selection bias, however, cannot be disregarded
as the decision to resect the primary tumor was taken prior
to randomization. Ferrand et al. 27 showed primary tumor
resection to be associated with an overall survival benefit in
stage IV colorectal cancer when compared with patients
starting first-line, single-agent palliative chemotherapy
(16.3 vs 9.5 months). Chemotherapeutic agents used were
leucovorin, 5-fluorouracil, and raltitrexed. They reported
resection of the primary tumor to be an independent
prognostic factor compared with other well-established
factors. Unfortunately, no tumor-specific mutation data
(BRAF/KRAS) was available, which the authors suggested
may have explained the poor median survival in the che-
motherapy group.
Venderbosch et al. showed in their analysis of patients
enrolled in single arms of the CAIRO and CAIRO2 studies
that there was a survival difference associated with resec-
tion compared with nonresection with respective
differences of 16.7 versus 11.4 months and 20.7 versus
13.4 months.23–25 Chemotherapy agents in the CAIRO trial
included capecitabine, irinotecan, and oxaliplatin.24 The
CAIRO2 trial included both anti-angiogenic therapy bev-
acizumab and anti-EGFR therapy cetuximab in their
treatment regimens.25 Resection of the primary tumor was
again identified as a prognostic factor for overall survival.
A major limitation of this study is that the decision to
resect the primary tumor was made prior to study entry and
no reason for nonresection was provided. However, in a
multivariate analysis that included these variables, resec-
tion of the primary remained a significant prognostic factor.
Further studies such as the GRECCAR-8 randomized
multicenter trial exploring the impact on survival of pri-
mary tumor resection in rectal cancer with unresectable
metastasis are ongoing.
In a previous systematic review by Verhoef et al.31
studies that included symptomatic patients were clearly in
favor of resection. In asymptomatic patients overall sur-
vival is improved, but because of the nonrandomized,
single-center, retrospective nature of studies, patient
selection is called into question. A Cochrane review by
Cirocchi et al. 32 looking specifically at resection of the
primary tumor in asymptomatic patients also concluded
that although there was no significant survival difference
associated with resection, current literature was insufficient
to demonstrate this. Cirocchi et al. included 7 studies, all of
which are included in this current study. Several retro-
spective studies and 1 analysis of patients in a single-arm
of a randomized controlled trial have since been published
and are included in this current study.11,12 In addition,
several studies that did not assess survival in resection
versus chemotherapy alone as the primary endpoint, but
which had assessable data, were included in this
study.10,22,23
A recently published study by Harris et al.33 has shown a
survival benefit associated with primary tumor resection in
stage IV breast cancer. A similar effect seen in colorectal
cancer suggests an underlying molecular mechanism by
which removal of the primary tumor influences survival.
Chemotactic cytokines such as chemokines 5 and 25 are
produced by colorectal cancers and regulate tumor cell
metastasis.34,35 The removal of the primary tumor may
reduce the circulating concentration of such protumorigenic
mediators. This is only 1 of many mechanisms described in
the literature by which resection may provide a survival
benefit. The contrary argument is that surgery itself may
induce a permissive environment for tumor growth.36,37
Current literature does not give a clear conclusion as to
whether or not there is a survival difference associated with
resection as there are no large, prospective, randomized
controlled trials. There are several limitations to our study.
All studies included in this meta-analysis are retrospective
in nature. Significant heterogeneity is seen in the results as

study populations differ in the inclusion of rectal and
colonic primaries and site and extent of metastases. Che-
motherapeutic regimens vary widely as the enrollment
intervals of studies span a significant time period in which
advancements in individualized therapies have been made.
In addition, the timing of chemotherapy differed in some
studies, and in a minority of studies a proportion of the
patients undergoing resection surgery were not treated with
chemotherapy.
This study describes a large international dataset and
shows that while current literature suggests a survival
difference associated with primary tumor resection, there is
significant selection bias present. Patients undergoing
resection are more likely to have a lower metastatic burden
that may significantly influence survival. All studies are
retrospective in nature, and the decision to resect the pri-
mary tumor has never been subject to randomization in the
setting of stage IV colorectal cancer with unresectable
metastases. In all cases, the risk of surgical morbidity and
mortality must be balanced against any potential survival
advantage. Randomized controlled trials to determine the
optimal treatment for patients with stage IV colorectal
cancer are urgently required.
DISCLOSURE No funding or financial assistance was received by
the authors.
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