Drugs (2018) 78:789–798

https://doi.org/10.1007/s40265-018-0921-7

CURRENT OPINION

Colorectal Cancer: Why Does Side Matter?

Claire Gallois1 • Simon Pernot1 • Aziz Zaanan1 • Julien Taieb1

Published online: 22 May 2018

Ó Springer International Publishing AG, part of Springer Nature 2018

Abstract Colorectal cancer (CRC) is a heterogeneous
disease, and the search for clinical and molecular prog-
nostic and predictive factors is thus necessary to better
tailor each individual patient’s management. Primary
tumor location (PTL) seems to act as a master prognostic
factor pooling different clinical, pathological, and molec-
ular poor prognostic factors. In fact, right-sided (RS) CRC
patients are more frequently female and elderly with
microsatellite unstable, BRAF mutated, CpG island
methylator phenotype (CIMP)-high, poorly differentiated
tumors, compared to left-sided (LS) CRC patients. PTL
does not seem to clearly influence disease-free survival
(DFS) in localised colon cancer even though the opposite
prognostic value of RS tumors on DFS depending on RAS/
BRAF mutational status has been recently suggested in
these patients. In metastatic CRC (mCRC), the poor
prognosis associated with RS tumors is confirmed in the
most recent publications in the era of double and triple
chemotherapeutic regimens and targeted agents. Concern-
ing the predictive value of PTL, in patients with RAS wild-
type mCRC in the first-line setting, anti-epidermal growth
factor receptor (EGFR) therapy combined with
chemotherapy appears to be more effective than beva-
cizumab in LS CRC, while patients with RS CRC benefit
less from anti-EGFR therapy, and intensive chemotherapy
plus bevacizumab may be more appropriate but EGFR
antibodies remain an option if objective response is needed.
Due to the limitation of the current data (unplanned and
retrospective analyses), these conclusions must be inter-
preted with caution. Clinical trials in RS CRC may be of
interest to clarify what is the best treatment strategy in
these patients.
Key Points
Right-sided colorectal cancer is becoming
increasingly frequent, and has particular clinical and
biological characteristics with a poor prognosis.
Primary tumor location does not seem to clearly
influence disease recurrence in non-metastatic colon
cancer, while the bad prognosis associated with
right-sided tumors seems to be valid in the most
recent publications in metastatic colorectal cancer
patients.
In patients with RAS wild-type metastatic colorectal
cancer, anti-EGFR therapy appears to be more
effective than bevacizumab in the first-line setting in
left-sided colorectal cancer, whereas bevacizumab
seems to increase progression-free survival more
than EGFR antibody therapy in right-sided colorectal
cancer.

& Julien Taieb 1 Introduction

jtaieb75@gmail.com
1 Colorectal cancer (CRC) is the third most common cancer
Department of Gastroenterology and Digestive Oncology,
Assistance Publique-Hôpitaux De Paris, Hôpital Européen in the world [1]. Due to the heterogeneous nature of CRC,
Georges Pompidou, Paris Descartes University, Paris, France research on clinical and molecular prognostic and
790
predictive factors has dramatically increased over the last
decade [2, 3] and has been shown to sometimes improve
patient management [4, 5]. Primary tumor location (right
vs. left-sided tumors) as one of these clinical prognostic
factors has been described since 30 years ago [6].
The boundary between the right and left colon, defined
by the embryological origin, is the distal third of the
transverse colon, and therefore is difficult to use in retro-
spective assessments of clinical databases. That is why
most studies used the splenic flexure to differentiate
between right-sided (RS) tumors and left-sided (LS) tumors
[7–9] and others exclude transverse colon tumors [10].
RS CRC is less frequent than LS CRC, generally 40
versus 60%, respectively [11]. An analysis of the Surveil-
lance Epidemiology and End Results (SEER) database in
the USA has shown a decrease in the frequency of CRC,
but an increase in the incidence of RS CRC of about 25%
over 30 years, possibly due to an aging population and a
higher proportion of RS CRC in the elderly people [12]. On
the other hand, another SEER database analysis has shown
a significant increase in LS colon cancer and rectal cancer
among adults under 50 years of age [13], perhaps due to a
higher prevalence of obesity among young people [14, 15]
and an increase in the consumption of red and processed
meat [16].
Little used previously, primary tumor location has
become a main focus of attention over the last 2 years due
to its potential ability to guide our therapeutic choices, as
initially suggested by the FIRE-3 study [8].
We review here old and recent data concerning the
clinical–biological differences between RS and LS tumors
and the potential impact of the primary tumor location on
our therapeutic decisions in 2018. We present data from
major trials, and discuss the different expert opinions on
the management of these patients.
2 Clinical Differences Between Right-Sided (RS)
and Left-Sided (LS) Colorectal Cancer (CRC)
Right and left colons have different embryological origins,
originating from the midgut and the hindgut, respectively
[17], and different vascularisation. The rectum also origi-
nates in the hindgut.
Older age, female [18], high TNM at diagnosis [18, 19],
poor differentiation [18, 19], mucinous contingent, and
inflammatory reaction [10] are more common in RS
tumors. One possible reason for higher TNM stage at
diagnosis in RS CRC could be less specific symptomatol-
ogy in early-stage RS than LS CRC [20]. Moreover, sig-
moid tumor resections have greater radial margin clearance
than RS CRC because of the retroperitoneal attachments of
the right colon [21]. Peritoneal carcinomatosis is more
C. Gallois et al.
frequent in RS CRC, which may explain in part the worse
prognosis, while pulmonary and hepatic metastases sites
are more common in LS CRC [10, 18].
However, the distribution of these characteristics
between RS CRC and LS CRC is not so clear when the
colon is segmented into several parts. Indeed, a study by
Benedix et al. [22] showed that tumors of the cecum and
the splenic flexure have a greater proportion of stage III/IV
and lymphatic invasion, whereas tumors of the ascending
and descending colons have the lowest.
3 Molecular Differences Between RS and LS CRC
Right and left CRC carcinogenesis seems also to be dif-
ferent. RS CRCs are more frequently diploid, hypermu-
tated, microsatellite instability (MSI)-high, CpG island
methylator phenotype (CIMP)-high, and more often have
deleterious mutations of RAS, BRAF, and PI3KCa, and a
serrated signature [10, 23, 24], whereas LS CRCs more
often derive from the typical adenoma-carcinoma sequence
of carcinogenesis described by Fearon and Volgenstein
[25] with aneuploidy, chromosomal instability (in
approximately 75% of cases), leading to chromosomal
amplification of regions hosting receptor tyrosine kinases,
including human epidermal growth factor receptor 2
(HER2) and epidermal growth factor receptor (EGFR)
[17, 26–29]. Tumors of the left colon and rectum have a
similar pattern of molecular abnormalities [28]. The
hypermutant state more frequent in RS CRC is in part due
to a deficient DNA mismatch repair system but is also
observed in microsatellite stable (MSS) tumors. Further-
more, in LS CRC, the expression levels of epiregulin and
amphiregulin (ligands of EGFR) are higher [10, 30]. The
down-regulation of gene expression of the two EGFR
ligands EREG and AREG in RS CRC could be induced by
a CIMP-high phenotype [31, 32]. Interestingly, CIMP-
high, MSI, and BRAF mutation gradually increase from the
rectum to the ascending colon [17]. A recently published
study [33] even showed that on the same side, tumors could
have different molecular profiles depending on the seg-
ment. For example, a very high rate of RAS mutation in
tumors of the cecum (70%), a gradual increase in the
BRAF V600E mutation rate from cecum (10%) to the
hepatic flexure (22%), and a gradual increase of APC and
TP53 mutations from the right colon to the left colon were
shown. In this study, transverse colon tumors had muta-
tional profiles closer to those of the left colon. Figure 1
summarizes the main molecular alterations found in the
different primary tumor locations.
The classification of CRC by these different molecular
pathways is in fact much more complex, as shown by the
study of Guinney et al. [2], which classified CRC into four
Colorectal Cancer: Why Side Matters
Fig. 1 Molecular make up of
colorectal cancer. CRC
colorectal cancer, MSI
microsatellite instability, HER2
human epidermal growth factor
receptor 2
consensus molecular subtypes (CMSs) based on six pub-
lished gene expression-based CRC subtyping algorithms.
In RS CRC, the more common CMS is CMS 1 (with
hypermutation, MSI, and strong immune activation) in
31% of RS CRC versus 7% in LS CRC, whereas CMS 2
(epithelial, marked WNT, and MYC signalling activation)
is found in 56% of LS CRC versus 26% in RS CRC
[2, 34, 35].
In addition, microbiota can also contribute to the
molecular differences and behaviors of RS and LS CRC.
The richness of the microbiota increases from proximal
colon to rectum [36] and bacterial phylotypes are different
between the two sides [36, 37]. The production of short-
chain fatty acids by fermentation reactions known for their
immunomodulatory and anti-inflammatory properties is
higher in the proximal colon [38]. Furthermore, the con-
centration of several hydrolytic and reductive bacterial
enzymes involved in the production of mutagenic or
genotoxic metabolites is variable within the colon [39].
Indeed, bacterial toxins or mutagenic CYP450 metabolites
could contribute to the hypermutation status observed in
RS CRC [10].
4 Prognostic Value of Primary Tumor Location
The prognostic value of the primary tumor location aims to
objectively evaluate the patient’s overall outcome between
the two sides regardless of treatment, and cannot be
extrapolated to analyse treatment efficacy.
791
4.1 All-Stage CRC
Between 2008 and 2010, three large-scale studies (in-
cluding between 17,641 and 82,926 patients) [18, 19, 40]
have shown a decrease in survival for patients with RS
CRC, independent of tumor stage, and two recent meta-
analyses confirmed these results [41, 42].
4.2 Stage I–III Colon Cancer (CC)
Using SEER data, Schrag et al. [43] reported that among
stage III CRC (n = 25,887), RS tumors were associated
with shorter overall survival (OS) compared to LS or rectal
tumors, and this association was less consistent for stage I
and II CRC.
The retrospective studies of Karim et al. and Weiss et al.
[7, 44], including, respectively, 6365 and 53,801 patients
with stage I–III CC, have shown no statistical difference in
survival between patients with RS CC and LS CC. How-
ever in subgroup analyses, patients with RS tumors had
lower mortality in stage II [44], while they had a worse
prognosis in stage III, compared to patients with LS tumors
[7, 44]. This opposite prognostic effect according to the
tumor stage could be at least in part due to MSI status,
which is more frequently associated with RS CC and
known as a good prognostic factor in stage II CC [45, 46].
In line with this assumption, in the studies of Sinicrope
et al. and Missiaglia et al. [10, 23], including stage II–III
CC patients enrolled in 5-fluorouracil (5-FU)-based adju-
vant trials, patients with RS tumors had a better disease-
free survival (DFS), but this was no longer true when
patients with MSI tumors were excluded.
792
A recent publication derived from the PETACC-8 trial
[47] analyzed the prognostic effect of primary tumor
location in more than 1800 patients. This was the only
work that included exclusively stage III CC patients treated
with oxaliplatin-based adjuvant chemotherapy with an
extensive molecular analysis of the study population. In
this work and that of Missiaglia et al. [10] for patients with
stage III CC, survival after recurrence (SAR) was signifi-
cantly decreased in patients with RS CC, independent of
MSI status, BRAF and (K)RAS mutation status, leading to
a reduced OS. Conversely, tumor sidedness was not prog-
nostic for DFS in either study. However, in the study of
Taieb et al. [47], patients with RAS/BRAF wild-type
tumors showed better DFS for LS tumors, whereas patients
with RAS-mutated tumors had better DFS in RS tumors.
Interestingly, the retrospective study of Zhang et al. [48]
including 895 stage III CC patients treated with oxaliplatin-
based adjuvant chemotherapy, the more distal the tumor
was, based on segmenting the colon into seven parts, the
longer the survival was (for recurrence-free survival and
OS) in multivariate analysis, but without adjusting for
prognostic factors such as BRAF and RAS mutations or
MSI.
4.3 Stage IV CRC
Having so many bad prognostic factors in metastatic CRC
(mCRC), such as RAS and BRAF mutations, MSI-high and
CIMP-high status [49–53], RS tumors logically represent a
worse prognosis at this disease stage. Numerous retro-
spective studies from phase II–III trials in the first-line
setting have shown RS primary tumor location as a poor
prognostic factor (in terms of progression-free survival
(PFS) and OS) in anti-EGFR trials and thus RAS wild-type
patients [8, 9, 54, 55], but also in studies including both
RAS-mutated and RAS wild-type patients [56–58]. Finally,
two recently published meta-analyses [59, 60] have con-
firmed the poor OS associated with RS tumors in the era of
modern treatments combining double chemotherapies and
a targeted agent. BRAF mutation is obviously more com-
mon in RS tumors, but these tumors remain of poor
prognosis even after adjustment of BRAF status [9, 55, 56]
and in the RAS/BRAF wild-type subgroup [9].
It should be noted that in the metastatic setting, the
prognosis of rectal tumors seems close to that of the left
colon [33, 58]. By segmenting the colon–rectum into sev-
eral parts, the study of Loree et al. [33] showed that hepatic
flexure tumors had the worst prognosis while splenic
flexure and rectosigmoid tumors had the best prognosis in
multivariate analysis adjusted for BRAF and KRAS
mutations.
C. Gallois et al.
5 Predictive Value of Primary Tumor Location
for the Efficacy of Treatment in mCRC
Predictive value of primary tumor location for treatment
efficacy aims to objectively evaluate the likelihood of
benefit from a specific treatment in RS and LS tumors.
5.1 Chemotherapy
Few data are available on the evaluation of efficacy of
5-FU, irinotecan, and oxaliplatin according to primary
tumor location in mCRC. Oxaliplatin may be less effective
in RS tumors partly because of a higher expression of
excision repair cross-complementation group 1 (ERCC1)
[56]. Indeed, ERCC1 allows the repair of DNA adducts
induced by platinum compounds through the nucleotide
excision repair pathway [61]. Several studies have shown
the association between expression of ERCC1 and resis-
tance to oxaliplatin in CRC [62, 63]. However, in the
recent study of Shimamoto et al. [64] on 1129 CRC
chemotherapy-naive patients, the highest level of ERCC1
mRNA was in recto-sigmoid tumors, and in the subgroup
of patients with CC only, expression of ERCC1 was similar
between the two sides. 5-FU could be more effective in RS
CRC due to a higher expression of thymidine phosphory-
lase and a lower expression of gamma-glutamyl hydrolase
[64–66], possibly favored by the CIMP-high status in RS
CRC [65] and able to induce better sensitivity to 5-FU plus
leucovorin, because of the maintenance of folate in the
polyglutamate form in the cells [65].
Nevertheless, we cannot reach a conclusion on a
potential different chemosensitivity between RS CRC and
LS CRC based only on these data. Currently there are no
published data on the potential predictive value of primary
tumor location for irinotecan.
5.2 Targeted Therapies
5.2.1 In the First-Line Setting
Some retrospective studies from phase II and III thera-
peutic trials, including patients with mCRC in the first-line
setting, analyzed the efficacy of targeted therapies (anti-
EGFR and bevacizumab) according to the primary tumor
location.
First, some studies analyzed the efficacy of chemother-
apy with or without targeted therapy according to the pri-
mary tumor location. In the CRYSTAL (FOLFIRI plus
cetuximab versus FOLFIRI) [54, 55] and PRIME (FOL-
FOX plus panitumumab versus FOLFOX) trials [9, 54] in
RAS wild-type patients, LS primary tumor location was
associated with better OS in the anti-EGFR arm than the
Colorectal Cancer: Why Side Matters
chemotherapy-alone arm [hazard ratio (HR): 0.65,
p = 0.002 and adjusted HR 0.73, p = 0.0112, respectively].
On the other hand, in patients with RS tumors, the addition
of anti-EGFR to chemotherapy provided no statistical dif-
ference in OS and PFS in the two trials, but a numerically
better response rate was observed in the anti-EGFR arm
(42% for anti-EGFR vs. 35% for chemotherapy alone). In
the PRIME trial, all these results were found in multi-
variate analysis and confirmed after adjustment for BRAF
mutational status and also confirmed in RAS/BRAF wild-
type patients.
Several studies analyzed the predictive effect of tumor
side in patients treated with first-line chemotherapy with or
without bevacizumab [56, 58]. In a first study [58], which
was not derived from a therapeutic trial, in patients treated
with CAPEOX plus bevacizumab (667 patients), primary
recto-sigmoid tumor location was associated with a better
survival compared to RS tumors, whereas in patients
treated with CAPEOX alone (213 patients), the efficacy of
treatment was independent of primary tumor location. In an
analysis [56] of the phase III trials AVF2107 g
(FOLFIRI ± bevacizumab) and NO16966 (FOLFOX/
XELOX ± bevacizumab), the efficacy of bevacizumab
was globally independent of primary tumor sidedness.
However, in this pooled analysis, no statistics were per-
formed to assess the benefit of bevacizumab in RS and LS
CRC and only histograms derived from patient outcomes
were shown.
Studies have also compared the efficacy of anti-EGFR
and bevacizumab according to the primary tumor location.
In the analyses of the FIRE-3 (FOLFIRI plus bevacizumab
or cetuximab) [8, 54], PEAK (FOLFOX plus bevacizumab
or panitumumab) [54], and CALGB 80405 (FOLFIRI/
FOLFOX plus bevacizumab or cetuximab) [54, 67] trials in
patients with LS tumors, OS was significantly longer in the
anti-EGFR arm in the FIRE-3 and CALGB 80405 trials
(HR 0.63, p = 0.002 and HR 0.77, p = 0.05 respectively),
but only numerically longer in the anti-EGFR arm in
PEAK multivariate analysis, possibly due to the relatively
small number of patients enrolled in this phase II trial. The
test was adjusted for BRAF mutational status in this
analysis (adjusted HR 0.77, p = 0.31). The same trends
were seen for PFS without reaching statistical significance.
In contrast, in patients with RS tumors, OS and PFS were
numerically longer in the bevacizumab arm without
reaching statistical significance in the three trials except for
CALGB 80405, with a significantly higher PFS in patients
treated with bevacizumab (HR 1.64, p = 0.007). With
regard to objective response rate (ORR), the best results
were seen in patients treated with anti-EGFR therapy in the
three trials.
Finally, the pooled analysis by Arnold et al. [54]
included 2159 RAS wild-type patients from six trials
793
(CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK, and
20050181) and compared chemotherapy plus anti-EGFR
(experimental arm) versus chemotherapy alone or
chemotherapy plus bevacizumab (control arm). All these
trials investigated treatment in the first-line setting except
the 20050181 trial [68], which investigated FOLFIRI plus
or minus panitumumab in the second-line setting. The
pooled analysis showed that patients with LS tumors
obtained benefit from being treated with anti-EGFR plus
chemotherapy for OS (HR 0.75, p \ 0.001) and PFS (HR
0.78, p \ 0.001), whereas this effect was not found in
patients with RS tumors (HR 1.12, p = 0.38 and HR 1.12,
p = 0.36 for OS and PFS, respectively). There was a trend
for better ORR in the anti-EGFR arm for both sides, but
this effect was more pronounced and significant in patients
with LS tumors [odds ratio (OR): 2.12] compared to
patients with RS tumors (OR: 1.47). In the pooled analysis
of trials involving cetuximab, a significant predictive effect
of tumor sidedness was observed, with better outcomes for
the cetuximab arm in LS tumors and for the control arm in
RS tumors, whereas in the subset of trials involving pani-
tumumab, this predictive effect was not significant. It
should be noted that these pooled analyses were not
adjusted for BRAF mutational status, because of its
unavailability in three of the six trials. Figure 2 shows the
forest plots for predictive analyses of primary tumor
location in these six trials, from the Arnold et al. study
[54].
This difference of targeted therapy efficacy according to
tumor side could be explained by the more frequent acti-
vation of the EGFR pathway and the higher expression
levels of EGFR ligands in LS CRC, leading to a greater
sensitivity to anti-EGFR therapies [10, 30].
Interestingly, a recent Japanese analysis [69] of two
phase II trials of first-line cetuximab combination
chemotherapy showed interesting results in a few patients
with RS mCRC in terms of depth of response, objective
response rate, and tumor shrinkage.
Considering triplet regimen ± targeted therapy, the
TRIBE trial [70, 71] (FOLFOXIRI plus bevacizumab vs.
FOLFIRI plus bevacizumab) has shown significantly
higher PFS and OS in the FOLFOXIRI plus bevacizumab
arm in the subgroup of RS mCRC (HR 0.66), and a less
pronounced effect in LS mCRC (HR 0.82).
5.2.2 Beyond the First-Line Setting
Few data are available of second-line treatment. In the
20050181 trial (FOLFIRI with or without panitumumab)
[68], LS primary tumor location was associated with a
significantly higher ORR (50 vs. 13%, p \ 0.001) in the
panitumumab arm and there was a trend toward better OS
and PFS in the panitumumab arm for both sides [54].
794 C. Gallois et al.

Fig. 2 Forest plots for

predictive analyses of primary
tumor location in trials
comparing chemotherapy plus
anti-EGFR (experimental arm)
with chemotherapy alone or
chemotherapy plus
bevacizumab (control arm),
based on the study of Arnold
et al. [54]. a Overall survival;
b progression-free survival;
c objective response rate. CI
confidence interval, CT
chemotherapy, EGFR epidermal
growth factor receptor, HR
hazard ratio, NA not available,
OR odds ratio
Colorectal Cancer: Why Side Matters
In chemorefractory metastatic patients, compared to best
supportive care, cetuximab was associated with better PFS
and OS only for patients with LS tumors in the NCIC
CO.17 trial [72].
6 Discussion
RS CRC is becoming increasingly frequent, and shows
particular clinical and biological characteristics, in part
related to different embryonic origins, vascularisation, and
microbiota between the right and left colon. Through a
certain level of heterogeneity in defining RS and LS CRC
in the literature, splenic flexure is now accepted as the most
relevant demarcation point.
Primary tumor location does not seem to clearly influ-
ence disease recurrence in non-metastatic CRC even
though differing prognostic values of RS tumors on DFS
depending on RAS/BRAF mutational status have been
recently suggested in these patients [73]. In contrast, in
metastatic patients—where this effect has been described
for decades—the bad prognosis associated with RS tumors
seems to be valid in the most recent publications in an era
of double and triple chemotherapeutic regimens and tar-
geted agents [9, 55–57, 74].
Although it may seem to some physicians and
researchers a bit surprising in an era of large worldwide
molecular classifications to move backward toward anat-
omy, sidedness seems clinically relevant in CRC patients
and can be seen as a master molecular marker. Indeed, poor
prognostic RS tumors are more often poorly differentiated,
MSI, BRAF mutated, and CIMP-high, all known to be bad
prognostic factors in mCRC [75–78].
In patients with RAS wild-type mCRC, anti-EGFR
therapy (cetuximab or panitumumab) appears to be more
effective than bevacizumab in first-line chemotherapy in
LS CRC [9, 54, 55, 74], whereas bevacizumab seems to
increase PFS more than EGFR-antibody therapy in RS
CRC [9, 54, 59]. The results are less clear for RS CRC,
possibly due to a smaller number of patients, reducing the
statistical power of the analyses. Moreover, anti-EGFR
therapy seem to induce more tumor shrinkage than beva-
cizumab, irrespective of the primary tumor location [9, 45].
Perhaps in the future, analysis of miR 31 3p expression
[79] could help to better select patients with RS mCRC
who might benefit from anti-EGFR therapy.
Nevertheless, it has to be emphasized that the retro-
spective and unplanned nature of all these analyses limits
the strength of conclusions that can be drawn from them.
Despite this, and based on all these data, the current
National Comprehensive Cancer Network Guidelines 2017
recommend using EGFR antibodies in first-line treatment
only for patient with RAS wild-type LS mCRC [80], while
795
the latest ESMO consensus guidelines published in 2016
for mCRC do not include primary tumor localisation in
first-line treatment recommendations [81]. However, the
pan-Asian ESMO consensus guidelines [82], published in
November 2017, also recommend the use of EGFR anti-
bodies in RAS wild-type LS mCRC, while in RAS wild-
type RS mCRC, if cytoreduction is the goal, the guidelines
recommend doublet/triplet chemotherapy plus beva-
cizumab but EGFR antibody therapy remains an option,
and if disease control is the goal, doublet regimen plus
bevacizumab.
In conclusion, in the metastatic setting, primary tumor
location is an important prognostic factor and should be a
stratification criterion in all future therapeutic trials. Based
on current knowledge, patients with RAS wild-type LS
mCRC should be preferentially treated with an anti-EGFR
antibody combined with chemotherapy in the first-line
setting. In contrast, it is more difficult to reach conclusions
for patients with RAS wild-type RS mCRC, in which
bevacizumab may be more appropriate; however, if tumor
shrinkage is the goal, EGFR antibodies remain an option.
Nevertheless, these conclusions must be interpreted with
caution due to the limitations of the current results: the
analyses were not pre-planned and retrospective in nature;
the studies included only small numbers of patients with
RS mCRC, limiting the statistical power of the results for
this subgroup; there is a lack of adjustment for major
prognostic molecular markers, such as BRAF mutational
status. For all these reasons, clinical trials dedicated to RS
mCRC seem justified to clarify the best treatment strategy
for these patients having a particularly aggressive disease.
For subsequent lines of treatment, tumor sidedness should
not be taken into account when making the therapeutic
decision due to the lack of sufficient data on treatment
sequences according to tumor side.
Compliance with Ethical Standards
Funding No funding was received for the preparation of this article.
Conflict of interest C. Gallois declares that she has no conflicts of
interest. S. Pernot has participated in advisory boards for Amgen, has
received support for travel to meetings from Amgen, Bayer, and
Servier, and has a received research grant from Roche. A. Zaanan has
participated in advisory boards for Merck Serono, Amgen, Roche,
Sanofi, and Lilly. J. Taieb has participated in consulting and/or
advisory boards for Lilly, Celgene, Shire, Servier, Merck KGaA,
Sanofi, Roche Genentech, Pfizer, and Amgen.
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