Abstract. Background: Microsatellite Instability (MSI)
status is a good prognostic factor for colorectal cancer
(CRC) but its predictive value for chemosensitivity remains
controversial. A previous meta-analysis (MA) in the adjuvant
setting showed that MSI-high (H) status did not predict the
efficacy of chemotherapy. The predictive value of MSI status
on the effect of metastatic chemotherapy was investigated by
MA. Patients and Methods: Studies were identified by
electronic search through PubMed, Embase and ASCO
proceedings online databases, using several key words
(colorectal cancer, chemotherapy, microsatellite instability).
For each study, the ratio of response rate (RR), complete
(CR) and partial response (PR) divided by stable disease
and progression was calculated. From 190 articles and 100
abstracts, only eight independent studies were selected. The
data were analysed with a random-effect model (due to
heterogeneity between studies) using EasyMA software.
Statistical calculations were performed on six studies
representing 964 patients (mean age 63 years; 91 MSI-H;
873 microsatellite stable (MSS) tumours). A total of 287
patients received 5-fluorouracil (5FU)-based chemotherapy,
whereas 678 patients received combinations of 5FU or
capecitabine with oxaliplatin and/or irinotecan. Results: No
benefit of metastatic chemotherapy in terms of RR for MSI-
H patients compared with MSS patients was found. The
global hazard ratio (HR) for RR was 0.82 (95% confidence
interval, CI: 0.95; 0.65-1.03; p=0.09). Conclusion: MSI
status does not predict the effect of chemotherapy which is
similar in MSI-H and MSS metastatic CRC tumours.
Colorectal cancer (CRC) is the third most common cancer
and the fourth most frequent cause of cancer death
worldwide (1). Chemotherapy is obviously the cornerstone
of treatment of metastatic CRC. In metastatic disease, 5-
fluorouracil (5FU) is usually combined with oxaliplatin or
irinotecan. However, to improve management of CRC and to
better select those patients who will respond to
chemotherapy, predictive factors are urgently needed.
Among the genetic abnormalities involved in carcinogenesis,
microsatellite instability (MSI) is a major pathway of cancer
development (2). MSI corresponds to a dysfunction of the
mismatch repair (MMR) system resulting in a reduction in the
length of highly repeated DNA sequences termed
microsatellites. The MMR system corrects mismatches of DNA
nucleotides occurring during replication. A germinal mutation
inactivating one of the MMR genes (MLH1, MSH2, MSH6,
PMS1 and PMS2) (3) may lead to a hereditary form termed
hereditary non-polyposis colon cancer (HNPCC). A previous
meta-analysis (MA) found that MSI status was a prognostic
factor in CRC (4). However the relative benefits of
chemotherapy (meaning predictive value) among MSI
heterogeneous (MSI-H) and microsatellite stable (MSS)
patients were not assessed. The issue of the comparative
benefits of chemotherapy according to MSI status is crucial
since no biological marker has so far been proved effective in
predicting response to chemotherapy (5). This is of importance
since MSI is not only found in the rare HNPCC forms (Lynch
syndrome), but also in 15% of sporadic forms of CRC (6).
Several studies have investigated the relationship between
MSI status and chemotherapy efficacy in metastatic CRC, i.e.
between MSI status and response rate (RR), relapse-free
survival (RFS) or overall survival (OS). The relationship
between MSI status and the efficacy of chemotherapy
differed among the studies. Therefore a MA of all published
studies was performed to determine the relevance of MSI
status as a predictive factor of chemotherapy efficacy. The
main goal of the MA was to assess the predictive value of
MSI-H compared to MSS status among patients receiving
chemotherapy for metastatic CRC.
Correspondence to: Dr. Gaëtan Des Guetz, Department of
Oncology, APHP, Hôpital Avicenne, 125 route de Stalingrad, 93009,
Bobigny, France. Tel: +33 612876251, Fax: +33 148955035, e-mail:
Key Words: Colorectal cancer, microsatellite instability, predictive
factor, chemotherapy, survival.
ANTICANCER RESEARCH 29: 1615-1620 (2009)
Microsatellite Instability does not Predict the
Efficacy of Chemotherapy in Metastatic
Colorectal Cancer. A Systematic Review and Meta-analysis
GAËTAN DES GUETZ1, BERNARD UZZAN2, PATRICK NICOLAS2, OLIVIER SCHISCHMANOFF3,
GERARD-YVES PERRET2and JEAN-FRANÇOIS MORERE1
Departments of 1Oncology, 2Pharmacology and 3Biochemistry, APHP, Hôpital Avicenne, Bobigny, France
Patients and Methods
Publication selection. The MA was performed according to a
predefined written protocol. To be eligible, the studies had to deal
with colon or rectum cancer and to assess the relationships between
MSI, chemotherapy and RR for metastatic patients. Studies (full
articles) were identified by an electronic search using online
PubMed, with a set of key words “colorectal cancer, chemotherapy,
microsatellite instability” used simultaneously. The last query was
updated on November 9th, 2008. An electronic search with the same
key words was also performed using online EMBASE. Examination
of the Cochrane database of systematic reviews did not retrieve
additional pertinent references. Our initial selection of articles relied
on careful reading of their abstracts. Abstracts concerning
microsatellite instability were also retrieved from the ASCO
(American Society of Clinical Oncology) proceedings of the annual
meetings from 1998 to 2008 available online. References from the
relevant literature were also screened, including all of the identified
studies, but also reviews and editorials for additional information
(4). Studies written in English or French were included as full
papers or as abstracts from the ASCO proceedings were included.
The duplication of data was carefully avoided, by examining, for
each publication, the names of all the authors and the different
medical centres involved. Studies in which survival data were not
available were excluded. In some cases, the authors were contacted
to obtain additional data allowing statistical calculations.
Methodological assessment. Information was carefully extracted
from all the publications in duplicate by two readers (Dr Gaëtan
Des Guetz and Dr Bernard Uzzan), using a standardised data
collection form, including the following items: complete reference
of the publication; original publication or update of a former
publication; mode of making up of the series of cases; prospective
study; inclusion of consecutive cases; randomised controlled trials
(RCT); median duration of follow-up; number of patients included
in the study; mean or median age; gender; anticancer treatment(s)
during follow-up; histological type (adenocarcinoma or mucinous);
tumour size; stage of disease; grade (good, moderate or poor
differentiation) and nodal status. Assessment of the methods used
to determine MSI status, immunohistochemistry of MLH1, MSH2
(mutL homolog 1, mutS homolog 2) or the molecular methods
(number and type of MSI; i.e. NCI (National Cancer Institute)
reference or pentaplex panels (7, 8) was conducted by Dr Olivier
Schischmanoff. To simplify the analysis of the data, MSI-low (L)
(9) and MSS patients were always pooled.
The choice of drugs in the metastatic setting was broad but was
exclusively based on 5FU up to 2004. The RR to chemotherapy and
RFS and OS were chosen as evaluation criteria in the studies. Due
to the lack of results available for OS and RFS, only the RR ratio
was analysed for comparing the MSI-H and MSS patients. To
summarise the information provided by the metastatic studies, the
complete responders (CR) and partial responders (PR) were
considered as responders and stable or progressive disease as non-
Disagreements were resolved by consensus between the three
readers. No predefined minimal number of patients was not set for
a study to be included in the MA, nor a minimal duration of median
follow-up were set. Individual studies were not weighed by a quality
score, because no such score has received general agreement for use
in a MA, especially of observational studies, making more difficult
the evaluation of its usefulness (10). When duplicate studies were
retrieved, only the study involving the highest number of patients
from which data could be extracted (usually the latest) was included
in the systematic review. This was done to avoid overlapping
between cohorts. In each study, the MSI determination was
performed retrospectively. The studies only included patients
receiving chemotherapy in the metastatic setting. Although their
methodological quality was rather similar, their design (phase II/III)
and the reliability of their conclusions were variable.
Statistical methods. In each study, the relationship between MSI
status and response rate was considered significant when the p-value
for the statistical test comparing survival distributions between the
MSI and MSS groups was below 0.05 in univariate analysis (two-
For each trial, the hazard ratio (HR) was estimated by a method
depending on the data provided in the publication. The simplest
method consisted of the direct collection of HRs, or odds ratios, and
their 95% confidence interval (CI) from the original article. If not
available, the total numbers of responses and the numbers of
patients at risk in each group were used to determine the RR ratio
Thus, a pooled HR estimate and its 95% confidence interval were
calculated by using a random-effect model (Der Simonian and Laird
method) due to heterogeneity between the studies. By convention, a
HR lower than 1 for MSI-H compared with MSS corresponded to a
better survival. The statistical calculations for the MA were performed
with EasyMA.net, (http://www.spc.univ-lyon1.fr/easyma.net/) online
available application (Department of Clinical Pharmacology,
Cardiology Hospital, Lyons, France). The statistical analysis was
performed by Dr Patrick Nicolas, who chose the best statistical
exploitation of the data, or decided on the exclusion of studies from
the MA because their data could not be exploited statistically.
The electronic data search using online PubMed retrieved a
total of 190 references including 58 reviews. The EMBASE
query did not provide any additional references. After
exclusion of the references which were out of the scope of this
MA (by reading the abstracts), there remained 7 studies
dealing with MSI status (11-17). No study was published in
duplicate. One hundred abstracts concerning microsatellite
instability were found in the ASCO proceedings (1998-2008).
For chemotherapy of metastatic CRCs, additional data
corresponding to only one recent abstract were retrieved (18).
This study could be included in the MA after the authors of
this article responded to some enquiries (by e-mail) (18). Two
articles, the latter provided by screening of recent literature on
biomarkers, were excluded due to inability by the authors
themselves to obtain HR for the treated patients and MSI
status (17, 19). Two other articles were excluded due to the
MSI methods immunohistochemistry without molecular
techniques (13, 20). Information about the inclusion process is
provided in the flow-chart of the MA (Figure 1).
The number of microsatellite markers analysed differed
greatly among the studies (from 5 to 10). However, the
ANTICANCER RESEARCH 29: 1615-1620 (2009)
Bethesda markers were used in four studies (11, 14-16).
Four studies included immunohistochemistry of MMR
proteins (one MLH1 and MSH2, and two MLH1, MSH2,
MSH6, PMS2 and one MLH1, MSH2 and MSH6 (14, 15,
18) (11) (Table I).
The MA was performed for six studies in the metastatic
setting (11, 12, 14-16, 18). The patients had been treated with
different schedules of newly marketed treatments now
considered FOLFIRI (combination of folinic acid, 5FU and
irinotecan) (14), FOLFOX or FUFOX (combination of folinic
acid, 5FU and oxaliplatin) (11, 12), XELOX (combination of
capecitabine and oxaliplatin) (11, 18) or only classical 5FU (15,
16). The global number of metastatic patients was 964 with a
mean age of 63 years and 91 MSI-H and 873 MSS tumours.
Due to the lack of results available for RFS or OS, only the RR
ratio was analysed, comparing MSI-H with MSS patients. A
major statistical heterogeneity was found between the studies
using a fixed effect model making it unsuitable. The RR ratio
was not statistically different from one when the random effect
model was used. No benefit of chemotherapy in terms of the
RR was observed for the MSI-H compared with the MSS
patients: 0.82 (CI: 0.95; 0.65-1.03; p=0.09) (Figure 2).
This MA on metastatic chemotherapy showed no difference
in RR ratios corresponding to MSI-H and MSS, but found a
major statistically significant heterogeneity, which might be
explained by the difference in chemotherapy regimens
between and even within the studies and by the large
differences in the numbers of patients included in the
studies. For instance Liang et al. used high doses of 5FU
(16) whereas Koopman et al. pooled different regimens of
chemotherapy with capecitabine, irinotecan and XELOX
(18). A MA based on individual data and stratified
according to the chemotherapy protocol would be time
consuming and might not help to clarify this issue since
multiplication of subgroup analyses (e.g. according to the
Des Guetz et al: Microsatellite Instability and Chemotherapy of Metastatic Colorectal Cancer
Figure 1. Flow-chart of the different steps of the meta-analysis (MA).
dose of 5FU, combination with or without folinic acid)
would limit their statistical power.
The studies included in the present MA included RCT
aiming to evaluate the best treatment in the metastatic setting
considering doses of 5FU (15, 16), combination of
chemotherapy (11, 18) and small phase II studies (12, 14).
The stratification according to MSI status was always
completed retrospectively, leading to various biases. A MA
could eventually permit an overview of the publications and
an analysis of these differences and similarities.
MSI-H status is a relatively rare biological event, with
frequencies of 5% for genetic abnormalities (corresponding
to HNPCC syndrome) and 15% for sporadic tumours. The
evaluation of MSI-H as a predictive factor in the metastatic
setting is particularly difficult because metastatic progression
is a rare event for MSI-H tumours (21, 22). The addition of
many patients from various studies was deemed useful to
answer the issue of chemotherapy treatment benefit for MSI-
H patients . In the present MA more than 10% MSI-H
patients were found (91 MSI-H patients/964) and for the first
time metastatic treatment was compared for many patients (the
median number of patients with MSI-H tumours in individual
studies is nine). Popat et al. previously found only two
references (15, 16) in a metastatic setting and it was not
possible to draw conclusions and their study mainly dealt with
the prognostic use of MSI status and not with its predictive
value on the effect of chemotherapy. Four additional studies
(11, 12, 14, 18), were included in the present MA.
At present, combined chemotherapy has replaced 5FU
monotherapy both in adjuvant (FOLFOX) and metastatic
settings (FOLFOX, FOLFIRI). However, until now, no
prospective study randomised chemotherapy according to
MSI status and compared its efficacy among MSI-H and
MSS patients. A major ongoing RCT, in the United-States,
including more than 3000 patients (stage II, colon cancer)
chose to randomise MSS patients between adjuvant
chemotherapy alone and with bevacizumab, whereas the
MSI-H patients will have no chemotherapy (23).
Since the study of Ribic et al. published in 2003, updated
in 2008 at the last ASCO meeting, a general opinion was
ANTICANCER RESEARCH 29: 1615-1620 (2009)
Table I. Main characteristics of the studies included in the meta-analysis.
First author Study from
N Colon Rectum
(markers) MSI/MSS MSS (%)
N patients RR MSI-H/ HR Results
HR PubMed (M/F) (n)chemistryEstimate
Muller et al.
5 4/100 1/4
YesC63.5 4024 16FOLFOX
Given by Inconclu-
authors (22/18) pentaplex sive
NoRCTnd 461 ndndXELOX,
Not done12/449 4/12
Given by Inconclu-
Brueckl et al.
Yes RCT 6043 33 10 5FU and
10 7/36 5/7
Fallik et al.
YesC 54 72 58 14Irinotecan
5 7/65 4/7
Liang et al.
YesC 65 244183 615FU and
C represents studies including consecutive patients, RCT randomized controlled trials. RR: Response Rate. A positive study showed a statistically significant
higher effect of chemotherapy among MSI-H patients. FUFOX or FOLFOX (combination of folinic acid and oxaliplatin) FOLFOX 4 (oxaliplatin 85
mg/m2), FOLFOX 6 (oxaliplatin 100 mg/m2), XELOX (combination of capecitabine and oxaliplatin), XELIRI (combination of capecitabine and irinotecan).
HR (hazard ratio) is positive for studies with higher response rate for MSI-H. nd: not defined. PCR: polymerase chain reaction.
that MSI-H patients were not sensitive to adjuvant
chemotherapy and moreover, chemotherapy could have by
itself a detrimental effect on survival (24) (25). In the
adjuvant setting, chemotherapy was essentially based on
5FU alone when the studies were began. Our previous MA
studied for the first time the value of MSI status to predict
the response to chemotherapy and we confirmed that MSI-
H patients had a better overall and relapse-free survival than
MSS patients in the adjuvant setting but found that MSI
status did not predict the efficacy of adjuvant chemotherapy
(26). In the present MA no difference was found in the
metastatic setting. These differences show the difficulties of
comparing adjuvant and metastatic settings especially
considering the heterogeneity of the disease biology and
types of treatments. In the metastatic setting, RR is the
direct effect of chemosensitivity, with variation of tumour
size according to treatment efficacy. However, in the present
MA, the different regimens used in the different studies did
not allow to evaluate the relative benefit of each drug. Now
target therapies (such as anti-EGFR; or anti-angiogenic) are
indicated in the metastatic setting either alone or more
frequently in combination with chemotherapy. Ki-ras testing
seems particularly useful for anti-EGFR antibodies and for
anti-VEGF treatments, many studies are performed to
determine predictive markers, but for chemotherapy,
molecular markers are always needed.
To conclude chemotherapy is not associated with a
significantly improved response rate in MSI-H compared
with MSS patients, in metastatic CRC. MSI-H status does
not seem to be a good predictive marker for evaluating
chemosensitivity in the metastatic setting
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Received December 10, 2008
Revised January 25, 2009
Accepted February 2, 2009
ANTICANCER RESEARCH 29: 1615-1620 (2009)