reviews Annals of Oncology 24: 1721–1730, 2013

doi:10.1093/annonc/mdt150
Published online 18 April 2013

Statins are associated with reduced risk of gastric

cancer: a systematic review and meta-analysis
P.P. Singh1* & S. Singh2

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1
Department of Medical Oncology; 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, USA

Received 22 December 2012; revised 8 March 2013; accepted 11 March 2013

Background: Several observational studies have shown that statins may modify the risk of gastric cancer (GC). We
carried out a systematic review and meta-analysis of studies evaluating the effect of statins on GC risk.
Patients and methods: We conducted a systematic search of multiple databases up to December 2012. Studies
that evaluated exposure to statins, reported GC outcomes and odds ratio (OR) or provided data for their estimation
were included in the meta-analysis. Pooled OR estimates with 95% confidence intervals (CIs) were calculated using the
random-effects model.
Results: Eleven studies (eight observational, three post-hoc analyses of 26 clinical trials) reporting 5581 cases of GC
were included. Meta-analysis showed a significant 32% reduction in GC risk with statin use (adjusted OR, 0.68; 95%
CI, 0.51–0.91). After exclusion of one study which was contributing to considerable heterogeneity, a significant 16%
reduction in GC risk was a more conservative, consistent estimate (adjusted OR, 0.84; 95% CI, 0.78–0.90). This
chemopreventive association was present in both Asian (adjusted OR, 0.68; 95% CI, 0.53–0.87) and Western
population (adjusted OR, 0.86; 95% CI, 0.79–0.93).
Conclusions: Meta-analysis of studies supports a protective association between statin use and GC risk, in both

reviews
Asian and Western population, in a dose-dependent manner.
Key words: cancer risk, chemoprevention, gastric cancer, statins

introduction In vitro and animal studies have shown that in addition to

With an annual incidence of nearly 1 million, gastric cancer
(GC) is the fourth most common cancer world wide and the
second most frequent cause of cancer death with >0.7 million
deaths annually [1]. Over 70% of new cases and deaths occur
in developing countries, predominantly in Eastern Asia and
Eastern Europe, which has been attributed to chronic
Helicobacter pylori infection and dietary habits. Unfortunately,
almost half of the patients present with advanced, inoperable
disease with a 5-year survival rate of <5% [2]. Even in patients
with resectable disease, prognosis is dismal with 5-year survival
rates in the order of 25–35% [3, 4]. Early endoscopic detection
of GC is feasible and could potentially improve outcomes, but
is cost prohibitive [5]. Current strategies for improving
outcomes in GC are aimed at reducing chronic H. pylori
infection, screening patients at highest risk and identifying
chemopreventive agents.
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA) reductase inhibitors, used for primary and secondary
prevention of cardiovascular diseases, decrease the risk of
certain cancers [6, 7] and reduce cancer-related mortality [8].
*Correspondence to: Dr Preet Paul Singh, Department of Medical Oncology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-284-2511;
Fax: +1-507-284-1803; E-mail: singh.preetpaul@mayo.edu
cholesterol reduction, statins have anti-proliferative, pro-
apoptotic, anti-angiogenic and immunomodulatory effects,
which prevent cancer development and growth [9]. This effect
also been shown in human GC-derived cell lines [10]. Some
recent observational studies have shown that statins may be
associated with a lower risk of GC [11, 12], whereas others
have shown no beneficial effect [13, 14].
To better understand this issue, we carried out a systematic
review with meta-analysis of existing randomized, controlled
trials (RCT) and observational studies that investigated the
association between statins and the risk of developing GC.
methods
This systematic review was conducted following guidance
provided by the Cochrane Handbook [15] and is reported
according to the Meta-analysis of Observational Studies in
Epidemiology guidelines [16]. The process followed a priori
established protocol.
data sources and search strategy
First, a systematic literature search of PubMed (1966 through 1
December 2012), Embase (1988 through 1 December 2012)
and Web of Science (1993 through 1 December 2012)

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reviews
databases was conducted for all relevant articles on the effect of
statins use on the risk of GC. Search terms used included
‘HMG-CoA reductase inhibitor(s)’, ‘statin(s)’, ‘atorvastatin’,
‘fluvastatin’, ‘lovastatin’, ‘pravastatin’, ‘rosuvastatin’,
‘pitavastatin’ or ‘simvastatin’ combined with ‘cancer’ or
‘neoplasm(s)’. The results were exported to a common
EndNote (reference manager) file. After this, duplicates were
removed, and a total of 2370 unique studies were identified.
Then, according to the protocol-defined study inclusion and
exclusion criteria (see below) both authors independently
reviewed the studies to see whether the inclusion criteria were
met. Based on the review of the title and abstract, 2281 studies
were excluded since they provided insufficient information on
the risk of GC and statins. For the remaining 89 articles which
were related to this topic, both authors reviewed the full text of
the articles, independently, and reported the studies that each
felt should be included or excluded. The coefficient of
agreement between the two reviewers (κ = 0.86, 95% CI, 0.73–
1.00) was excellent. Second, we searched the bibliographies of
these selected articles as well as relevant narrative and
systematic review articles to identify any additional studies.
Third, we also searched conference proceedings of major
oncology (American Society of Clinical Oncology annual
meeting as well as the Gastrointestinal Research Forum;
European Society of Medical Oncology annual meeting and
World Congress on GI Cancer) and gastroenterology
conferences (Digestive Diseases Week, American College of
Gastroenterology annual meeting) from 2005 to 2012 for
studies that had been published only in the abstract form.
Figure 1 summarizes the study identification and selection
process.
study selection
Studies considered in this meta-analysis were either RCTs or
observational studies that met the following inclusion criteria:
(i) evaluated and clearly defined exposure to statins, (ii)
reported GC incidence and (iii) reported relative risks (RR)
(for cohort studies) or odds ratio (OR) (for case–control
studies) or provided data for their calculation. Inclusion was
not otherwise restricted by study size, language or publication
type. Articles were excluded from the analyses if there were
insufficient data for determining an estimate of RR/OR and a
95% confidence interval (CI), though these were included in
the systematic review and described qualitatively. When there
were multiple publications from the same population, only
data from the most recent comprehensive report were included.
data abstraction and quality assessment
Data were independently abstracted onto a standardized form
by both the authors. The following data were collected from
each study: study design, time period of study/year of
publication, country of the population studied, primary
outcome reported, type, dose and duration of statin use,
information source for exposure measurement, total number of
persons in each group (exposed to statins versus not exposed),
OR and 95% CIs with and without adjustment for potential
confounders and potential confounders used for adjustment.
Data on the following confounding risk factors for GC were
 | Singh and Singh
Annals of Oncology
extracted from each study: age, sex, race, cigarette smoking,
body mass index (BMI), history of H. pylori, diet, other
medication use [aspirin/non-steroidal anti-inflammatory drugs
(NSAID)] and alcohol use. Conflicts in data abstraction were
resolved by consensus, referring back to the original article.
The methodological quality of case–control and cohort
studies was assessed by both the authors independently using
the Newcastle–Ottawa scale, with very good agreement
(κ = 0.77; 95% CI, 0.65–0.90) [17]. In this scale, observational
studies were scored across three categories: selection (four
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questions) and comparability (two questions) of study groups,
and ascertainment of the outcome of interest (three questions),
with all questions with a score of one, except for comparability
of study groups, where separate points were awarded for
controlling age and/or sex (maximum two points). A score of
≥7 was suggestive of a high-quality study. The methodological
quality of randomized trials was assessed using the Cochrane
Collaboration’s tool for assessing the risk of bias in randomized
trials [15]. Any discrepancies were addressed by a joint
re-evaluation of the original article.
outcomes assessed
The primary analysis focused on assessing the risk of GC
among users of statins. A priori hypotheses to explain potential
heterogeneity in the direction and magnitude of effect among
different studies included location of study (Asian population
versus Western population), study design (observational
studies versus clinical trials) and study setting (hospital-based
versus population-based).
In the three studies which provided data on relationship
between dose/duration of statin use and risk reduction in GC
[11, 12, 14], long duration of statin use was defined as: more
than median cumulative defined daily dose of statins [11] or
>2 years of statin use [12] or >4–6 years [14]. Likewise, short
duration of statin use was defined as: less than median
cumulative defined daily dose of statins [11] or 0.5–1.0 years of
statin use [12] or 1–2 years [14].
data synthesis and analysis
We used the random-effects model described by
DerSimonian and Laird to calculate summary OR and 95%
CI [18]. We assessed heterogeneity between study-specific
estimates using two methods [19]. First, the Cochran’s Q
statistical test for heterogeneity, which tests the null
hypothesis that all studies in a meta-analysis have the same
underlying magnitude of effect, was measured. Because this
test is underpowered to detect moderate degrees of
heterogeneity [20], a P value of < 0.10 was considered
suggestive of significant heterogeneity. Second, to estimate
what proportion of total variation across studies was due to
heterogeneity rather than chance, I 2 statistic was calculated.
In this, a value of >50% was suggestive of considerable
heterogeneity [21]. Once heterogeneity was noted, between-
study sources of heterogeneity were investigated using
subgroup analyses by stratifying original estimates according
to study characteristics (as described above). In this analysis
also, a P value for differences between subgroups of <0.10
was considered statistically significant (i.e. a value of
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 Annals of Oncology
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Table 1. Characteristics of included studies assessing the risk of gastric cancer (GC) with statin use

Study Study design Location/setting Time Period Exposure ascertainment Outcome assessment All subjects On statins Not on Statins Confounding
GC Total GC Total GC Total variables
adjusted fora
Observational studies
Chiu et al. [11] C–C Taiwan; Population-based 2005–2008 National Pharmacy Database Medical diagnostic codes 337 1685 56 354 281 1331 1,2,6,7,10, 13
Huakka et al. [28] Nested C–C Finland; Population- 1996–2005 National Pharmacy Database Record linkage, with 1667 944 962 770 472 481 897 472 481 1,2,14
based Finnish Cancer Registry
Kaye et al. [13] C–C UK; Population-based 1990–2002 National Pharmacy Database Medical diagnostic codes 39 18 088 4 3244 35 14 844 1,2,4,5,10, 14
Graaf et al. [27] Nested C–C Netherlands; Population- 1985–2008 PHARMO Record Linkage Hospital discharge records 104 20 105 NR 1444 NR 18 661 1,2,8,9,10, 12,14
based
Vinogradova et al.[14] Nested C–C UK; Population-based 1998–2008 National Pharmacy Database Medical diagnostic codes 1992 10 271 322 1685 1670 8586 1,2,4,5,8,1112,13,14
Lee et al. [12] C–C South Korea; Hospital- 1999–2008 Pharmacy dispensing records Medical diagnostic codes 983 1966 99 466 884 1500 1,2,8
based
Friedman et al.[26] Cohort USA; Population-based 1994–2003 Pharmacy dispensing records Kaiser Permanente Cancer 137 4 222 660 NR 361 849 NR 3 860 811 8,13
Registry
Marelli et al. [29] Nested C–C USA; Population-based 1991–2009 Pharmacy dispensing records Electronic Medical Record 31 91 714 13 45 857 18 45 857 1,2,3,4,5
review
Randomized, controlled trials (RCTs)
Cholesterol Treatment 22 RCTs (post-hoc) Europe/USA /Australia; – Individual drug dispension Adverse event reporting by 192 134 537 92 67 258 100 67 279 Variable
Trialists’ (CTT) [25] Hospital-based investigators
Matshushita et al. [30] Three clinical trials Japan; Hospital-based – Individual drug dispension Adverse event reporting by 95 13 724 43 7375 52 6349 Variable
(individual. patient data) investigators
Sato et al. [31] RCT (post-hoc) Japan; Hospital-based 1991–1995 Individual drug dispension – 4 263 3 179 1 84 1,2,5
doi:10.1093/annonc/mdt150 | 

a
1, age, 2, sex, 3, race, 4, BMI, 5, smoking/alcohol, 6, H. pylori, 7, peptic ulcers, 8, other medications (aspirin/NSAIDs), 9, other lipid lowering agents, 10, healthcare utilization, 11, socioeconomic status, 12,
comorbidities, 13, calender year, 14=region.
C–C, case–control; CTT, cholesterol treatment trialists’ Collaboration; RCT, randomized, controlled trials; NR, not reported.

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P < 0.10 suggested that stratifying based on that particular
study characteristic partly explained the heterogeneity
observed in the analysis). The presence of publication bias
was assessed quantitatively using Egger’s regression test
( publication bias considered present if P ≤ 0.10) [22] and
qualitatively, by visual inspection of funnel plots of the
logarithm of ORs versus their standard errors [23].
Additionally, using the Rosenthal’s ‘fail-safe N’ method, we
estimated the number of unpublished null studies (which
fail to show an association between statins and risk of GC)
needed to remove the significance from the findings of this
meta-analysis [24]. All P-values were two-tailed. For all tests
(except for heterogeneity and publication bias), a probability
level of <0.05 was considered statistically significant.
Since outcomes were relatively rare, ORs were considered
approximations of RR. We also calculated the number needed
to treat with statins to prevent one case of GC in the general
population, based on the current estimates of incidence of
GC. All calculations and graphs were carried out using
Comprehensive Meta-Analysis version 2 (Biostat,
Englewood, NJ).
results
search results
Eleven studies met the defined inclusion criteria for this meta-
analysis (seven case–control, one cohort, three post-hoc
analysis of 26 clinical trials) [11–14, 25–31]. An abstract search
from meeting proceedings did not yield any additional articles.
These cumulatively reported 5581 cases of GC in 5 459 975
patients. Of the total, 962 192 patients were classified as statin
users (16.7%). There were two Taiwanese studies from the
same cohort [11, 32] and hence, only the most comprehensive
report from these was included [11].
characteristics of included studies
The characteristics of these studies are shown in Table 1. The
earliest study period began in 1985, and the latest ended in
2009. Seven studies were carried out in the Western population
(four in Europe, two in United States and one was
collaboration of multi-center trials across Europe, North
America and Australia); [13, 14, 25–29] four studies were in
the Asian population (two in Japan, one in South Korea, one
in Taiwan) [11, 12, 30, 31]. The studies used both lipophilic
and hydrophilic statins.
Chiu et al. carried out a case–control study on Taiwanese
patients >50 years of age with new diagnosis of GC from 2005
to 2008 [11], while Huakka et al. [28], Graaf et al. [27] and
Vinogradova et al. [14] carried out nationwide population-
based nested case–control studies on statin exposure and the
risk of various cancers, in Finland, the Netherlands and UK,
respectively, through record linkage between the pharmacy
dispensing records and the national cancer registries. Marelli
et al. carried out a propensity-matched cohort analysis of the
incidence of cancer in older adults who had or had not used
statins, using the General Electric Centricity electronic medical
records database of >11 million patients [29]. Friedman et al.
used the pharmacy information management system and
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Annals of Oncology
cancer registry of the Kaiser Permanente Medical Care
Program of northern California, United States to estimate the
risk of cancer in patients exposed to statins [26]. Lee et al.
carried out a single-center, matched case–control, hospital-
based study in patients with diabetes mellitus to assess the
association between GC and statin use [12]. Matsushita et al.
carried out an analysis of individual patient data from three
large-scale clinical trials in patients with hyperlipidemia in
Japan [30]. Emberson et al. carried out an individual patient
data analysis of 22 RCTs of statins versus controls conducted
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by the Cholesterol Treatment Trialists’ (CTTs) collaboration to
assess cancer incidence with statin exposure [25].
quality of included studies
Six observational studies were considered high-quality
(Newcastle–Ottawa score ≥7) [11, 13, 14, 27–29]. Tables 2 and
3 depict the methodological quality of all studies. Though most
studies adjusted or matched for demographic variables, they
did not consistently account for other potential confounders:
BMI (3 of 11), smoking and/or alcohol use (3 of 11), history of
H. pylori (2 of 11) and other medication use (aspirin/
NSAIDs) (4 of 11). None of the studies adjusted for dietary
risk factors for GC. For outcome ascertainment, most studies
relied on medical diagnostic codes for GC, others reported
record linkage through the cancer registry; both strategies had
been validated to have high accuracy in the respective
databases. In order to account for detection bias, three studies
adjusted for the frequency of healthcare utilization in statin
users and non-users [11, 13, 27]. In all included studies, a
temporal relation of development of GC to statins was
established by excluding cases of GC developing before
exposure to statins, though there was variable duration of
minimum statin use before new incident GC cases were
included for analysis (0 months–2 years were reported). The
overall quality of included RCTs was moderate to high [25, 30,
31]. However, all clinical trial studies were post-hoc analyses of
RCTs carried out to assess the safety and efficacy of statins in
the management of hyperlipidemia and/or coronary heart
diseases.
risk of gastric cancer
On meta-analysis of all studies assessing the risk of GC, the
use of statins was associated with a statistically significant 30%
reduction in GC incidence (unadjusted OR, 0.70; 95% CI,
0.51–0.97) (Figure 2). There was, however, considerable
heterogeneity observed across studies (Cochran’s Q-test,
P < 0.01; I 2 = 93%). This risk reduction with statins persisted
even after adjusting for potential confounders (adjusted OR,
0.68; 95% CI, 0.51–0.91) (Figure 2), though the heterogeneity
persisted (Cochran’s Q-test, P < 0.01, I 2 = 89%). For the
remainder of the analysis, the maximally adjusted OR reported
in each study was used.
On restricting analysis to high-quality observational studies
[11, 13, 14, 27–29], statin use continued to be associated with
reduced risk of GC (n = 6 studies; adjusted OR, 0.83; 95% CI,
0.76–0.90). Moreover, the results were consistent across studies
with minimal heterogeneity (Cochran’s Q-test P = 0.71;
I 2 = 0%).
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Table 2. Newcastle–Ottawa scale for assessment of quality of included studies—case–control studies (each asterisk represents if individual criterion within
the subsection were fulfilled)

Quality assessment criteria Acceptable(*) Chiu Huakka Kaye Graaf Vinogradova Lee Marelli
et al. et al. [28] et al. et al. et al. [14] et al. et al. [29]
[11] [13] [27] [12]
Selection
Is the case definition Yes, with independent validation – – – – – * –
adequate?
Representativeness of Consecutive or obviously representative series * * * * * – *

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cases? of cases
Selection of controls? Community controls * * * * * – *
Definition of controls? No history of gastric cancer (GC) * * * * * * *
Comparability
Study controls for age/ Yes * * * * * * *
gender
Study controls for at Race, smoking, body mass index (BMI), * – * – * – *
least three additional history of Helicobacter pylori, diet, other
factors medication use (aspirin/NSAIDs), alcohol
use, healthcare utilization
Exposure
Ascertainment of Secure record, structured interview by a * * * * * * *
exposure? healthcare practitioner, blind to
case–control status
Same method of Yes * * * * * * *
ascertainment of cases/
controls?
Non-response rate? Same for both the groups * * * * * – –
Overall quality score 8 7 8 7 8 5 7
(maximum = 9)

NSAIDs, Non-steroidal anti-inflammatory drugs.

Table 3. Newcastle–Ottawa scale for assessment of quality of included studies—cohort studies (each asterisk represents if individual criterion within the
subsection were fulfilled)

Quality assessment criteria Acceptable(*) Friedman

et al. [26]
Selection
Representativeness of exposed cohort? Representative of average adult in community (age/sex/being at risk of disease) *
Selection of the non-exposed cohort? Drawn from same community as exposed cohort *
Ascertainment of exposure? Secured records, structured interview *
Demonstration that outcome of interest was not Only incident cases of gastric cancer (GC) *
present at the start of the study?
Comparability
Study controls for age/sex? Yes –
Study controls for at least 3 additional risk factors? Race, smoking, body mass index (BMI), history of Helicobacter pylori, diet, other –
medication use (aspirin/NSAIDs),alcohol use, healthcare utilization
Outcome
Assessment of outcome? Independent blind assessment, record linkage *
Was follow-up long enough for outcome to occur? Follow-up >3 years *
Adequacy of follow-up of cohorts? Complete follow-up, or subjects lost to follow-up unlikely to introduce bias –
Overall quality score (maximum = 9) 6

NSAIDs, non-steroidal anti-inflammatory drugs.

subgroup analysis of these stratifications could account for the heterogeneity

We carried out pre-planned stratified analyses of studies observed in the overall analysis. Statin use was associated
based on study design, location and setting (Table 4). None with a reduced risk of GC in observational studies, and a

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Figure 1. Flowsheet summarizing study identification and selection.

Figure 2. Summary of unadjusted and adjusted odds ratios (OR) assessing the risk of gastric cancer (GC) with statin exposure. No significant differences
were observed in the summary estimates of adjusted and unadjusted OR (Pinteraction = 0.70), suggesting the absence of significant confounding, and
confirming an independent relationship between statin use and the risk of GC. Significant heterogeneity was observed in the overall analysis (Cochran’s Q
P < 0.01; I 2 = 89%). This was primarily attributed to a single study by Lee et al., which was positive outlier. On exclusion of this study, the summary adjusted
and unadjusted ORs were 0.84 (0.78–0.90) and 0.88 (0.83–0.95), respectively. After excluding this study, the previously observed heterogeneity resolved
(Cochran’s Q-test P = 0.76, I 2 = 0%).

non-significant reduction in risk was in post-hoc analyses of there was a similar trend in the Asian studies, though this
RCTs. Statin use was associated with a reduced risk of GC was not statistically significant and considerably
in a subset of studies carried out in the Western population; heterogeneous.

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Annals of Oncology reviews
Table 4. Subgroup analysis of all studies

Grouping variable Subgroups No. of studies Unadjusted OR 95% CI Adjusted OR 95% CI Heterogeneity between
groups (Pinteraction)a
All studies
Study design Observational 8 0.66 0.45–0.99 0.65 0.45–0.93 0.25
RCT (post-hoc analyses) 3 0.85 0.65–1.07 0.83 0.66–1.05
Study location Western 7 0.90 0.84–0.97 0.86 0.79–0.93 0.18
Asian 4 0.51 0.21–1.25 0.50 0.23–1.09
Study setting Population-based 7 0.89 0.82–0.96 0.84 0.78–0.91 0.38

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Hospital-based 4 0.56 0.20–1.55 0.56 0.22–1.39
After excluding Lee et al. [12]
Study design Observational 7 0.89 0.82–0.96 0.84 0.78–0.91 0.91
RCT (post-hoc analyses) 3 0.85 0.65–1.07 0.83 0.66–1.05
Study location Western 7 0.90 0.84–0.97 0.86 0.79–0.93 0.09
Asian 3 0.71 0.56–0.91 0.68 0.53–0.87
Study setting Population-based 7 0.89 0.82–0.96 0.85 0.79–0.91 0.85
Hospital-based 3 0.85 0.65–1.07 0.83 0.66–1.05
a
for adjusted OR.
No, number; OR, odds ratio; RCTs, randomized, controlled trials.

A trend toward a dose–duration response was seen on publication bias

pooled analysis of three studies which provided sufficient data
for this analysis [11, 12, 14]. A ‘long’ duration of statin was
significantly more likely to have chemopreventive effect
(adjusted OR, 0.35; 95% CI, 0.16–0.76) than ‘short’ duration of
statin use (adjusted OR, 0.73; 95% CI, 0.51–1.05). Sufficient
information was not available to carry out stratified analysis
based on the age, gender, location of GC (cardia or non-
cardia) or on the type of statins (lipophilic versus hydrophilic).
sensitivity analysis
To assess whether any one study had a dominant effect on the
meta-analytic OR, each study was excluded and its effect on
the main summary estimate and Cochran’s Q-test P value for
heterogeneity was evaluated. While no study significantly
affected the summary estimate, exclusion of the study by Lee
et al. resulted in resolution of the previously observed marked
heterogeneity in the analysis [12]. The favorable and strong
effect sizes observed in this single study were causing
heterogeneity in the strength, but not the direction, of overall
association. On analysis after excluding this study, the
summary OR for both unadjusted (OR, 0.88; 95% CI,
0.83–0.95) and adjusted analysis (OR, 0.84; 95% CI, 0.78–0.90)
remained significant and no heterogeneity was observed in the
analysis (for unadjusted OR, Cochran’s Q-test, P = 0.56,
I 2 = 0%; for adjusted OR, Cochran’s Q-test, P = 0.74, I 2 = 0%).
Subgroup analyses were repeated after excluding this study
(Table 4). The previously statistically non-significant
association between statin use and GC risk in the Asian
population became statistically significant.
On replacing one Taiwanese study [11] with another study
from Taiwan from the same cohort [32], the overall results
(adjusted OR, 0.64; 95% CI, 0.47–0.88), as well as in the
subgroup of Asian studies (adjusted OR, 0.38; 95% CI,
0.17–0.85), were unchanged.
There was no evidence of significant publication bias, both
quantitatively (Egger’s regression test, P = 0.54) and on visual
inspection of the funnel plot (data not shown). Furthermore,
we estimate that 136 unpublished null studies (which fail to
show a chemopreventive association between statins and risk of
GC) would be needed to remove the significance from the
findings of this meta-analysis.
number needed to treat
Due to significant heterogeneity between studies and varying
incidence of GC across different regions of the world, a single
summary estimate for the number needed to treat with statins
to prevent one case of GC could not be inferred. Using an age-
adjusted incidence rate of GC in men in East Asia of 42.4 per
100 000 person years and a 32% reduction in GC risk with
statin use, 7372 East Asian men would need to be treated with
statins to prevent one case of GC per year [1]. Similarly, using
an age-adjusted incidence rate of GC of 9.0 per 100 000 person
years in Western Europe and a 14% reduction in GC risk with
statin use, 79,371 men would need to be treated to prevent one
case of GC [1].
discussion
With the high incidence of GC and very poor prognosis
associated with the diagnosis, identification of potential
chemopreventive agents is highly desirable. While aspirin and
NSAIDs [33, 34] and H. pylori eradication therapy may be
associated with reduced risk of GC [35], they are not without
significant side-effects. In this comprehensive meta-analysis of
all existing studies in almost 5.5 million patients with 5581
cases of GC, we found that statin use is associated with a 32%
reduction in the risk of GC, after adjusting for multiple
confounding factors. Given considerable heterogeneity
attributed to one study, a 16% risk reduction with statin use

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may be a more conservative and consistent estimate. Such a
chemopreventive effect of statins has also been observed for
some inflammation-associated cancers (including
hepatocellular cancer [6], esophageal cancer [36]), but not for
others (such as sporadic colorectal cancer [37], breast cancer
[38] and prostate cancer [38]) This is comparable with 22%
reduction in the risk of GC seen with aspirin/NSAID use (OR,
0.78; 95% CI, 0.69–0.87) seen in a previous meta-analysis of
observational studies [34]. Importantly, the latter may
confounded by indication, since patients with gastric ulcers (a
group at high risk for GC) may be less likely to be prescribed
aspirin/NSAIDs, thereby overestimating the apparent
chemopreventive effect of these medications.
The strengths of this analysis include the comprehensive and
systematic literature search of both observational studies and
RCTs, consistency of association between statins and GC, ability
to evaluate the potential influence of measured confounders on
the summary estimates and evaluation of duration–response
effect. The likelihood of important selection or publication bias
in our meta-analysis is small. During the identification and
selection process, we did not exclude any article because of
methodological characteristics. Our results are consistent with a
previous small meta-analysis. Kouppala et al. included only two
cohort studies in their analysis and observed a significant
chemopreventive effect of statin use (OR, 0.59; 95% CI 0.40–
0.88) [38]. In our analysis, we added numerous additional
studies, including data from RCTs, to bring the evidence base
up to date, and provide a more robust pooled estimate on the
effect of statins on GC risk. With the larger number of studies,
we were able to carry out multiple subgroup analyses, evaluate
heterogeneity and the presence of publication bias.
anti-neoplastic effect of statins
GC has two histological subtypes that have distinct carcinogenic
pathways [39]. Intestinal or well-differentiated tumors progress
through atrophic gastritis followed by intestinal metaplasia,
dysplasia and carcinoma, whereas diffuse or poorly differentiated
carcinomas are not characterized by preceding steps other than
the chronic gastritis associated with H. pylori infection. Among
the genetic changes implicated in the multi-stage gastric
carcinogenesis, amplification of c-myc and mutations of K-ras
have been commonly reported [40]. In mice models,
atorvastatin has been shown to block MYC phosphorylation and
activation, suppressing tumor initiation and growth through a
HMG-CoA reductase-dependent pathway [41]. The anti-
neoplastic effects of statins have also been demonstrated in
human GC cell lines through reduced cell division and increased
apoptosis. Using human GC cell line HGT-1, Follet et al. have
shown that lovastatin strongly suppresses genes involved in cell
division on whole transcriptome microarrays [10]. Lovastatin
also induced upregulation of cell-cycle inhibitor p21 and
suppression of anti-apoptotic survivin and Mcl-1 proteins in
these GC cell lines.
differences in observational studies
and clinical trials
The chemopreventive effect of statins was seen primarily in
observational studies which accounted for a large majority of
 | Singh and Singh
Annals of Oncology
the included GC cases (5290 cases, 94.8%). RCTs included in
the study did not demonstrate any significant chemopreventive
effect of statins though there is a trend toward statistical
significance (adjusted OR, 0.83; 95% CI, 0.66–1.05).
Importantly, the RCTs included in the meta-analysis
represented post-hoc analyses of 26 clinical trials carried out on
the effect of statins on cardiovascular morbidity [25, 30, 31].
By design, the patients enrolled in these RCTs were not at high
risk of development of GC. Also, these studies were not
adequately powered to detect a significant difference in GC
Downloaded from http://annonc.oxfordjournals.org/ at Frankfurt University Library, Section Stadt- und Universitaetsbibliothek on August 22, 2014
incidence. Moreover, since the occurrence of cancer was not
the primary objective of these trials, patients were not routinely
screened for development of GC; this might have affected the
detection rate of GC. The follow-up duration in these RCTs
was short. These factors may explain why current clinical trials
of statins do not demonstrate a statistically significant
chemopreventive effect of statins against GC.
On the other hand, the chemopreventive effect of statins seen
in observational studies may also over-estimate its true effect.
Observational studies lack the experimental random allocation
of the intervention necessary to test exposure-outcome
hypotheses optimally. Despite adjusting for numerous
covariates, it is not possible to eliminate the potential of residual
confounding. It is possible that the observed decreased risk of
GC seen in statin users may relate to a ‘healthy user’ bias [42].
Patients taking statins may be more likely to be prescribed
preventive medications and/or be more compliant with
preventive health measures, when compared with patients not
taking statins. The latter poorly compliant patients may have
other unhealthy lifestyle practices predisposing them to GC. In
our analysis, on restricting analysis to studies which adjusted for
frequency of healthcare utilization, statins continued to show a
stable and consistent chemopreventive effect against GC
(adjusted OR, 0.68; 95% CI, 0.52–0.90) [11, 13, 27]. Hence,
given the strength and consistency of association along with in
vitro data that suggest biological plausibility of preventive effects
of statins on GC, ‘healthy user’ effect is unlikely to be the
primary driver of results. Observational studies are inherently
not able to definitely establish when the intervention may exert
its influence, the minimum effective dose–duration and
frequency of medication intake that is required to achieve a
benefit. Although we found a potential duration benefit,
differing exposure definitions between studies make
recommendations regarding dosing regimens difficult.
limitations
First, the included studies did not provide data based on the
location or histological subset of GC, which are associated with
different pathogenesis and prognosis. Second, all studies did
not adjust for the same confounders. Importantly, studies
failed to adjust for H. pylori infection which is strongly
associated with GC risk. However, though biologically
plausible, multiple RCTs and meta-analyses have failed to
show a clinically significant reduction in GC risk with
H. pylori eradication [35, 43–45]. Moreover, in our analysis,
there was no significant difference in the pooled analysis of
unadjusted and maximally adjusted data from each study,
suggesting that any difference attributable to using different
Volume 24 | No. 7 | July 2013
Annals of Oncology
confounders for adjustment is likely small. Another potential
limitation that particularly applies to case–control studies
evaluating GC is recall bias. However, in most studies
pharmacy drug prescriptions information was used, and hence,
the effects of this are likely minimal. The significant
heterogeneity observed in the meta-analysis could be explained
by excluding a single study. In their single-center study of a
diabetic cohort in high-risk South Korean population, Lee et al.
observed a marked 70%–80% reduction in GC risk [12]. This
marked decrease in risk may be related to detection bias in this
referral center study as well as potential confounding by
concomitant use of other putative chemopreventive effect of
aspirin and metformin [46]. Finally, we did not contact
authors of RCTs to solicit unpublished data, and this may have
resulted in reporting bias. However, we estimated that 136
unpublished null studies (which fail to show a
chemopreventive association between statins and risk of GC)
would be needed to remove the significance from the findings
of this meta-analysis.
conclusion
Based on this comprehensive meta-analysis, statins appear to
have chemopreventive effects against GC in both Asian and
Western population. However, since the observed magnitude of
GC risk reduction associated with statins is relatively modest,
especially in the Western population, the number needed to
treat to prevent one case of GC would be large. A definitive,
randomized chemoprevention trial is needed to more
rigorously assess the effects of statins on incident GC, but
would be lengthy, logistically challenging and resource
intensive. To facilitate further clarification of statins’ GC
chemopreventive potential, clinical evaluation in an enriched
patient population (i.e. East Asian men with history of gastric
atrophy or ulcers) may be the first best step. Meanwhile, in
patients with borderline eligibility for statin therapy, other risk
factors for GC may be informative with respect to balancing
risks versus benefits for clinical decision-making.
disclosure
The authors have declared no conflicts of interest.
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Annals of Oncology 24: 1730–1740, 2013

doi:10.1093/annonc/mdt152
Published online 26 April 2013

Targeted therapies and the treatment of non-clear cell

renal cell carcinoma
J. Bellmunt1*† & J. Dutcher2
1
Solid Tumor Oncology (GU & GI), Medical Oncology Service, University Hospital del Mar-IMIM, Barcelona, Spain; 2St Luke’s-Roosevelt Hospital Center, Beth Israel
Medical Center, Continuum Cancer Centers, New York, USA

Received 6 November 2012; revised 30 January 2013; accepted 11 March 2013

Background: Targeted therapies have shown profound effects on the outcome of patients with advanced renal cell
carcinoma (RCC). However, the optimal treatment for RCC of non-clear cell histology (nccRCC)—typically excluded
from trials of targeted agents—remains uncertain.
Materials and methods: By carrying out extensive searches of PubMed and ASCO databases, we identified and
summarised research into the biological characteristics, clinical behaviour and treatment of different histological
subtypes of nccRCC, focusing on targeted therapy.
Results: The available data suggest that treatments currently approved for RCC are active in ncc subtypes, although
the overall clinical benefit may be less than for clear cell RCC. Temsirolimus has proven benefit over interferon-alfa
(IFN-α) in patients with nccRCC, based on phase III data, while everolimus, sunitinib and sorafenib have all
demonstrated some degree of activity in nccRCC in expanded-access trials. No clear picture has emerged of whether
individual histological subtypes are particularly responsive to any individual treatment.
Conclusions: Further molecular studies into the pathogenesis of RCC histological subtypes will help direct the
development of novel, appropriate targeted agents. Clinical trials specifically designed to evaluate the role of targeted
agents in nccRCC are ongoing, and data from trials with sunitinib and everolimus will be reported soon.
Key words: chromophobe renal cell carcinoma, non-clear cell RCC, papillary RCC, sarcomatoid features, targeted
therapies, Xp11 translocated RCC

*Correspondence to: Dr Joaquim Bellmunt, Section Chief, Solid Tumor Oncology

(GU & GI), Medical Oncology Service, University Hospital del Mar-IMIM, Paseo Maritimo
25-–29, Barcelona 08003, Spain. Tel: +34-93-2483137; Fax: +34-93-2483366;
E-mail: jbellmunt@parcdesalutmar.cat
†
Present address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.

© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.