Download The Prevention of Colitis-Related Cancer by 5

nature publishing group
EDITORIAL
737
The Prevention of Colitis-Related Cancer by
5-Aminosalicylates: An Appealing Hypothesis that
Remains Unproven
Jonathan P. Terdiman, MD1
Abstract: Whether or not 5-aminosalicylates can
prevent colorectal cancer among patients with colitis
remains an open question. The observational studies
examining this question have provided conflicting
results, but none of these studies have been of
sufficient quality to provide a definitive answer one
way or another.
include performance of surveillance colonoscopy with biopsy (6).
However, colonoscopic surveillance is far from a perfect solution,
both because of the intrusiveness of the procedure, and because
the benefits in terms of risk reduction remain uncertain (6).
Therefore, the interest in using a safe class of pharmaceuticals,
such as the 5-ASAs, to reduce the risk of colitis-related cancer is
understandable.
Am J Gastroenterol 2011; 106:737–740; doi:10.1038/ajg.2011.56
CHEMOPREVENTION OF COLITIS-RELATED CANCER
BY 5-ASAS IS BIOLOGICALLY PLAUSIBLE
INTRODUCTION
The idea that cancer risk among patients with colitis can be reduced
by therapy with 5-aminosalicylates (5-ASAs) was first suggested
by Pinczowski et al. (1) in 1994. Since that time, a large number of
observational studies have been published on the topic, including
one by Bernstein et al. (2) in this edition of the American Journal
of Gastroenterology. The results have been conflicting, a source of
frustration to practitioners. As of this writing, I believe it remains
plausible, but still unproven, that 5-ASAs can reduce the risk of
colitis-related colorectal cancer (CRC). Why is it that we cannot
agree on the answer one way or another?
WHAT WE CAN AGREE UPON
Most studies (3), but not all (4), agree that patients with longstanding extensive ulcerative or Crohn’s colitis have an increased
risk for CRC, with a cumulative lifetime risk in the range of
10–20%, representing a two- to fivefold increased risk compared
with the risk in the general population (3). Established risk factors for developing CRC in the setting of colitis include the extent,
age of onset, and duration of the disease, along with the severity
of the inflammation over time (3,5). Other unequivocal risk factors include the presence of primary sclerosing cholangitis and a
family history of sporadic CRC (3). Efforts to mitigate the risk
There are ample pre-clinical studies reporting on the molecular
mechanisms by which 5-ASAs might prevent CRC (7). These
pre-clinical studies indicate that the potential beneficial effects
of 5-ASAs extend beyond simply reducing colonic inflammation
over time. 5-ASAs may interfere with cell-cycle progression and
induce apoptosis in neoplastic cells, scavenge reactive oxygen or
nitrogen metabolites to reduce the risk of DNA damage, or impact
on signaling pathways crucial to neoplastic progression (7). Some
of the most compelling data indicate that 5-ASAs may stop
cell-cycle progression by activating replication checkpoints resulting in S-phase arrest (8). The activation of replication checkpoints
can improve the fidelity of DNA replication in colorectal cells
(9,10). Other recent important work on the topic suggests that
5-ASAs may stop neoplastic progression by inhibiting β-catenin
signaling (11).
Though these pre-clinical studies are of interest, they cannot,
however, confirm that 5-ASAs reduce the risk of developing
colitis-related cancer.
THE PROBLEM WITH OBSERVATIONAL STUDIES
All of the studies examining the association between exposure
to 5-ASAs and development of CRC have been observational,
either case–control or cohort studies, and herein is the root
of our problem. Though randomized, controlled trials are
1
Gastroenterology Division, University of California, San Francisco, San Francisco, California, USA. Correspondence: Jonathan P. Terdiman, MD, Gastroenterology
Division, University of California, San Francisco, 2330 Post Street, Suite 610, San Francisco, California 94115, USA. E-mail: [email protected]
Received 12 January 2011; accepted 25 January 2011
© 2011 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
INFLAMMATORY BOWEL DISEASE
see related article on page 731
INFLAMMATORY BOWEL DISEASE
738
Terdiman
imperfect, they are preferable to observational studies, even welldone ones, for assessment of a treatment effect (12,13). Observational studies are prone to introduce bias even when it appears
that the treated and control groups are similar with respect to
key risk factors, and the results can veer unpredictably in either
direction (12). A randomized, controlled trial of 5-ASAs in the
prevention of colitis-related cancer, however, has been considered
impossible to undertake because of the large number of subjects
and long duration of follow-up required. If we concede that we
must use observational data to address this question, what would
be the features of the ideal study? The study population needs to
be sufficiently large and well described, and the study population
must be followed for a sufficient length of time. The study subjects need to be comparable in terms of the presence or absence of
other established risk factors for colitis-related cancer, comparable for exposure to other interventions that might impact on their
risk for colitis-related cancer such as surveillance colonoscopy or
even just visits to the doctor, and comparable for the likelihood
that they would be treated with 5-ASAs. Information on the exposure to 5-ASAs needs to be sufficiently detailed in terms of dose
and duration and adherence, and these data need to be assessed in
a standardized, valid, and reliable manner. Similarly, the outcome
of interest, CRC and/or dysplasia, needs be assessed in a standardized and reliable manner.
PREVIOUS STUDIES OF 5-ASA USE THE RISK OF
COLITIS-RELATED CANCER
Unfortunately, none of the observational studies published or
presented on this topic completely satisfy the high-quality standard
outlined above. Let’s briefly review a number of key studies, both
positive and negative to understand their strengths and weaknesses.
The seminal case–control study by Pinczowski et al. (1) found
that ≥3 months of 5-ASA therapy was protective against the development of colitis-related cancer (relative risk, 0.38; 95% confidence interval (CI), 0.2–0.69). The study had the virtue of being
first to make this observation, and it was the only one to find a
protective effect specifically for sulfasalazine. The study was large,
population based, and the length of follow-up was appropriate, though imprecisely specified. The study however is limited
by a lack of data on the dose and duration of treatment with
5-ASAs. In fact, the investigators could only categorize subjects as
having used more or less than 3 months of therapy over time.
The study also used very imprecise surrogates to establish disease
activity over time, and importantly, the data for the study were
all collected by a single investigator by chart review, who was not
blinded to the outcome of interest.
Eaden et al. (14) undertook a case–control study using very
similar methods to that employed by Pinczowski. Eaden et al.
found that regular 5-ASA use reduced cancer risk by 75%. The
Eaden study provided more detailed information about drug
exposure, and more detailed information about other healthrelated behaviors that might reduce CRC risk than was reported
by Pinczowski. Eaden et al. established that not all 5-ASAs may
The American Journal of GASTROENTEROLOGY
be protective, with a protective effect only seen with the use of
mesalamine and not sulfasalazine, and Eaden et al. found that
visiting a doctor regularly also reduces risk. To some, the latter
finding suggests that regular use of 5-ASAs might simply be a
marker of healthy behavior, which might result in a lower cancer
risk, rather than a true chemopreventive agent. The Eaden study
did not ascertain cases and controls from the same population,
and it still employed unblinded chart review to collect the data.
The case–control study by van Staa et al. (15) was the first on
the topic to use a well-validated, population-based data set, the
United Kingdom’s General Practice Research Database. Use of the
General Practice Research Database would be expected to provide
higher-quality data than usually available through chart review,
and the General Practice Research Database includes computerized data regarding drug prescriptions. The study, however, was
limited to users of 5-ASAs, and therefore only compared regular
users as compared with irregular users, and no drug data were
available beyond the prior 24 months. The study did have data
on exposure to important health-related behaviors, such as seeing
the doctor or having a colonoscopy, but not regarding the extent
or severity of the colitis. A protective effect for regular 5-ASA
therapy in the year preceding CRC was found (odds ratio (OR),
0.60; 95% CI, 0.38–0.96).
The studies by Pinczowski et al. (1), Eaden et al. (14), and van
Staa et al. (15) all found a protective effect for 5-ASA use with
respect to the development of colitis-related cancer. However,
a growing number of studies, including the one by Bernstein
et al. (2), in this edition of AJG, have produced less certain (5,16),
or frankly negative results (2,17,18). Let’s review several of these
studies in more detail.
Rutter et al. (5) published a case–control study using data from
the St. Mark’s Hospital dysplasia surveillance database. The study
is notable because both the cases and controls are drawn from
a well-characterized group of patients all undergoing surveillance colonoscopy. The study also does a very admirable job of
assessing the severity of colonic inflammation over time. Unfortunately, data regarding drug exposure are not very detailed. Rutter
et al. found that use of 5-ASAs for > 10 years was not protective
for colorectal neoplasia (cancer or dysplasia) (OR, 2.38; 95% CI,
0.67–8.54). However, when sulfasalazine users were excluded
from the analysis, a protective effect for mesalamine use was suggested, but could not be confirmed (OR, 0.65; 95% CI, 0.26–1.62).
Unfortunately, the reported risk associated with 5-ASA use was
not adjusted in a multivariate analysis that included other key
variables, such as the histological inflammation score.
My colleagues and I performed the largest case–control study to
date regarding the impact of 5-ASA therapy on colitis-related cancer risk, and the results were unequivocally negative (18). Using
two large insurance administrative claims databases, we compared
364 cancer cases with 1172 controls. The study had the virtues of
being large, population-based, and having access to computerized
drug prescription data. The study suffers, however, from a lack of
long-term drug data, with the analysis limited to drug use in the
12 months before the CRC diagnosis, and from a complete lack
of detail regarding the extent and severity of the colitis over time.
|
VOLUME 106 APRIL 2011 www.amjgastro.com
Use of 5-ASA therapy of any dose or duration during the 12 months
before the CRC diagnosis was not associated with a reduced risk
of CRC (OR, 0.97; 95% CI, 0.77–1.23), nor was there a protective
effect when the analysis was limited to mesalamine users.
The Bernstein study (2) represents an expansion of a previously
published work (19), and it has many virtues. This study is really
two studies in one, a restrospective cohort study assessing CRC
incidence among 8,744 subjects with inflammatory bowel disease,
comparing 5-ASA users (ever, ≥1 year, ≥5 years, ≥7.5 years of
cumulative use) with nonusers, and a case–control study assessing exposure to 5-ASA therapy among 101 subjects with CRC as
compared with 303 controls. Data for both studies were obtained
from the University of Manitoba Inflammatory Bowel Disease
Epidemiology Database, which contains computerized data on
prescription drug use dating back to 1995. Both studies found no
protective effect for 5-ASA therapy. For example, in the cohort
study, subjects who used 5-ASAs for at least 5 years (n = 1,109)
the hazard ratio for developing CRC was 2.01 (95% CI, 1.04–3.9).
In the case–control study, CRC cases had a similar prevalence of
5-ASA use compared with controls with respect to the number
of prescriptions or median days the drug was supplied. The OR
for developing CRC among those with ≥5 years of 5-ASA was
1.96 (95% CI, 0.84–4.55). The study by Bernstein has the virtues
of large size and adequate length of follow-up and detailed data
regarding prescription drug refills. The median number of days
the drug was supplied for the entire study population was 590,
with 66% of the cohort having ever taken a 5-ASA and 38% with
1 year of cumulative use and 13% with 5 years of cumulative use.
The study has important limitations too. Though we are provided
with detailed data on total drug exposure, the consistency of dosing over time and the actual daily dose was not reported. Is it
possible that the chemopreventive effect of 5-ASAs was lost, even
among those subjects with a large cumulative dose of the medication, because their use was very inconsistent over time, or because
the daily dose was too small? More importantly, the investigators
were unable to control for the extent and severity of disease over
time. Certainly, the positive association of 5-ASA use with the
occurrence of CRC may be the consequence of subjects with more
inflammation over time being more likely treated with 5-ASAs.
SO WHAT SHOULD WE CONCLUDE?
All of the observational studies summarized above, and the others
published to date, are lacking in important ways, from the methods of data collection, to the populations studied, to the length
of follow-up, to the lack of data regarding critical issues such as
drug exposure, or the extent and severity of the disease over time.
Also, as one reads through the observational studies summarized
above, you are struck by the feeling that patients treated regularly
with 5-ASAs are fundamentally different than patients who are
not, especially during recent years in which 5-ASA use seems to
be so ubiquitous.
In the end, we must conclude that none of the published studies published to date are sufficiently robust to definitively answer
the question at hand, and I am afraid that further attempts to
© 2011 by the American College of Gastroenterology
pool the results of the published studies, as we have done previously (20) will not provide the answer either. Is it possible for
any observational study to be of sufficient size and quality to sway
us? The answer is yes, but it will not be easy. Given the limits of
observational data in general, and the mixed results of the studies
to date, we must remain skeptical that 5-ASAs prevent cancer. For
an observational study to change our minds, it must have clear cut
results and it must be one of very high quality, far beyond what has
been published so far. The GETAID group from France has yet to
publish their case–control study on the subject using data from the
CESAME cohort, but the results were presented last year at DDW
(21). These investigators did find a protective effect of any 5-ASA
use in the year before the occurrence of CRC among the 94 colitis
patients at greatest risk for colitis-related cancer (OR, 0.46; 95% CI,
0.24–0.85), and unlike previous published studies, the investigators
adjusted for the propensity of the cases and controls to be treated
with 5-ASAs, a more sophisticated way of adjusting for important
differences in the exposed and nonexposed groups. Though we can
reserve final judgment until the study is published, I think the lack
of detailed data regarding drug exposure and disease severity will
lead us to conclude that this study is not the last word on the topic.
So what is the final word on whether or not 5-ASA therapy can
reduce the risk of colitis-related cancer? As of now, I think we
must conclude that the hypothesis has not been proven, though it
has not been definitely disproven either. In the absence of a clear
answer, I think it is wrong to advise patients that 5-ASAs are likely
to be protective against cancer, or to treat patients with 5-ASA
medications for this purpose. I still hold out hope that observational data of sufficient quality will be generated to provide us
with a definite answer, but because of the inherent limitations of
observational studies, it will not be easy to achieve this goal.
CONFLICT OF INTEREST
The author declares no conflict of interest.
REFERENCES
1. Pinczowski D, Ekbom A, Baron J, Yuen J, Adami H. Risk factors for
colorectal cancer in patients with ulcerative colitis: a case-control study.
Gastroenterology 1994;107:117–20.
2. Bernstein CN, Nugent Z, Blanchard JF. A population-based study of
5-aminosalicylate use and colorectal cancer in IBD. Am J Gastroenterol
2011;106:731–6 (this issue).
3. Bergeron V, Vienne A, Sokol H et al. Risk factors for neoplasia in
inflammatory bowel disease patients with pancolitis. Am J Gastroenterol
2010;105:2405–11.
4. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Long-term risk of
cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clin Gastroenterol Hepatol 2004;2:1088–95.
5. Rutter M, Saunders B, Wilkinson K et al. Severity of inflammation is a
risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology
2004;126:451–9.
6. Collins PD, Mpofu C, Watson AJ, Rhodes JM. Strategies for detecting
colon cancer and/or dysplasia in patients with inflammatory bowel disease.
Cochrane Database Syst Rev 2006;19:CD000279.
7. Lyakhovich A, Gasche C. Systematic review: molecular chemoprevention of
colorectal malignancy by mesalazine. Aliment Pharmacol Ther 2010;31:202–9.
8. Luciani MG, Campregher C, Fortune JM, Kunkel TA, Gasche C. 5-ASA
affects cell cycle progression in colorectal cells by reversibly activating a
replication checkpoint. Gastroenterology 2007;132:221–35.
9. Gasche C, Goel A, Natarajan L, Boland CR. Mesalazine improves replication fidelity in cultured colorectal cells. Cancer Res 2005;65:3993–7.
The American Journal of GASTROENTEROLOGY
739
INFLAMMATORY BOWEL DISEASE
Editorial
INFLAMMATORY BOWEL DISEASE
740
Terdiman
10. Campregher C, Honeder C, Chung H, Carethers JM, Gasche C. Mesalazine
reduces mutation in transforming growth factor beta rector II and activin
type II receptor by improvement of replication fidelity in mononucleotide
repeats. Clin Cancer Res 2010;16:1950–6.
11. Brown JB, Lee G, Managlia E et al. Mesalamine inhibits epithelial
beta-catenin activation in chronic ulcerative colitis. Gastroenterology
2010;138:595–605.
12. Deeks JJ, Dinnes J, D’Amico R et al. Evaluating non-randomized
intervention studies. Health Technol Assess 2003;7:1–173.
13. Vandenbroucke JP, von Elm E, Altman DG et al. STROBE Initiative.
Strengthening the reporting of observational studies in epidemiology:
explanation and elaboration. Ann Intern med 2007;147:W163–94.
14. Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal
cancer prevention in ulcerative colitis. Aliment Pharmacol Ther
2000;14:145–53.
15. van Staa TP, Card T, Logan RF, Leufkens HGM. 5-aminosalicylate use and
colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 2005;54:1573–8.
The American Journal of GASTROENTEROLOGY
16. Velayos FS, Loftus EV, Jess T et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.
Gastroenterology 2006;130:1941–9.
17. Jess T, Loftus EV, Velayos FS et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county,
Denmark and Olmsted county, Minnesota. Am J Gastroenterol 2007;102:829–36.
18. Terdiman JP, Steinbuch M, Blumentals WA, Ullman TA, Rubin DT. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients
with inflammatory bowel disease. Inflamm Bowel Dis 2007;13:367–71.
19. Bernstein CN, Metge C, Blanchard JF, Yogendran M. Does the use of 5aminosalicylates in inflammatory bowel disease prevent the development of
colorectal cancer? Am J Gastroenterol 2003;98:2784–8.
20. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of
observational studies. Am J Gastroenterol 1995;100:1345–53.
21. Carrat F, Seksik P, Bouvier AM et al. Aminosalicylates, thiopurines and the
risk of colorectal cancer in inflammatory bowel disease: a case-control study
nested in the CESAME cohort. Gastroenterology 2010;138:S–47 (A 255).
|
VOLUME 106 APRIL 2011 www.amjgastro.com