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Annu. Rev. Med. 2000. 51:511–523Copyright q 2000 by Annual Reviews. All rights reserved
0066–4227/00/0201–0511$12.00 511
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
AND CANCER PREVENTION
John A. Baron1 and Robert S. Sandler2
1Departments of Medicine and Community and Family Medicine, Dartmouth MedicalSchool, Hanover, New Hampshire 03755; e-mail: [email protected] of Digestive Diseases and Nutrition, Department of Medicine, Center forGastrointestinal Biology and Disease, University of North Carolina at Chapel Hill,Chapel Hill, North Carolina 27599; e-mail: [email protected]
Key Words aspirin, sulindac, colorectal neoplasms, adenoma
Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin,appear to have clinically significant anticarcinogenic effects in the gastrointestinaltract. Epidemiological data indicate that use of these drugs is inversely associated withthe risk of sporadic colorectal cancer, and clinical trials among patients with familialpolyposis coli show that NSAIDs can lead to the regression of large bowel adenomas.Animal studies have reported a similar efficacy of NSAIDs against experimental car-cinogenesis. A consistent pattern in this research is that continued long-term use ofNSAIDs is required for an anticancer effect—up to 15 or 20 years before a reducedrisk of colorectal cancer appears. Epidemiological data also suggest possible protec-tive effects in the stomach and esophagus. The mechanisms underlying any chemo-preventive effect of NSAIDs are not clear. Inhibition of cyclooxygenase is onepossibility, but pathways independent of cyclooxygenase and prostaglandins are alsopossible.
INTRODUCTION
Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have a longand distinguished history in internal medicine. Aspirin has served as an anti-inflammatory drug, analgesic, and antipyretic for over a century, and morerecently has emerged as an effective agent for the secondary prevention of car-diovascular disease. Strikingly consistent recent findings regarding aspirin andother NSAIDs now suggest a new role for these compounds—the chemopre-vention of cancer.
SPORADIC COLORECTAL CANCER AND ADENOMAS
In humans, research regarding the possible anticarcinogenic effect of NSAIDshas focused on the effect of aspirin in the large bowel. Most published epide-miological studies have reported an inverse association of colorectal cancer risk
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with aspirin use (1–9). A large, hospital-based, case-control study (2) generatedconsiderable interest in the NSAID hypothesis and provided data that typify muchof what followed. In this study, regular NSAID users (largely aspirin users) wereabout half as likely to develop colorectal cancer as nonusers [multivariate relativerisk 0.5 (95% CI 0.2–0.9)]. The protective effect was seen for both colon andrectal cancer, for men and women, and for all age groups. Longer use was asso-ciated with a lower risk, although the trend was not statistically significant. Sub-jects who had stopped taking NSAIDs more than a year before they wereinterviewed did not have decreased risk, a pattern that suggests that the drug mayhave delayed rather than prevented cancer development.
Subsequent studies have confirmed these findings (10). Two other investiga-tions are particularly persuasive. In a very large cohort study, .1 million menand women provided information on personal habits and were monitored pas-sively for mortality over 6 years (3, 4). More than 620,000 subjects provided dataon the use of aspirin. In this group, the age-adjusted relative risk of developingcolon cancer for subjects who used aspirin 16 or more times per month was 0.60(95% CI 0.40–0.89) among men and 0.58 (95% CI 0.37–0.90) among women.There was a clear pattern of decreasing risk with increasing frequency of aspirinuse, and adjustment for multiple covariates did not affect the findings (4). Similar,although somewhat less consistent, findings were reported for rectal cancer (3).More detailed data regarding the association of aspirin with colorectal cancer riskwere provided by a follow-up study of 89,644 nurses (7). Aspirin clearly had aprotective effect, although this became significant only after 20 years of regularuse (Figure 1). Low doses appeared to be effective, but there was no protectiveassociation after cessation of use (Figure 1).
One study conducted in a California retirement community failed to demon-strate a protective effect of NSAIDs on colorectal cancer risk (11). This investi-gation differed from others in its focus on the elderly: The median age of thesubjects was 73 years, in contrast to ,60 years in the large cohort studies thatpublished relevant data (4, 7). This raises the possibility that the effects of aspirinon large-bowel neoplasia are less pronounced or absent in older individuals, apattern seen in some other studies (2, 9). Also, a high proportion of the Californiacohort was taking aspirin for cardiovascular protection, i.e. presumably in lowdoses. Such findings are consistent with a higher dose requirement for an effecton large-bowel cancer, although other studies suggest that low cardioprotectivedoses also reduce risk of colon cancer (5–8, 12).
NSAIDs may operate early in the carcinogenesis sequence. Aspirin has beenassociated with a reduced risk of sporadic large-bowel adenomas, presumed pre-cursors of most cancers (5, 13–16). The relative risk has been about 0.5 for regularusers compared with nonusers, and the studies have shown remarkably consistentresults. Research on both colorectal cancer and adenoma indicates that a protec-tive effect of NSAIDs on neoplasia appears to require continued use; infrequentor previous use has generally not been associated with a reduced risk (1–4, 7, 9,13, 14).
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Figure 1 Colorectal cancer risks. (a) Multivariate relative risks of colorectal cancer and95% CI based on the level of aspirin use among women who used aspirin from 1980through 1984, compared with nonusers. (b) Age-adjusted relative risks of colorectal cancerand 95% CI based on the number of consecutive years of regular aspirin use among aspirinusers compared with nonusers. (Adapted with permission from Reference 7.)
There has been relatively limited investigation regarding the possible cancer-protective effects of NSAIDs other than aspirin. As a group, these agents havebeen associated with a reduction in risk of colorectal cancer similar to that ofaspirin (1, 8, 12, 17). Three investigations of colorectal adenomas also reportedsimilar effects for aspirin and other NSAIDs (5, 13, 16). A protective effect hasgenerally not been found for acetaminophen or paracetamol, other analgesic anti-
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pyretic agents that are pharmacologically quite distinct from aspirin (3, 4, 6, 8,14, 16). This pattern of findings suggests that the association between NSAIDsand reduced risk of colorectal cancer is not due to the effects of the underlyingdisorders for which analgesics or antipyretics are taken.
The observational studies described above have provided important supportfor the aspirin hypothesis, but stronger evidence would come from a controlledtrial in which participants are assigned to aspirin or placebo at random. ThePhysicians’ Health Study, a trial in which one treatment was 325 mg of aspirinevery other day, is the only clinical trial that has studied colorectal cancer (18,19). In the aspirin group, there was an increased risk of diagnosed colorectalcancer within 3 years of randomization—an effect that would be expected ifaspirin use led to the diagnosis of cases present (but unrecognized) at study entry.The relative risk fell over time to 0.77 for the period $5 y after randomization(p for trend 4 0.09). The risk of diagnosed sporadic adenoma was modestlydecreased in the aspirin group, but because no uniform bowel surveillance wasapplied, the relative incidence of adenomas in general was not estimated (18).The number of adenomas observed in the trial was considerably fewer thanexpected from population prevalence figures, suggesting that the study methodsmay have been insensitive for the detection of these benign tumors. As discussedabove, the 5-y treatment and follow-up period was probably too short to dem-onstrate an effect of aspirin on risk. The investigators extended the follow-upperiod to 12 y, although the longest treatment period was still only 7 y (19). Againno protective effect of aspirin against colorectal cancer was found.
Four intervention studies have focused on the effect of NSAIDs on the regres-sion of sporadic adenomas. In two uncontrolled, unblinded series, the findingshave been mixed (20, 21). A small, randomized trial found hints of a regressiveeffect of sulindac, but the results were not statistically significant (22). A subse-quent, placebo-controlled study, published only in abstract form to date, reportedmore marked efficacy (23).
NEOPLASIA IN FAMILIAL POLYPOSIS COLI
Patients with familial adenomatous polyposis coli (FAP) are at particularly highrisk for colon cancer. Patients with this syndrome have an inherited mutation inthe APC gene, an important tumor-suppressor gene in the large bowel (24).Although the genetic changes in the adenomas indicate that the underlying processis likely to be similar to that in sporadic colorectal cancer, studies of FAP are notnecessarily generalizable to the population at large.
The first clinical hints that NSAIDs might be effective against neoplasia inFAP came from small, unblinded, uncontrolled studies of short duration (25, 26).There were striking findings after the administration of sulindac (300–400 mg/day) in 11 patients: All polyps were eliminated except for a few in the rectumand anal canal. Even patients with more than 1000 polyps had virtually complete
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remission. When several patients stopped their medication, their adenomasrecurred. Indomethacin, on the other hand, did not lead to regression of adenomas,suggesting that there was no general effect of NSAIDs.
Randomized, placebo-controlled, double-blind trials of NSAIDs amongpatients with FAP have been conducted more recently. In a study among patientswho had previously undergone colectomy and ileorectal anastomosis (27),patients given sulindac at 300 mg/day had a complete or near-complete regressionof polyps after 4 months of treatment, whereas in the placebo group there was atendency for an increase. When the drug was withdrawn in the crossover portionof the study, polyps soon recurred.
A larger trial was conducted with sulindac in 22 patients with familial pol-yposis, many of whom had not undergone prior surgery (28). The investigatorscounted and measured polyps in the distal 20 cm of large bowel. At 9 months,the number of polyps in the sulindac group had decreased 44%, and the size haddecreased 35%; no patient had complete resolution of polyps. The number andsize of polyps increased 3 months after cessation of sulindac but remained lowerthan baseline values (Figure 2).
These data are exciting indications that NSAIDs may actually lead to theregression of established neoplasia. However, like the observational data dis-cussed above, these studies indicate that the neoplastic effect of NSAIDs is rapidlyreversible after cessation of NSAID use. Also, reports of FAP patients who hadregression of adenomas on NSAIDs but developed carcinoma nonetheless empha-size the fact that protection from NSAIDs is incomplete (29).
Patients with FAP also develop premalignant adenomas in their duodenum andperiampullary region, and duodenal adenocarcinoma has become an importantcause of death in FAP patients who have undergone colectomy. One randomized,blinded, placebo-controlled trial with sulindac demonstrated regression of bothrectal and duodenal polyps (30). In contrast, an uncontrolled study found nobenefit of sulindac for periampullary polyps (31).
CARCINOGENESIS STUDIES
NSAIDs also have important effects on experimental carcinogenesis (32). In moststudies, these agents have inhibited the growth and clinical expression of trans-planted tumors and carcinogen-induced skin tumors in rats (33–35). NSAIDs alsoprevent experimental intestinal cancers induced by both directly and indirectlyacting chemical agents or by radiation (36–39). The activity of NSAIDs has beenseen when they are given weeks after carcinogen administration or during theearly promotion or late initiation phases of carcinogenesis. Although most inves-tigations have given the drugs orally, others used subcutaneous or intraperitonealadministration and reported similar efficacy. As in the human epidemiologicaland experimental findings, the anticancer effect is reversible; tumor occurrenceincreases shortly after discontinuation of the agent, rapidly equaling that in
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untreated animals (36, 37). In Min/` mice (a murine analog of human FAP,heterozygous for an APC mutation), NSAIDs (usually sulindac) inhibit tumorformation and cause regression of existing tumors (39–41).
CONCLUSIONS REGARDING NSAIDS ANDCOLORECTAL CANCER
On balance, the literature on aspirin and NSAID prevention of colorectal neopla-sia is extremely compelling. With only rare exceptions, studies with differentdesigns, populations, locations, agents, and investigators have reached the sameconclusions: Aspirin and other NSAIDs appear to decrease the risk for colorectalneoplasia by approximately half. Studies have shown that drugs of this class
Figure 2 Mean (5SE) percent change from base line in the number (a) and size (b) ofpolyps. (Adapted with permission from Reference 28.)
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decrease the risk not only of colorectal cancer but also of adenomas. Experimentalstudies with sulindac in patients with FAP show regression of adenomas; lessconsistently, polyp regression has been observed in patients with sporadic ade-nomas. Up to 20 years of regular use seems to be required before the incidenceof invasive cancers is decreased. The findings from human studies are supportedby data from experimental investigations in animals. One clinical trial of aspirindid not find a reduced risk of colorectal cancer, but the design of the study madethe detection of an effect unlikely (18, 19).
Cancers Outside the Large Bowel
Several studies have published data regarding the relationship between aspirinuse and the risk of cancer at gastrointestinal sites outside the large bowel.Although these data are less extensive than those for the colorectum, use ofNSAIDs has also been inversely related to the risk of cancer of the esophagusand stomach (3, 42–44).
Although some studies have reported that regular aspirin use may reduce therisk of breast cancer in women (45, 46), other investigations have found no asso-ciation (2, 3, 47). In general, there does not seem to be any association betweenaspirin use and the risk of hematopoietic malignancies or cancers of the bladderor female genital tract (2, 3, 9, 11).
Thus, aspirin and other NSAIDs appear to have antineoplastic properties thatseem to be manifest in the lumen of the digestive tract, especially the large bowel.Although research at other sites is not extensive, it appears unlikely that aspirinor other NSAIDs are effective in preventing cancer at other anatomic sites.
Mechanisms of the Anticarcinogenic Effect of NSAIDs
The mechanisms that could explain a protective effect of NSAIDs on carcino-genesis are not clear, although several possibilities have emerged. In vitro inves-tigation has found that NSAIDs either stimulate (48) or decrease (49–52) cellgrowth. The decrease in proliferation is associated with a shift in the cell cycleaway from S phase and G2/M and toward G0/G1 in conjunction with a reductionin several cyclin-dependent kinases (32). Applied topically on skin, NSAIDsinhibit phorbol-ester–induced increases in ornithine decarboxylase (ODC) activityor DNA labeling, but seem to have little impact when applied without phorbol-esters (35, 53, 54). In rat bowel, findings have varied. NSAIDs have been reportedboth to stimulate and to decrease mucosal proliferation, as well as to decrease theproliferative response to bile acid (55–57). In a series of small studies in humans,NSAIDs had no effect on the proliferation of the normal rectal mucosa (27, 58–61) or decreased proliferation (30). Thus, the in vivo effect of NSAIDs on cellproliferation is not clear and may depend on other stimuli.
In contrast to the conflicting data regarding proliferation, numerous in vitrostudies have shown that NSAIDs can directly induce programmed cell death(apoptosis) in both transformed and nontransformed colon cell lines (51, 52).
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More limited in vivo data confirm these findings. In Min mice, which havedecreased apoptosis in intestinal flat (normal-appearing) mucosa compared withwild-type littermates, sulindac increased apoptosis to normal levels (39). Similarfindings have been reported for mice without APC mutations (62). Sulindac alsoincreased apoptosis in azoxymethane-induced tumors in F344 rats (63, 64). Inhumans with FAP, one study found that sulindac increased apoptosis in the nor-mal-appearing mucosa (59).
Despite different chemical structures, aspirin and other NSAIDs share anability to inhibit prostaglandin (PG)-endoperoxide synthase (cyclooxygenase)enzymes in the synthetic pathway of PGs (32, 52). Two isoforms of cyclooxy-genase (COX) have been identified: COX-1 (constitutively expressed in mostmammalian tissues) and COX-2 (an inducible form associated with inflamma-tion). Because PGs have marked cytologic and metabolic effects and are importantregulatory factors for epithelial cell function, and because NSAIDs are effectiveagainst inflammatory diseases because of their inhibition of PG production, it istempting to ascribe any anticancer effect of NSAIDs to their inhibition of PGs.Although PGs are probably not carcinogenic in themselves, they have been impli-cated in experimental carcinogenesis (65). Production of PGs is greatly increasedin experimental tumors, and, under certain circumstances, PGs can stimulate pro-liferation and DNA synthesis and suppress aspects of the immune response toneoplastic cells (52, 65, 66). Moreover, there is some evidence that prostaglandinanalogs can reverse antineoplastic activities of NSAIDs, such as inhibition of cellproliferation (67), inhibition of ODC induction (35), and inhibition of tumor pro-motion itself (67). In humans, high concentrations of PGs have been found in avariety of tumors; prostaglandin E2 concentrations are elevated in human colo-rectal cancers and adenomas (32). COX-2 mRNA and COX-2 protein (but notCOX-1 products) are overexpressed in sporadic large-bowel adenomas and can-cers (32).
NSAIDs could also affect carcinogenesis through pathways independent ofPGs. COX inhibition may lead to an increased cellular arachidonic acid pool,which in turn could induce apoptosis through stimulation of sphingomyelinaseand the production of ceramide (68). Also, COX enzymatic activity has the poten-tial to activate procarcinogens and may catalyze the production of malondialde-hyde, a known carcinogen (32, 52). Carcinogen-DNA adducts generated by COXhave been demonstrated (32), and NSAIDs can inhibit the formation of theseadducts (32). This carcinogen-detoxification mechanism does not explain theregression of adenomas associated with NSAID use in FAP, nor the reversal ofmalignant transformation (32).
There is also evidence that antineoplastic effects of NSAIDs may be indepen-dent of COX. NSAIDs have been found to inhibit proliferation of colon cancercell lines that do not express COX and do not produce PGs (32, 52). Sulindacsulfone, a sulindac metabolite that does not inhibit COX, prevents experimentalcolorectal cancer as effectively as sulindac itself and induces apoptosis (32, 52,69). In some in vitro models, cytostatic effects of NSAIDs have been found
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not to correlate with anti-inflammatory potency or to resist reversal by additionof PGs.
PROSPECTS FOR NSAID CANCERCHEMOPREVENTION
Considerable observational research and some data from clinical trials in FAPsuggest that NSAIDs may exert chemoprotective effects in the large bowel. Morelimited data indicate similar effects in the esophagus and stomach. Assuming forthe moment that these findings reflect a causal protection, what are the prospectsfor effective chemoprevention?
A lower risk of colorectal cancer from NSAIDs does not mean that their wide-spread use should be recommended. First, the proper dose and duration areunknown. More importantly, serious adverse effects, such as gastrointestinalbleeding and hemorrhagic stroke, can occasionally occur with these medications.Recommendations regarding widespread chemopreventive use should await theresults of ongoing randomized trials and the clarification of the risk-benefit bal-ance of long-term use.
There are several research needs at this point. One is confirmation of thecancer-sparing effect in the large bowel, ideally through clinical trials. Dose andduration requirements might be elucidated through such trials or might requireadditional observational analysis. Clarification of the extent of the cancer-sparingeffect at other tumor sites is also important. Hopefully, such investigation wouldalso identify the mechanism by which aspirin exerts its anticarcinogenic effect.
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Annual Review of Medicine Volume 51, 2000
CONTENTSInferior Vena Cava Interruption: How and When?, Philippe Girard, Bernard Tardy, Hervé Decousus 1Ductal Carcinoma In Situ of the Breast, Melvin J. Silverstein 17Gene Therapy for Adenosine Deaminase Deficiency, Robertson Parkman, Kenneth Weinberg, Gay Crooks, Jan Nolta, Neena Kapoor, Donald Kohn 33Acupuncture: An Evidence-Based Review of the Clinical Literature, David J. Mayer 49Role of Telomerase in Cell Senescence and Oncogenesis, Virginia Urquidi, David Tarin, Steve Goodison 65Coronary Artery Disease in the Transplanted Heart, M. Weis, W. von Scheidt 81Measures of Success and Health-Related Quality of Life in Lower-Extremity Vascular Surgery, Joe Feinglass, Mark Morasch, Walter J. McCarthy 101
New Horizons in the Treatment of Autoimmune Diseases: Immunoablation and Stem Cell Transplantation, Alberto M. Marmont 115The Surgical Treatment of Parkinson’s Disease, Kenneth A. Follett 135Atherogenic Lipids and Endothelial Dysfunction: Mechanisms in the Genesis of Ischemic Syndromes, Mark R. Adams, Scott Kinlay, Gavin J. Blake, James L. Orford, Peter Ganz, Andrew P. Selwyn 149Management of Patients with Hereditary Hypercoagulable Disorders, C. Kearon, M. Crowther, J. Hirsh 169Neurocysticercosis: Updates on Epidemiology, Pathogenesis, Diagnosis, and Management, A. Clinton White Jr. 187Anti-Cytokine Therapy for Rheumatoid Arthritis, R. N. Maini, P. C. Taylor 207Artificial Skin, J. T. Schulz III, R. G. Tompkins, J. F. Burke 231Age-Associated Increased Interleukin-6 Gene Expression, Late-Life Diseases, and Frailty, William B. Ershler, Evan T. Keller 245Streptococcal Toxic Shock Syndrome Associated with Necrotizing Fasciitis, Dennis L. Stevens 271Role of Cytokines in the Pathogenesis of Inflammatory Bowel Disease, Konstantinos A. Papadakis, Stephan R. Targan 289Anorexia and Bulimia Nervosa, W. H. Kaye, K. L. Klump, G. K. W. Frank, M. Strober 299The Role of Protein Traffic in the Progression of Renal Diseases, Piero Ruggenenti, Giuseppe Remuzzi 315Carotid Artery Dissection, C. Stapf, M. S. V. Elkind, J. P. Mohr 329Bacterial Vaginosis, Jack D. Sobel 349Current Concepts in Cobalamin Deficiency, Ralph Carmel 357Adjuvant Therapy for Breast Cancer, G. Hortobagyi 377
Kidney Transplantation from Living Unrelated Donors, J. Michael Cecka 393Global Epidemiology of Influenza: Past and Present, N. J. Cox, K. Subbarao 407The Spectrum of Human Herpesvirus 6 Infection: From Roseola Infantum to Adult Disease, Mark Young Stoeckle 423
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Catheter Ablation for Atrial Fibrillation, Pierre Jaïs, Dipen C. Shah, Michel Haïssaguerre, Meleze Hocini, Jing Tian Peng, Jacques Clémenty 431Genetic Disorders Affecting Proteins of Iron Metabolism: Clinical Implications, Sujit Sheth, Gary M. Brittenham 443Genetics of Psychiatric Disease, Wade H. Berrettini 465The Marfan Syndrome, Reed E. Pyeritz 481Nonsteroidal Anti-Inflammatory Drugs and Cancer Prevention, John A. Baron, Robert S. Sandler 511Lymphatic Mapping and Sentinel Lymph Node Biopsy in Patients with Breast Cancer, Charles E. Cox, Siddharth S. Bass, Christa R. McCann, Ni Ni K. Ku, Claudia Berman, Kara Durand, Monica Bolano, Jessica Wang, Eric Peltz, Sarah Cox, Christopher Salud, Douglas S. Reintgen, Gary H. Lyman 525
The Genetics of the Amyloidoses, Joel N. Buxbaum, Clement E. Tagoe 543
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