Aspirin1

1. Chemical and Physical Solubility Characteristics One gram dissolves in 300 ml water at 25°C, in 100 ml water at 37°C, in 5 ml ethanol, 17 ml 1.1 Narne chloroform, 10-15 ml ethyl ether; less soluble Chemical Abstracts Services Registry Number in anhydrous ether 50-78-2 Spectroscopy Chemical Abstracts Primary Name Ultraviolet, infrared, nuclear magnetic reso- Salicylic acid acetate nance and mass spectral data have been reported.

IUPAC Systematic Name Stabilty Benzoic acid, 2-acetyloxy Stable in dry air but gradually hydrolyses in contact with moisture to acetic and salicylic Synonyms acids. Decomposes in boilng water. Also unsta- 2-(Acetyloxy)benzoic acid; 2-acetoxybenzoic ble in solutions of alkali hydroxides and car- acid; o-acetylsalicylic acid; acidum acetylsali- bonates (pKa 3.49 at 25°C) cylicum; acetylsalicylic acid 1.4 Technical products

1.2 Structural and rnolecular forrnulae and Trade names relative rnolecular rnass Aspirin is marketed throughout the world under many trade names, which include the foIlowing: AAS, Acentérine, Acesal, Acetard, COOH Aceticyl, Acetilum Acidulatum, Acetophen, Acetosal, Acetosalic Acid, Acetyl, Acetylin, Acetylo, Acetylsal, Actispirine, Acylpyrin, Adiro, Albyl, Albyl-Selters, Angettes, Apernyl, ~O-C-CH3 Arthrisin, Artria, A.S.A., Asadrine, Asaferm, oIl Asalite, Asatard, Aspalox, Aspegic, Aspergum, Aspinfantil, Aspirin, Aspirina, Aspirinetta, CgHa04 Relative molecular mass: 180.15 Aspirisucre, Aspisol, Aspro, Asrivo, ASS, Asteric, Astrix, Bamycor, Bamyl, Bamyl S, Bebesan, Bonakiddi, Bufferin, Calmantina, Calmo Yer 1.3 Physical and chernical properties Analgesico, Caprin, Cardiprin, Cartia, The data presented are taken from Budavari Casprium Retard, Catalgine, Cemirit, (1989) and Reynolds (1993), unless otherwise Chefarine-N, Claradin, Claragine, Codalgina specified. Retard, Colfarit, Contradol, Contrheuma, Cosprin, Delgesic, Dispril, Disprin, Dolean pH Description 8, Doleron, Dolomega, Domupirina, Dreimal, Colourless or white needle-Iike crystals or white Dulcipirina, Duramax, Easprin, ECM, Ecotrin, crystallne powder; odourless or almost odourless Empirin, Encaprin, Endydol, Enterosarin, Enterosarine, Entrophen, Extra Strength Tri- Melting-point Buffered Bufferin, Flectadol, Gepan, Globentyl, 135°C Godamed, Halgon, Helicon, Helver SaI, Idotyl,

1 AspirintI is the Bayer trade mark for acetylsalicylic acid in more than 70 countries. 43 rARC Handbooks of Cancer Prevention

Istopirine, Ivépirine, Juvéprine, Kalcatyl, Kilos, When aspirn is used as an analgesic and Kynosina, Lafena, Levius, Licyl, Longasa, antipyretic, the convention al dose is 0.3-0.9 g, Magnecyl, Magnyl, Measurin, Mejoral Infantil, which may be repeated every 4-6 h according Melabon, Monobeltin 350, Neuronika, to clinical needs, up to a maximum of 4 g daily Novasen, Novid, Nu-Seals, Okal Infantil, (Reynolds & Prasad, 1982). GeneraIly, 4-8 g Orravina, Platet, Premaspin, Primaspan, daily in divided doses are used for acute mus-

Primaspin, Protectin-OPT, Pyracyl, Rectosalyl, culoskeletal and joint disorders su ch as Resprin, Reumyl, Rhodine, Rhonal, Riane, SaI, rheumatoid arthritis and osteoarthritis. Salacetin, Salcetogen, Saletin, Salicilna, Use of aspirin in children has been dramati- Sanocapt, Santasal, Saspryl, Sinaspril, Solprin, cally decreased after reports of a relationship Solpyron, Solusprin, Soparine, Spalt, SRA, between its use and the development of Reye Supasa, Superaspidin, Temagin ASS, Togal ASS, syndrome, a very rare but possibly fatal combi- Trineral, Trombyl, Winsprin, Xaxa, ZORprin. nation of hepatic insufficiency and encephalo- Aspirin is also marketed in many fixed com- pathy. One of the few indications in which binations with other compounds, and especial- aspirin therapy is stil considered for children is ly with ascorbate, codeine and caffeine. juvenile rheumatoid arthritis. Suggested doses for this condition are 80 and 100 mg/kg bw 2. Occurrence, Production, Use, daily in five or six divided doses, although up Analysis and Human Exposure to 130 mg/kg daily are employed for some chil- dren. 2.1 Occurrence Aspirin is used for the secondary prevention Aspirin is not known to occur as a natural product. of myocardial infarct and stroke in patients with a history of su ch disorders. Large clinical 2.2 Production studies have shown that doses of more th an Aspirin, the acetyl derivative of salicylic acid, is 300-325 mg daily are unnecessary, and some synthesized from the acid with acetic authorities recommend doses of about anhydride using sulfuric acid as catalyst 75-100 mg daily. (Roberts & Caserio, 1965). The basis of com- mercial production, which is approximately 2.4 Analysis 40 000 t/year worldwide, was not known to the Accepted standard procedures for the assay of Working Group. aspirin are given in the national pharmacopoeias of Argentina, Australia, Brazil, China, the Czech 2.3 Use Republic, Egyt, France, Germany, Hungary, India, Aspirin and its salicylate metabolite have anal- Italy, Japan, Mexico, the Netherlands, Poland, gesic, anti-inflammatory and antipyretic prop- Portgal, Romania, the Russian Federation, Spain, erties. Aspirin was first marketed in 1899 (Vane Switzerland, Turkey, the United Kingdom and the et aL., 1990). It is used for the relief of mild-to- United States, and in the European, Nordic and moderate pain such as headache, dysmenor- international pharmacopoeias. rhoea, myalgia and dental pain. It is also used Aspirin as its metabolite salicylic acid can in acute and chronic inflammatory disorders be analysed in urine, plasma and saliva by such as rheumatoid arthritis, juvenile rheuma- colorimetry, thin-Iayer chromatography and toid arthritis and osteoarthritis. Aspirin inhibits high-performance liquid chromatography platelet aggregation and is used in the preven- (Legaz et al., 1992). ln pharmaceutical prepara- tion of arterial and venous thrombosis. tions, it can be determined by high-per- Aspirin is usuaIly taken by mouth. Various formance liquid chromatography (Menouer et dosage forms are available, including plain al., 1982) gas-liquid chromatography (Galante uncoated, buffered, dispersible, enteric-coated et al., 1981) and differential spectrophoto- and modified-release tablets. Aspirin may be metric analysis (Amer et aL., 1978) using proton administered rectaIly or intravenously as a magnetic resonance spectrometry (Vinson & complex with lycin. Kozak, 1978; AI-Badr & Ibrahim, 1981).

44 Aspirin

2.5 Hurnan exposure Table 1. Aspirin use in a California retire- Use of aspirin in the general population has ment community been estimated from studies on use of non- Aspirin use Men (5051) Women (8818) steroidal anti-inflammatory drugs (NSAlDs) No. % No. % and cancer risk with data on the consumption None 3490 69 6021 68 of aspirin by study cohorts and by community Less than daily 685 14 1417 16 control groups. Daily 876 17 1380 16 ln a study by Kune et al. (1988) in Australia, Total use 1561 31 2797 32 of 727 community controls (average age, 65 From Paganini-Hil et al. (1989) years), 67 of the 398 men (17%) and 80 of the 329 women (24%) reported using aspirin. No data were provided on the frequency or dura- per week) in each questionnaire and 15% tion of use. Paginini-Hil et al. (1989) reported reported no aspirin use in any of the periods. aspirin use in a California retirement commu- Greenberg et aL. (1993) questioned 793 nity (Table 1). The average age at the time of patients involved in a clinical trial of nutrient responding to the questionnaire was 73 years. supplements on two occasions and categorized Schreinemachers and Everson (1994) found them as using aspirin not at aIl, intermittently that 59% of 12 668 subjects (age range, 25-74 or consistently, depending on whether they years) had reported aspirin use within 30 days listed aspirin as one of their medications on of interview in the US National Health and zero, one or two questionnaires, respectively. Examination Study. The results are shown by age in Table 2. ln a study by Giovannucci et al. (1994), Aspirin use increased by 4% among men 47900 US male health professionals aged 40-75 with coronary heart disease or at high risk for years were surveyed by questionnaire. Regular coronary heart disease foIlowing publication of aspirin use was defined as more than twice the results of trials on the cardiovascular pre- weekly. A total of 33 806 (70%) did not use vention effects of aspirin. Nearly 50% of partici- aspirin (average age, 56 years) and 14 094 (30%) pants who reported a history of myocardial did (average age, 59 years). The reasons for tak- infarct, however, apparently did not take ing aspirin were surveyed in 185 men, who aspirin regularly (Shahar et aL., 1996). reported one or more of the foIlowing: cardiovas- Although the population-based data on cular disease, 25%; decrease in risk for cardiovas- aspirin use are limited, particularly with respect cular disease, 58%; joint or musculoskeletal pain, to dose, two general observations are warranted: 33%; headache, 25% and other reasons, 7.0%. · Aspirin consumption is high, in keeping Giovannucci et al. (1995a) also questioned with its ready availabilty, low cost and value in 121 701 female participants in the Nurses' a wide range of conditions. Health Study (age range, 30-55 years) on four · Because the incidence of musculoskeletal occasions over eight years; 15% reported regu- and cardiovascular disease increases with age, lar aspirin use (defined as two or more tablets aspirin use ris es concomitantly.

Table 2. Aspirin use in a clinical trial of nutrient supplements, by age Age (years) No use Intermittent use Consistent use No. % No. % No. %

-: 50 54 82 8 12 4 6

50-59 170 79 26 12 19 9

60-69 277 72 51 13 59 15

2: 70 92 74 13 10 20 16 From Greenberg et al. (1993)

4S IARC Handbooks of Cancer Prevention

3. Metabolism, Kinetics and Genetic (Spenney, 1978), liver (Ali & Kaur, 1983) and Variation erythrocytes (Costello et al.i 1984). Salicylic acid is further metabolized in the liver and kid- 3.1 Human studies neys into its glycine conjugate salicyluric acid 3. 1. 1 Metabolism and its glucuronic acid conjugates, salicyl phe- The metabolism of acetylsalicylic acid (aspirin) nolic glucuronide and salicyl acyl glucuronide. is summarized in Figure 1. Ring hydroxylation products of salicylic acid Aspirin is rapidly hydrolysed to salicylic acid are also formed, albeit in much smaller (2-hydroxybenzoic acid) in the intestinal waIl amounts; these include gentisic acid

Figure 1. Main metabolic pathways of aspirin

~ 1 OCOCH3 (XCOOH Aspirin l

~ ~ 1 (XI~ OHCOOC6Hg06 .. (XI:: OHCOOH (XCOOHOC 6H906 Salicylacyl glucuronide Salicylic acid Salicylphenolic glucuronide

Á. . l~ HOvyCOOH (/COOH YOH (XI~ OHCONHCH2C02H OH ~OH 2,3-Dihydroxy- Gentisic acid Salicyluric acid benzoic acid

y J H0'(CONHCH2C02H '7 1 ~ 1 ~ OH (XCONHCH2C02H~ OC6Hg06 Salicyluric acid Gentisuric acid phenolic glucuronide

From Patel et al. (1990). Dotted Iines indicate min or pathways

46 Aspirin

(2,5-hydroxybenzoic acid) and 2,3-dihydroxy- amounts of salicyluric acid and salicyl phenolic benzoic acid. Additional metabolites, also glucuronide do not increase further and larger formed in minor amounts, include gentisuric amounts of gentisic acid, salicyl acyl glu- acid and salicyluric acid phenolic glucuronide curonide and other compounds are produced. (Ali & Kaur, 1983; Costello et al.i 1984; Hutt et As would be expected, the percentage of each aL., 1986; Grooteveld & HallweIl, 1988). Small metabolic product in the total pool of aspirin amounts of salicylic acid remain unchanged metabolites varies with dose (Patel et aL., 1990). and are excreted. These findings, consistent with those of oth- The first step in the metabolism of aspirin, ers (Levy et al.i 1969; Levy, 1979; Bochner et ai.i its hydrolysis to salicylic aCid, is catalysed by a 1981; Hutt et al., 1986), demonstrate clearly the family of enzymes that are aIl serine esterases dose-dependent saturabilty of the primary (Inoue et aL., 1979a,b, 1980; White & Hope, pathways and the contribution of salicylic acid 1984). The esterases in the intestinal waIl and to the total elimination of salicylate after toxic

liver perform most of the hydrolysis of aspirin doses, wh en the other major metabolic path- (Rowland et al.i 1972); however, the erythro- ways are saturated. cyte esteras es also contribute significantly to Auto-induction of aspirin metabolism was this process (CosteIlo et aL., 1984). Thus, the suggested by observations in patients treated haematocrit can be an important determinant with aspirin for long periods. ln these patients, of the half-life of aspirin. The rate of hydrolysis the serum salicylate levels decreased with the of aspirin to salicylic acid can vary considerably length of treatment (Purst et ai.i 1977; Muller et with age (Windorfer et al., 1974), sex (Gupta & al., 1977; Rumble et al.i 1980). The amount of Gupta, 1977) and concomitant disease (Needs salicyluric acid in urine was increased, indicat- & Brooks, 1985). ing self-induction of aspirin metabolism. After conversion of aspirin to salicylic aCid, several fairly weIl characterized metabolic and 3.1.2 Pharmacokinetics elimination pathways affect the ultimate dispo- The pharmacokinetic properties of aspirin have siton of aspirin (Needs & Brooks, 1985). The been reviewed by Needs and Brooks (1985). major pathways for the metabolism of salicylic acid are conjugation with glycine to form sali- (a) Absorption cyluric acid and conjugation with glucuronic After oral administration, aspirin is rapidly and acid to form salicyl phenolic glucuronide. Both extensively absorbed from the stomach but follow Michaelis-Menten kinetics and are sat- mostly from the upper small intestine (Plower urable. ln contrast, the remaining pathways are et al., 1985). Absorption occurs rapidly, by pas- minor and foIlow first -order kinetics (Levy & sive diffusion of the non-ionized lipophilic Tsuchiya, 1972). molecules; for example, the absorption haU-lie Two properties of these pathways are critical of aqueous aspirin ranges from 4.5 to 16 min to the metabolism and elimination of aspirin: (Rowland et al.i 1972). ln this study, 68% of the the saturabilty of the 'primary' pathways and dose reached the systemic circulation unhy- the self-induction of the metabolism. These drolysed. phenomena are summarized below. Many factors affect the rate of absorption of Salicylic acid, formed after a low, 325-mg, aspirin, including the pH at the mucosal sur- dose of aspirin, is metabolized by the pa th ways faces, the rate of gastric emptying, conditions leading to salicyluric acid and salicyl phenolic that affect intestinal transit time and, if tablets glucuronide. As the am ou nt of aspirin ingested are given, their dissolution rate. Of these fac- is increased, these two pathways become satu- tors, the most important is the last. Liquid rated and the minor pathways are used to a preparations are absorbed most rapidly: Serum greater extent, leading to increased amounts of levels peak 15-20 min after intake of liquid for- their products. Thus, when increasing doses of mulations, 2-4 h after ingestion of regular aspirin saturate the two main metabolic path- tablets, and 4-6 h or more after intake of ways, the serum salicylate levels increase, the enteric-coated aspirin. The latter, which resists

47 lARC Handbooks of Cancer Prevention

dissolution in the acidic stomach, dissolves fixed doses of aspirin at constant intervals mainly after passing into the alkaline environ- increases more than proportionally with ment of the small intestine (Liberman & Wood, increasing doses. The time required to attain 1964; Briggs et aL.1 1977; Ross-Lee et aL.1 1982). the plateau also increases with dose. It was It is of interest that, in patients on long-term observed clinically that a 50% increase in the treatment, the bioavailabilty of enteric-coated daily dose of aspirin produced about a 300% aspirin is similar to that of regular preparations, rise in the concentration of salicylate in the as the two formulations provide comparable serum (Paulus et aL.1 1971). This ri se was attrib- steady-state concentrations of salicylate uted to the fact that the saturable processes (Orozco-Alcala & Baum, 1979). When absorp- (formation of salicyluric acid and salicyl phe- tion is delayed by prolonged gastric emptying, nolic glucoronide) contribute less to the elimi- metaclopramide can accelerate it (Ross-Lee et nation of salicylate from the body as the aL.1 1983). amount of salicylate in the body increases. The effect of pH is of particular interest These observations account for the pronounced (reviewed by Gugler & Allgayer, 1990; Brouwers effects that relatively smaIl changes in the & De Smet, 1994). Aspirin, with a pKa of 3.5, is maintenance dosage of aspirin have on salicy- a weak acid and is 99% non-ionized at pH 1; it late concentrations in body fluids and the phar- can therefore diffuse through lipid membranes. macological effects of aspirin. If the pH of the stomach is increased, more A compartmental model has been used to aspirin is ionized, and this decreases its rate of evaluate the absorption, metabolism and excre- absorption (Plower et aL.1 1985). ln the case of tion of aspirin and salicylic acid given in low tablets, however, a rise in pH increases the sol- (30 and 100 mg) or moderate (400 mg) doses ubilty and thus tablet dissolution; the overall (Dubovska et aL.1 1995). The model confirmed effect is to enhance absorption. High doses of the linearity of the kinetics of aspirin, showed antacids increase urinaiy pH, thus increasing that the apparent volume of distribution and urinary excretion of salicylic acid, leading to clearance of aspirin are independent of dose decreased plasma levels (Clissold, 1986). and showed that the metabolic kinetics of sali- ln patients prescribed long-term aspirin use, cylic acid at 400 mg are dose-dependent. the rate of absorption is not very important: Both aspirin and salicylic acid are partially accumulation is controIled entirely by oral bound to proteins, especiaIlyalbumin; 80-95% bioavailabilty and the rate of plasma clearance of salicylic acid is bound to plasma albumin (Verbeeck, 1990). A high absorption rate (Murray & Brater, 1993). The binding of sali- reduces the lag time between drug intake and cylic acid is reversible, but aspirin acetylates the pharmacological effect, su ch as pain relief. human serum albumin (Hawkins et al.i 1968; This type of effect is useful in the treatment of Pinckard et al.i 1968). Salicylic acid reaches: acute conditions such as dysmenorrhoea and (i) synovial fluid, where its concentration is headaches (Chan, 1983; Diamond & Preitag, lower than that in plasma (Rabinowitz et al.i 1989). 1982); (ii) cerebrospinal fluid, where both aspirin and salicylic acid diffuse slowly because (b) Distribution of the high degree of ionization at plasma pH After absorption, aspirin is distributed through- (Plower et aL.1 1985); (iii) saliva, where its con- out the body tissues and fluids, mainly by pH- centration is proportional to that in plasma dependent passive processes, and binds to plas- (Roberts et al.i 1978) and (iv) breast milk ma proteins, especially albumin. The apparent (Pindlay et aL.1 1981). volume of distribution of salicylate ranges from Salicylates administered to the mother are 9.6 to 13 litres in adults (Graham et aL.1 1977) transferred readily to the fetus (Schoenfeld et and children (Wilson et aL.1 1982). aL.1 1992). As aspirin has a short half-life, only a Aspirin has unusual accumulation charac- small amount of unmetabolized compound teristics. The plateau level of salicylate in the reaches the fetus. The fetus binds less salicylates body attained by repetitive administration of in plasma than adults and has reduced

48 Aspirin

metabolic activity, in particular glucuronida- area un der the concentration-time curve tion, and less effective elimination. Therefore, increased. fetuses and newborns whose mothers took sali- The pharmacokinetics of a low dose of cylates before delivery may have plasma con- aspirin (60 mg/day) were studied during the centrations up to four times higher than those second and third trimesters in pregnant women of their mothers. at high risk for placental insuffciency (Asymbekova et al., 1995). ln the 16 women (c) Elimination with uncomplicated pregnancies, the changes After oral intake, the plasma levels of aspirin in the kinetics of aspirin were a lower concen- rise sharply, reaching a maximum at tration-time index, higher total clearance and a 15-20 min. They then decline rapidly, and only larger distribution volume. Similar changes small amounts remain after 2 h (Rowland et al., were found in the four women with advanced 1972). Although the haU-lie in the declining placental insufficiency. phase is short, it is always longer than the half- life of aspirin administered intravenously, due (d) Drug interactions to continued absorption of aspirin during the The pharmacokinetic interactions of aspirn declining phase. The salicylic acid levels rise and various salicylates have been reviewed rapidly and eventiiaIly exceed those of aspirin, extensively (Miners, 1989; Verbeeck, 1990). because of slower elimination rather than Metabolic drug interactions involving aspirin differences in distribution (Rowland et al., are theoreticaIly possible, but no studies have 1967). shown conclusively that hydrolysis of aspirin is Hydrolysis of aspirin to salicylic acid in the altered by co-administered drugs. A number of plasma is rapid, with a haU-lie of 15-20 min treatments, however, affect the rate or extent of (Rowland et al., 1972). Salicylic acid is removed absorption of aspirin, including activated char- from the body by parallel, competing pathways coal, antacids, cholestyramine and metoclo- of renal elimination and formation of metabo- pramide. Caffeine and metoprolol have been lites. Renal excretion of salicylic acid is sat- reported to increase the peak salicylic acid con- iirable (Dubovska et al., 1995), occurs by first- centration after administration of aspirin, and order kinetics and is extremely sensitive to uri- co-administration of dipyridamole and aspirin nary pH, urinary organic acids and urinary flow results in higher plasma aspirin concentrations. rate. The mechanism(s) responsible for the latter No differences in pharmacokinetics have observation remains unknown. been demonstrated between old and young Many of the drug interactions involve dis- adults (Roberts et al., 1983; Silagy, 1993). placement of the co-administered drug from Diseases in which the serum albumin concen- plasma protein, as, for example, in the case of tration is altered are characterized by changes interactions with diclofenac, flurbiprofen, in the free salicylate fraction. For example, ibuprofen, isoxicam, ketoprofen, naproxen, hypoalbuminaemic cirrhotic patients had phenytoin and tolmetin. After displacement of increased unbound salicylic acid concentra- these agents, the clearance of total drug increas- tions, although the kinetics of aspirin and sali- es and, consequently, the plasma concentration cyclic acid were not altered (Roberts et al., of total drug decreases. Althoiigh generally not 1983). Zapadnyuk et al. (1987) reported, measured, the unbound concentration of the however, that the pharmacokinetics of aspirin interacting drug should not be markedly were not the same in people aged 20-30, 60-74 altered. Salicylic acid also increases the total and 75-89 years after a single oral administra- plasma clearance of fenoprofen, but, unlike the tion of 14 mg/kg body weight (bw). The interactions with other propionic acid non- constants of absorption and elimination and steroidal compounds, plasma protein binding the total clearance value decreased with age; displacement does not appear to be involved. and the half-life declined from 4 to 12 h across There is no firm evidence that salicylic acid the age range. ln the older patients, the induces the metabolism of co-administered

~a 49 lARC Handbooks of Cancer Prevention

drugs; however, it can inhibit their metabolism. luric acid formation was high and, in cases of Such an effect has been reported for salicyl- overdose, compensation by other routes was amide, valproic acid and zomepirac. Certain co- incomplete. administered drugs may alter the metabolism ln another study in rats, the concentration of salicylic acid; its metabolism is inhibited in major tissues and organs of aspirin labelled after treatment with benzoic acid, salicylamide, with 14C on both the acetyl and carboxyl zomepirac and possibly cimetidine. Salicylic groups was determined by measuring the distri- acid elimination is enhanced by oral contra- bution of 14C tracers in tissue sections (Hatori et ceptives and by corticosteroids. aL.1 1984). During the first 10-30 min after oral administration, the degradation to salicylate 3.2 Experimental models was 38% in the stomach wall, 64% in the liver The pharmacokinetics of aspirin have been and 86% in the lung. studied in many species, including rats and The age-dependence of aspirin metabolism dogs (Sechserova et al.i 1979; Aonuma et aL.1 was demonstrated in a study in calves 1982; Rabinowitz et aL.1 1982; Laznicek & (Sechserova et al.i 1979). The older the animaIs, Laznickova, 1994). The fate of aspirin has been the lower were the total salicylate and salicylic acid foIlowed by using radiolabeIled salicylate or by levels and the higher the salicyluric acid leveL. simply measuring its plasma concentrations or Two serine esterases involved in the hydrol- those of its metabolites (Iwamoto et aL.1 1982; ysis of aspirin to salicylic acid have been Hatori et al.i 1984). purified to homogeneity from rat liver (Kim et After intravenous or oral administration of al.i 1990). Both have a low Km for aspirin and a aspirin at 10 mg/kg bw to male Wistar rats, 88 wide substrate spectrum. At present, these and 86% of the dose, respectively, was excreted enzymes are categorized as arylesterases (EC in urine, mostly as salicylic acid and its conju- 3.1.12) and carboxyesterases (EC 3.1.1.1). gated forms. This finding suggests that the gas- trointestinal absorption of aspirin in rats is 3.3 Genetic variation essentially complete. Orally administered No data were available to the Working Group. aspirin is subject to first-pass metabolism in both the gut and liver of rats (Iwamoto et aL.1 1982). 4. Cancer-preventive Effects The kinetics of sodium salicylate are dose- dependent, and its plasma concentration 4.1 Human studies declines by a first-order process (Yue & Varma, 4.1.1 Studies of colorectal cancer 1982). The metabolism of oraIly administered 14C-aspirin in rats over a 10-fold dose range (a) Methodological considerations (10-100 mg/kg bw) resulted in excretion of Most of the data on aspirin and colorectal cancer 81-91 % of the dose in urine during the first or adenomas come from epidemiological (obser- 24 h; salicylic acid was the major urinary vational) studies of sporadic disease in the gen- metabolite (43-51%) (Patel et al.i 1990). The eral population. It was not possible in these excretion of salicyluric acid decreased with studies to completely separate use of aspirin increasing dose, whereas that of gentisic acid from that of other NSAIDs; however, as use of and salicyl phenolic and acyl glucuronides non-aspirin NSAIDs became widespread rela- increased. The profie of aspirin metabolites tively recently, long-term use in studies of the was qualitatively similar in humans and rats, general population involved predominately aspirin. but there were quantitative differences. A limit- Intervention studies are generally considered ed capacity to form salicyluric acid was to be more reliable than observational studies observed in both species. ln rats, the depen- in the investigation of causal relationships. dence on this pathway was low and was com- This may not be the case, however, if long-term pensated by increased use of other routes. ln use is a necessary parameter, and clinical trials contras t, in humans, the dependence on salicy- may be limited by the fact that the randomized

50 Aspirin

treatment is too brief. ln such instances, obser- cancers of the stomach (51/54) and rectum vational studies may be informative because (7/11) in males. Women had fewer than expect- individuals who report longer use can be id en- ed cancers of the stomach (80/100) and rectum tified and studied. (20/35); the reductions were statisticaIly signif- Several potential problems should be consid- icant (p -( 0.05). ered in interpreting the epidemiological studies: Laakso et al. (1986) conducted a much smaIl- (i) bleeding and other aspirin-induced symp- er study of 500 men and 500 women treated for toms can prompt doser medical surveilance rheumatoid arthritis at a National Rheumatism earlier than would otherwise occur; (ii) changes Foundation hospital in Finland between 1970 in aspirin use may be precipitated by the early and 1980. The cohort largely overlapped with symptoms of neoplasia; and (iii) other behav- that of lsomäki et al. (1978) and is omitted from iour that affects colorectal cancer risk may be Table 3. The numbers of deaths from associated with use of aspirin. An overaIl per- cancer were: one from oesophageal cancer spective of these issues is presented on p. 63. (2 expected), three from stomach cancer Throughout this section, the term 'relative (11 expected), none from colon cancer risk' is used in a generic sense to refer to mea- (3 expected) and one from rectal cancer sures of association such as odds ratios, risk (none expected). None of these differences was ratios and 'rate ratios'. significant. A larger study in Sweden by Gridley et al. (b) Cohort studies (1993) comprised 11 683 men and women with Nine published cohort studies provide informa- a diagnosis of rheumatoid arthritis recorded in tion on aspirin-containing drugs and the risk a population-based registry between 1965 and for colorectal cancer. The studies are discussed 1983. These patients were followed from the chronologically; those completed before 1991 date of discharge from hospital through 1984 address NSAIDs as a side issue, whereas later in the national cancer and mortality registries. . studies focus directly on aspirin and other For men and women combined, the numbers NSAlDs. The relevant studies are summarized in of cases observed and expected, the standard- Table 3. ized incidence ratio (SIR) and the 95% confi- Studies of cancer occurrence in patients with dence intervals (Cls) for cancers of the digestive rheumatoid arthritis have been conducted in tract were as follows: oesophagus, i 1/8.3, Finland and Sweden. Su ch studies were consid- SIR=1.32, 0.7-2.4; stomach, 39/62, SIR=0.63, ered to be relevant by the Working Group 0.5-0.9; colon, 44/70, SIR=0.63, 0.5-0.9; rec- because of the prolonge d, intense use of aspirin tum, 28/39, SIR=0.72, 0.5-1.1. and to a lesser extent NSAIDs by such patients; (The Working Group noted the potential for however, it was recognized that the effects of confounding by underlying disease in the se aspirin could not be separated from those of studies.) other drugs used to treat rheumatoid arthritis Stemmermann et al. (1989) wrote a brief or from those of the disease itself. description of the lapan-Hawaii Cancer Study lsomäki et aL. (1978) identified 46 101 conducted in 1971-75 on 137 lapanese men patients (11 483 men, 34 618 women) in residing in Hawaii who reported use of aspirin, Finland who were reimbursed for treatment of an aspirin and caffeine combination, or dextro- rheumatoid arthritis by the national health propoxyphene for at least one week during the insurance between 1967 and 1973. Using com- previous month. Among analgesic users, three puter linkage with the national cancer registry colorectal cancers were observed, with 4.3 for that period, the authors found approxi- expected on the basis of the incidence among mately the same numbers of newly diagnosed 652 non-us ers in the study. cases as expected among the arthritis patients Paganini-Hil et al. (1989) identified newly for cancers of the oesophagus (males: diagnosed cases of various chronic diseases 5 observed, 7.5 expected; females: 21/20), and from hospital records for 13 987 residents of a colon (11/9.9 and 33/39, respectively) and for California retirement community between .. 51 ~ 1 1 n~ ::¡: :: 0. Table 3. Cohort studies of use of non-steroidal anti-inflammatory drugs and the risk for colorectal cancer in the general cr population 0 "":; Reference Population Study size End-point Drug Frequency Results (RR)8 Comments 0.. n Isomäki Rheumatoid arthritis, Women Colon cancer Therapy for Heavy use 0.84 (NS) ¡: :: (" et al. (1978) Finland; 34 618 women 33 cases Rectal cancer arthritis 0.58 (p .: 0.05) (1.. and 11 483 men, 20 cases ..'" (1 Men Colon cancer 1.1 (NS) ~ 1967-73 (1 :: 11 cases Rectal cancer 0.64 (NS) ,. õ' 7 cases (incidence) ::

Gridley et al. (1993) Rheumatoid arthritis, 44 cases Colon cancer Therapy for Heavy use 0.63 Risk for stomach cancer also reduced Sweden: 7933 women arthritis (0.5-0.9) and 3750 men, 1965-84 28 cases Rectal cancer 0.72 (incidence) (0.5-1.1 )

Paganini-Hill et al. US retire ment commu- 181 cases Colon cancer Aspirin Daily 1.5 Median age, 73 nit y; 13987 elderly men, No data on aspirin after baseline (1989, 1991); (incidence) (1.1-2.2) and women, 1981-87 Paganini-Hill (1995)

Thun et al. (1991, 1992, American Cancer 950 deaths Colon cancer Aspirin ;;16 times/ 0.58 Multivariate estimates 1993) Society, (fatal) month (0.45-0.74 ) No data on aspirin after baseline 662 424 US adults, 138 deaths Rectal cancer Aspirin 0.66 Decreased risk mostly confined to 1982-88 (fatal) (0.37-1.2) users of ;" 1 0 years

Schreinemachers & 12 688 US adults, 169 cases Colorectal cancer Aspirin Last 30 days 0.74 RR reduced under age 65 Everson (1994) 1971-87 (incidence) (0.49-1.1)

Giovannucci et al. Harvard Health Profes- 251 cases Colorectal cancer Aspirin ;" 2 tablets/ 0.68 Ali cancers and metastatic or fatal (1994) sionals: 47 900 US men, (incidence) week (0.52-0.92) cancers 1986-91

Giovannucci et al. US Nurses Health Study, 297 cases Colorectal cancer Aspirin ;; 2 tablets 0.56 Risk decreased with duration but not (1995) 89 446 women, 1984-92 (incidence) /week (0.36-0.90) with dose :; 2-4 months ;" 20 years RR, relative risk; NS, not significant 8 ln parentheses, 95% confidence interval Aspirin

1981 and 1987. The median age of the partici- and colon cancer risk; the diseases included pants at the time of enrolment was 73 years. prevalent cancer, heart disease, stroke or report- The study population consisted mostly of ing being 'sick' at the time of enrolment. Use of white, moderately affuent, weIl-educated peo- acetaminophen was not associated with a lower ple, about two-thirds of whom were women. risk for colon cancer (Thun et aI.i 1991). People who reported on a mailed questionnaire The trend of decreasing colorectal cancer risk in 1989 that they used aspirin at least daily had with more frequent aspirin use was stronger a 50% higher incidence of colon cancer than among people who had used aspirin for :: 10 did those who used aspirin less th an monthly years than in those with a shorter duration of (40 cases; RR, 1.5; 95% CI, 1.1-2.2). Two subse- use. SpecificaIly, the RR for fatal colon cancer quent reports on the same study reported fol- among people who reported using aspirin 16 or low-up of the cohort through May 1991 more times per month for :: 10 years was 0.36 (Paganini-Hil et al.i 1991; Paganini-Hil, 1995). in comparison with people who reported A statistically nonsignificant 38% higher inci- no aspirin use, whereas the RR for the group dence of colon cancer was found in men but who reported this level of use for 1-9 years was not women. This study differs from those that 0.71. For both men and women, aspirin use show an inverse relation between aspirin 16 or more times per month for at least one use and the risk for colorectal cancer: the year reduced the risk for fatal colon cancer participants were older, no data were available (RR, 0.58; CI, 0.45-0.74) and fatal rectal cancer on the duration of aspirin use, and the partici- (RR, 0.66, CI, 0.37-1.2) (Thun et aI.i 1993). pants lived in a single retire ment community. Because of its size, prospective design, The finding that ischaemic heart disease was dose-response trends and internaI consistency, significantly more common in daily aspirin the American Cancer Society study gave sup- users than in non-users (men: RR, 1.9; 95% CI, port to the NSAID hypothesis. Its limitations 1.1-3.1; women: RR, 1.7; 95% CI, 1.1-2.7) rais- are the use of a single, brief, self-administered es the possibilty that patients with coronary questionnaire, the lack of data on dose (as symptoms or risk factors for vascular disease opposed to frequency or duration) and on use

may have begun taking aspirin shortly before of NSAIDs other th an aspirin and the reliance enrolment in the study because of local medical on death from cancer rather than incidence to practices. (The Working Group noted that define the presence of disease. changing local medical practices disproportion- Schreinemachers and Everson (1994) report- ately affect smaU regional studies, increasing ed on 12 668 people aged 25-74 who provided misclassification of long-term exposures.) information on aspirin use when enrolled in Thun et al. (1991, 1992, 1993) measured the First National Health and Nutrition Examina- death rates from colonic and other cancers tion Survey between 1971 and 1987. Over the according to aspirin use at enrolment in the average follow-up of 12 years (through 1987), American Cancer Society study of 662 424 US the incidence of colorectal cancer was 26% adults, who were followed from 1982 to 1988. lower among participants who had used any People who reported using aspirin or an aspirin in the 30 days before interview than aspirin-caffeine combination 16 or more times among those who had used no aspirin (RR, per month for at least one year had 40% lower 0.74; CI, 0.49-1.1). The analyses controlled for death rates from colon cancer than those who obesity but not for physical activity or diet. The reported no aspirin use (men: RR, 0.60; CI, question on aspirin did not differentiate con- 0.40-0.89; women: RR, 0.58, CI, 0.37-0.90). tinuing use from brief or occasional use. Adjustment in the analysis for obesity, dietary Giovannucci et aL. (1994) assessed the vegetable and fat consumption and physical incidence of colorectal adenoma and carcino- activity did not attenuate the reduction in risk. ma among 47 900 men aged 40-75 in the The results were also not changed by exclusion Harvard Health Professionals study. Regular from the analysis of people whose underlying users of aspirin (two or more tablets pei week disease might have affected both aspirin use in 1986) had a lower risk for colorectal cancer .. 53 lARC Handbooks of Cancer Prevention at aIl stages (RR, 0.68; CI, 0.52-0.92) and and deaths and newly diagnosed cases of colo- at advanced (metastatic or fatal) stages rectal cancer were ascertained over eight years. (RR, 0.51; CI, 0.32-0.84) than non-users. Age, The duration of aspirin use correlated most history of polyps or previous endoscopy, strongly with the reduced risk for colorectal parental history of colorectal cancer, smoking, cancer. The RR for colorectal cancer decreased body mas s, leisure time physical activity progressively with years of use (Figure 2; p for and intakes of red meat, vitamin E and alcohol trend = 0.008). Nurses who reported taking two were controlled for in the analyses. The inverse or more aspirin tablets weekly for 20 or more association became progressively stronger with years had a significantly lower risk than non- more consistent use of aspirin, Le. regular users (RR, 0.56; CI, 0.36-0.90). Although the RR use reported on more than one questionnaire. appeared to be decreasing after five years of reg- Colorectal adenomas were less common ular use, the decrement did not become statis- in aspirin users than in non-us ers whether ticaIly significant until more prolonged use. or not the patients had been found to have Controllng for several dietary factors, physical occult blood in the faeces, suggesting that activity, alcohol and smoking did not alter bleeding and early diagnosis of polyps these results. (The Working Group noted that did not account for the lower cancer risk one strength of this study is the repeated mea- in aspirin users. The inverse association sures of aspirin use, which aIlow more detailed was strongest with metastatic or fatal colorectal analysis of dose and duration th an is possible in cancer. other studies.) Giovannucci et al. (1995) reported the inci- dence of colorectal cancer in relation to the (c) Case-control studies dose and duration of use of aspirin among Six published case-control studies examined 89 446 US female nurses from 1984 through the risk for colorectal cancer in relation to use 1992. Data on aspirin use were obtained by of aspirin-containing drugs (Table 4). A further questionnaire in 1980, 1982, 1984 and 1988, two studies addressed the risk for colorectal

Figure 2. Age-adjusted relative risks for colorectal cancer and 95% confidence intervals according to the number of consecutive years of regular use of aspirin as compared with non-users of aspirin

1.5

. .¡:ti 1.0

CI .2: -ct ~ 0.5 1

0.0 o 1-4 5-9 10-19 ;: 20 Years of regular use From Giovannucci et al. (1995). Regular aspirin use defined as consumption of two or more tablets per week

54 Aspirin

cancer in relation to medical conditions that decreased with duration of use and increased served as a praxy for aspirin use. after cessation of NSAID use, although neither Kune et al. (1988) assessed whether the risk trend was statistically significant. The ho spi- for newly diagnosed colorectal cancer was asso- tal-based design of the study did not aIlow ciated with ilnesses, operations and medica- complete exclusion of bias fram the selection of tions, using a population-based tumour registry contraIs or confounding by diet or physical in Melbourne, Australia. Personal interviews activity, which were not measured. were conducted to determine whether 715 his- Suh et al. (1993) compared aspirin use tologicaIly confirmed cases and 727 randomly among 830 patients hospitalized for colorectal selected contraIs had used any of eight medica- cancer (490 colon, 340 rectum) at the RosweIl tions, two of which were aspirin-containing Park Memorial Institute, USA, with that in two drugs or other NSAIDs. People who responded contraI graups: 1138 healthy visitors from a 'yes'; were asked to characterize their use as screening clinic and 524 hospital patients who 'daily', 'weekly' or 'don1t know'. Those who had neither cancer nor digestive diseases. The used aspirin (exact usage unspecified) had a cases were aIl diagnosed in 1982-91. Patients 40% lower incidence of colorectal cancer than who took at least one aspirin daily had a lower persons who reported no aspirin use (RRJ 0.60; risk for colorectal cancer than did non-users in CI, 0.0.82). Persons who used other NSAIDs had analyses including the screening clinic contraIs a 23% lower incidence of colorectal cancer (RR, (RR in men, 0.24; CI, 0.12-0.50; RR in women, 0.77; CI, 0.60-1.0). Having chranic arthritis was 0.54; CI, 0.26-1.13). Similar estimates with also inversely associated with the risk for wider confidence intervals were seen in colorectal cancer (RR, 0.66, CI, 0.53-0.83). The analyses that included the hospitalized con- association with aspirin use was similar in 392 traIs. No clear gradient of increasing risk was cases of colon cancer and in 323 cases of rectal seen with the frequency of aspirin use, nor were cancer, and the inverse association remained analyses by duration of aspirin use presented. after adjustment in the analysis for diet and Peleg et al. (1994) compared hospital phar- vitaffin supplementation. Information on how macy records for 97 newly diagnosed cases of long people in the study had used NSAIDs was colorectal cancer and 388 contraIs, who were collected but not presented. (The Working followed for at least four years at a municipal Graup noted that contraIs were not selected hospital in Atlanta, Georgia, USA. Medications contemporaneously and that the analyses of were supplied free or at low cost to poor use of non-aspirin NSAIDs did not adjust for patients, thus praviding monthly records of the simultaneous use of aspirin.) issuance of prescription and non-prescription Rosenberg et al. (1991) examined the rela- aspirin, non-aspirin NSAIDs and aceta- tionship between use of NSAIDs and newly minophen. The risk for colorectal cancer diagnosed colorectal cancers in a large, ho spi- decreased with the use of both aspirin and tal-based, case-contraI study in four northeast- non-aspirin NSAIDs but not with aceta- ern US cities. Nurses interviewed 1326 patients minophen. As shown in Table 4, The inverse with colorectal cancer, aged 30-69, and 4891 trend was more strangly associated with dura- hospitalized contraIs (1011 with other cancers, tion of use (estimated as the number of days for 3880 with trauma or acute infection) about the which NSAIDs were dispensed during the four- use of salicylates (aspirin), indoles (indo- year risk period) than with the dose of NSAIDs. methacin), fenamates (mefanamic acid), pyra- Diet and physical activity could not be con- zolones (phenylbutazone) and oxicams (piraxi- tralled for. ln a second report, Peleg et al. (1996) cam). Regular use was defined as use on at least described 93 cases of colorectal cancer that four days a week for at least three months. were included in the above study. The paper is VirtuaIly aIl of the NSAID use was of aspirin. discussed separately in relation only to sporadic Regular NSAID users had a 50% lower risk for adenomatous polyps (Table 5). colorectal cancer than those who had never Muscat et aL. (1994), at the American Health used NSAIDs (RR, 0.5; CI, 0.4-0.8). The risk Foundation, interviewed 511 patients with "" 55 ;;:: ~ 1 n l':: :: cr0- Table 4. Case-control studies of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk for colorectal cancer in the o '""" general population ,.o Drug Frequency Comments Reference Population Study size End-point Results (RR)8 nl' n:: Kune et al. Population-based, 715 cases Colorectal cancer Aspirin Daily (7) 0.60 (0.44-0.82) Adjusted for diet ..ro 0.77 (0.60-1.01) (1988) Melbourne, Australia, 727 controls (incidence) .."' Unadjusted for aspirin use ro 1980-81 NSAIDs Daily (7) ~ ro Rosenberg et al. Hospital-based, four 1326 cases Colorectal cancer Mostly aspirin ;¡ 4 days/week 0.5 (0.4-0.8) Trend with duration NS; ,.:: ;¡ 3 months risk increased after õ' (1991) cities in eastern USA, 4891 controls (incidence) :: 1977-88 cessation

Suh et al. Hospital-based, Roswell 830 cases Colorectal cancer Aspirin ;¡ 1 per day in 4 years 0.24 (0.12-0.50) Men Women (1993) Park, USA, 1138 c1inic controls (incidence) before study 0.54 (0.26-1.1) 1982-91 524 hospital controls Peleg et al. Hospital-based, Atlanta, 97 cases Colorectal cancer Aspirin and non- Used aspirin ~ 624 days 0.08 (0.01-0.59) Urban poor (1994) USA, 1988-90 388 controls (incidence) aspirin in 4 years before study Used NSAIDs ~ 313 0.25 (0.09-0.73) days in 4 years before study

Muscat et al. Hospital-based, 511 cases Colorectal cancer NSAIDs ;¡ 3 times/week 0.64 (0.42-0.97) Men 0.32 (0.18-0.57) Women (1994) American Health 500 contrais (incidence) for ;¡ 1 year Foundation, 1989-92

Müller et al. Hospital-based, 12 304 cases Colon cancer NSAIDs Not stated 0.52-0.91 For 6 diseases treated with NSAIDs (1994) US veterans, 1988-92 49 216 controls (incidence) Other 1.2-1.3 For diseases treated with anticoagulants other anticoagulants

Reeves et al. Population-based, 184 cases Colorectal cancer Aspirin and non- ;¡ 1 tablet at least twice 0.65 (0.40-1.0) Non-aspirin NSAIDs more strangly associated than (1996) women in Wisconsin, 293 controls (incidence) aspirin weekly for ;¡ 1 uear 1991-92 aspirin Bansal & Hospital-based, US 371 cases among Colorectal cancer NSAIDs Not stated 0.68 (0.65-0.72) Sonnenberg veterans, 1981-93 11 446 veterans with (incidence) (1996) and 52 243 without inflammatory bowel disease

RR, relative risk; NS, not significant 8 ln parentheses, 95% confidence interval Aspirin

colorectal cancer and 500 hospitalized con troIs adjustment was made for age, previous about use of NSAIDs and acetaminophen. Use sigmoidoscopy, family history and body mass was defined as consumption at least three times index. A statistically significant trend of a week for at least one year before hospitaliza- decreasing risk was seen with increasing dura- tion of the patient. By this definition, NSAID tion but not with the frequency of NSAID use. use was associated with a significantly lower Non-aspirin NSAIDs were associated with a risk for colorectal cancer in both men (RR, 0.64; stronger reduction in colorectal cancer risk (RR, CI, 0.42-0.97) and women (RR, 0.32; CI, 0.43; CI, 0.20-0.89) th an aspirin (RR, 0.79; CI, 0.18-0.57). There were too few cancers for a 0.46-1.4). reliable assessment of the trend in risk with Bansal and Sonnenberg (1996) examined duration of NSAID use or of differences among whether diseases potentiaIly associated with subgroups of people taking NSAIDs for different use of NSAIDs were associated with the risk for indications. Acetaminophen was not associated colorectal cancer among II 446 veterans hospi- with a lower risk for colorectal cancer. talized for inflammatory bowel disease at MüIler et aL. (1994) tested whether gastroin- Veterans Administration hospitals between testinal bleeding induced by aspirin might le ad 1981 and 1993. ln a comparison of 371 patients to colonoscopy, early diagnosis and surgi cal with both colorectal cancer and bowel disease removal of adenomatous polyps, rather than and 52 243 with colorectal cancers only, the aspirin truly inhibiting tumorigenesis. By com- researchers found a lower risk for death from paring 12 304 patients first treated for colon colorectal cancer in patients with other condi- cancer at a Veterans Administration hospital in tions usuaIly associated with use of NSAIDs the USA between 1988 and 1992 with 49 216 than in patients not likely to take these drugs con troIs matched to the cases for age, sex and (RR, 0.68; CI, 0.65-0.72). (The Working Group race, the researchers assessed whether the inci- noted that the cases of colon cancer first diag- dence of colon cancer was increased or nosed between 1988 and 1992 at a Veterans decreased among veterans with conditions Administration hospital would overlap with treated by aspirin or NSAIDs (su ch as ischaemic those in the study of Müller et aL. (1994); how- heart disease, peripheral vascular disease, arter- ever, the designs of the two studies are suffi- ial embolism and thrombosis, osteoarthrosis ciently different to be reported separately.) and spondylosis), in comparison with patients with conditions treated with non-aspirin anti- (d) Randomized clinical trial of colorectal coagulants (atrial fibrilation, phlebitis and cancer and adenomatous polyps thrombophlebitis). The incidence of colon can- One randomized clinical trial provides some cer was significantly lower in veterans with the information on aspirin use in relation to colo- six conditions generaIly treated with aspirin rectal cancer. The US Physicians' Health Study (RR, 0.52-0.91) and was significantly higher in (Gann et al.i 1993) was a double-blind, placebo- those with the diseases treated with non-aspirin controIled trial of 22 071 male physicians, anticoagulants (1.2-1.3). which was designed to evaluate the effects of Reeves et al. (1996) conducted a popu- alternate daily doses of aspirin (325 mg) and lation-based study of 184 women in Wisconsin, ß-carotene on the risks for cardiovascular dis- USA, whose invasive colorectal cancer was first ease and cancer. The men taking aspirin were reported to the State tumour registry between removed from the trial after a mean foIlow-up 1991 and 1992, and 293 population-based con- of five years because of a significant reduction troIs. AIl of the women were aged 40-74 years. in the incidence of non-fatal myocardial infarct. NSAID use was ascertained by telephone inter- ln a subsequent analysis of the 33 cases of colo- view; regular use was defined as taking at least rectal cancer, an end-point that the trial had one tablet at least twice weekly for at least one not been designed to evaluate, it was found month. Regular use was associated significantly that the RR for invasive cancer associated with with a lower incidence of colorectal cancer use of aspirin compared with the placebo was (RR, 0.65; CI, 0.40-1.0) in analyses in which 1.2 (95% CI, 0.80-1.7) over the five years of

57 IARC Handbooks of Cancer Prevention

treatment. An additional analysis of colorectal that aIl participants underwent fuIl colono- cancer incidence by year of treatment showed scopy at predefined intervals, minimizing the RRs of 2.0 (0.75-5.3) for year 1, 1.2 (0.53-2.7) possibility that bleeding induced by aspirin for year 2, 1.3 (0.58-2.8) for year 3, 1.0 might bias detection of polyps. (0.48-2.1) for year 4 and 0.77 (0.34-1.8) for Giovannucci et aL. (1994) examined colorec- year 5 or later, which may be compatible with tal adenomas as weIl as carcinomas in the an emerging protective effect of aspirin with Harvard Health Professionals study. The analy- increasing duration of treatment. sis was based on 472 distal adenomas among ln a subsequent analysis of 13 years of fol- 10 521 men who reported having had a low-up, after most of the patients on placebo colonoscopy or sigmoidoscopy between 1982 had begun ta king aspirin, the findings for colo- and 1986 for reasons other than bleeding. The rectal cancer were re-examined in two ways: by diagnosis of adenoma was verified from med- classifying participants according to their ini- ical records. The RR, adjusted for other mea- tial randomization (RR, 1.1; Ci, 0.85-1.3 sured risk factors for the occurrence of adeno- (Sturmer et al., 1996)) and by actual aspirin use mas of the descending and sigmoid colon and (RR, 0.88; 0.59-1.3). (The Working Group noted rectum, in men who reported aspirin use in that, even with the longer foIlow-up, use of 1986 was 0.65 (Ci, 0.42-1.0) in comparison aspirin could not have exceeded 13 years and with non-users. Adenomas were less common the study stil had limited statistical power for among aspirin users than non-users whether or addressing the risk for colorectal cancer.) not the patients had faecal occult blood. Giovannucci et al. (1995) also assessed colo- 4.1.2 Studies of sporadic adenomatous rectal adenoma incidence in relation to aspirin polyps in the colon use among 89 446 US nurses from 1980 The relationship between the presence of ade- through 1990. The analyses included 564 cases nomatous polyps and subsequent development of adenomatous polyps of the descending and of colorectal cancer is discussed in the General sigmoid colon (371) or rectum (193), confirmed Remarks. The studies described below are sum- by a histopathological report. Having had an marized in Table 5. endoscopy between 1980 and 1990 was report- ed slightly more often by women who took 14 (a) Cohort studíes or more aspirin tablets per week in i 980 th an Greenberg et al. (1993) assessed whether in non-us ers (21.5% vs. 17.6%); however, large self-reported use of aspirin modified the recur- adenomas (:? 1 cm in diameter) were no more rence of adenomatous polyps among 793 common in women who used aspirin at this patients participating in a randomized trial of level (0.38%) than in non-users (0.40%). (The nutrient supplements and antioxidants. AIl par- Working Group noted that these findings could ticipants had a histologicaIly confirmed col- be compatible either with inhibition of the orectal adenoma removed within three months growth by aspirin or early detection and removal before enrolment in the study, leaving no of sm aller adenomas in nurses taking aspirin.) known polyps in the colon. Participants report- ed their use of medications at six and 12 (b) Case-control studíes months after enrolment, and had a second Logan et aL. (1993) examined the risk for colo- colonoscopy after one year. 'Consistent' aspirin rectal adenomas in relation to aspirin use us ers (people who reported taking aspirin on among subjects in a randomized trial of faecal both questionnaires) had a lower recurrence of occult blood screening in Nottingham, United adenoilatous polyps th an did non-users (25% Kingdom. A total of 147 patients who had fae- vs 34%, RR, 0.52; Ci, 0.31-0.89). Similar results cal occult blood and an adenomatous polyp were found after four years of observation (RR, were compared with two control groups: 176 0.58; Ci, 0.36-0.91) (Tosteson et al., 1995). An with blood in the faeces but no adenoma or car- important strength of this study, despite the cinoma detected by colonoscopy, sigmoid- self-reported non-randomized aspirin use, was oscopy or barium enema and 153 people with

58 Table 5. Studies of non-steroidal anti-inflammatory drugs (NSAIDs) and risk for sporadic adenomatous polyps Reference Population Study size Drug Frequency Results (RR)a Comments Cohort studies Greenberg et al. US polyp prevention trial; 259 recurrent polyps Aspirin Any use at start and 0.52 (0.31-0.89) Colonoscopy minimized (1993) 793 adults with previous end of 1 year detection bias adenomas

Giovannucci et al. Harvard Health 472 distal adenomas Aspirin ~ 2 tablets/week 0.65 (0.42-1.0) Inverse association stranger (1994b) Prafessionals: 10 521 US with regular use reported on men, 1986-91 more than one questionnaire

Giovannucci et al. Harvard Health 564 distal adenomas Aspirin ~ 14 tablets Not given No effect on incidence of (1995) Prafessionals, 89 446 US adenomas ;: 1 cm female nurses, 1980-90 Case-control studies Logan et al. (1993) Within randomized trial of 147 cases NSAIDs Any use 0.49 (0.3-0.8) VS. controls with no FOB FOB testing; Nottingham, Contrais: VS. controls with FOB United Kingdom 176 negative FOB 0.66 (0.4-1.1) 153 positive FOB

Suh et al. (1993) Hospital-based, Roswell 212 cases Aspirin ~ 2 times/day 0.61 (0.26-1.4) VS. screening c1inic controls Park, USA Contrais: 1138 screening c1inic VS. hospital controls 524 hospital 0.53 (0.19-1.5)

Martinez et al. (1995) Endoscopy patients at 157 cases NSAIDs ~ 1 daily 0.36 (0.20-0.63) gastrointestinal c1inics, 480 controls 0.7 (0.39-1.6) Texas, USA ~ weekly

Peleg et al. (1996) Hospital-based, Atlanta, 113 cases with NSAIDs (aspirin .: 320 CCDs 0.59 (0.23-1.5) CCD ~ 700 equals 'standard USA, 1990-93 adenoma and non- 0.56 (0.20-1.5) dose' of NSAIDs on 42% of 226 controls aspirin) 320-700 CCDs 0.31 (0.11-0.84) days of observation

~ 700 CCDs RR, relative risk; FOB, faecal occult blood; CCD, calculated cumulative dose a ln parentheses, 95% confidence interval

"";¡ "2... ~ 1 S' lARC Handbooks of Cancer Prevention

no blood in the faeces and who were not exam- days a patient was prescribed a 'standard daily ined further. When the latter were used as the dose' of any NSAID during the study. Patients referent, the RR for colorectal adenoma in per- prescribed a cumulative dose of ~ 700 (equiva- sons ever having used aspirin was 0.49 (CI, lent to receiving a 'standard dose' of NSAIDs for

0.3-0.8). This inverse association was also pre- 400 days du ring the two-year-and-seven- sent, but weaker, when the cases were com- month study), had a significantly reduced risk pared with the con troIs who had faecal occult. for adenoma than controls (RR, 0.31; CI, blood (RR, 0.66; CI, 0.4-1.1). There were no 0.11-0.84). Data for cumulative doses of -( 320 clear trends with frequency of use, but use for and 320-700 are given in Table 5. (The Working longer th an five years resulted in a lower risk Group noted that the 'standard daily dose' than use for shorter periods. NSAIDs other than defined in this study is intermediate between an aspirin, but not acetaminophen, were also asso- anti-inflammatory dose and an analgesic dose and ciated with a lower risk for adenomas. approximately one-half of the anti-inflammatory Suh et al. (1993), at the Roswell Park level. The researchers did not define their interpre- Memorial Institute, compared aspirin use tation of a 'standard dose' of aspir.) among 212 hospitalized patients found to have adenomatous polyps of the colon or rectum (c) Randomized clinical trial with that of two control groups: 1138 healthy The efficacy of aspirin in inhibiting sporadic visitors from a screening clinic and 524 ho spi- adenomatous polyps was examined in one ran- tal patients who had neither cancer nor diges- domized trial (Gann et al., 1993). ln the US tive diseases. AlI of the cases were diagnosed Physicians1 Health Study, men randomized to between 1982 and 1991. Patients who took 325 mg aspirin every other day for five years aspirin two or more times daily had a lower risk had a slightly lower risk for cancer in situ or for colorectal cancer than did non-users. The self-reported polyps than did men receiving the RR for adenomas in comparison with the placebo (122 vs. 142 cases; RR, 0.86; CI, screening clinic controls was 0.61 (CI, 0.26-1.4) 0.68-1.1). (The Working Group noted that it and that in comparison with the hospital con- was impossible to exclude the possibilty that troIs was 0.53 (0.19-1.5). polyps existed at the time of enrolment. This Martinez et al. (1995) conducted a retrospec- would have tended to dilute any beneficial tive, clinic-based study of 157 patients with ade- effect of aspirin on colorectal cancer incidence. nomatous polyps and 480 controls, aIl of whom It was also impossible to distinguish between had undergone endoscopy at coIlaborating gas- adenomatous and hyperplastic polyps.) troenterology clinics in Houston, Texas, USA. The RR for adenomatous polyps among persons 4.1.3 Studies of oesophageal and gastric who took aspirin or other NSAIDs at least daily cancers when compared with those who never used These studies are summarized in Table 6. NSAIDs was 0.36 (CI, 0.20-0.63); the estimate Isomäki et al. (1978) found five incident for use one to six times per week was 0.77 (CI, cases of cancer of the oesophagus (7.4 expect- 0.39-1.6). An advantage of this study was that aIl ed) and 51 cases of cancer of the stomach (54 of the patients underwent endoscopy, reducing expected) in patients with rheumatoid arthritis the potential for screening bias. in Finland in 1967-73. The number of cases Peleg et al. (1996) compared the hospital expected was calculated from general popula- pharmacy records for 113 cases of colorectal tion rates. Gridley et al. (1993) likewise found adenoma diagnosed between 1 August 1990 fewer cases of gastric cancer than expected and 1 March 1993 with those of 226 controls (observed/expected, 39/62; RR, 0.63; CI, from the same municipal hospital in Atlanta, 0.5-0.9) but not of oesophageal cancer (11/8.3; Georgia, USA. Using these records, the RR, 1.3; CI, 0.7-2.4) among patients with researchers computed calculated cumulative rheumatoid arthritis in Sweden. ln neither of doses of aIl NSAIDs over the 55-month study: these studies were covariates other th an age, This corresponds roughly to the number of sex and time period controlled for. -- 60 Table 6. Cohort studies of use of non-steroidal anti-inflammatory drugs and risks for oesophageal and gastric cancers Reference Population Study size End-point Drug Frequency Results (RR)" Comments Isomäki et al. (1978)Finland; Rheumatoid arthritis, 34 5 cases618 Oesophageal arthritis cancer Therapy for Heavy use 0.67 (NS) women and 11 483 51 cases Gastric cancer 1.1 (NS) men, 1967-73 (incidence)

Gridley et al. (1993) Rheumatoid arthritis, 11 cases Oesophageal cancer Therapy for Heavy use 1.3 (0.7-2.4) Sweden; 8787 arthritis women and 3750 39 cases Gastric cancer 0.63 (0.5-0.9) men, (incidence) 1965-84 Thun et al. (1993) American Cancer 176 deaths Oesophageal cancer Aspirin 2: 16 times/month 0.78 (0.42-1.4) Multivariate estimates Society, 635 031 US (fatal) adults, 1982-88 308 deaths Gastric cancer Aspirin 0.49 (0.22-1.12) No data on aspirin after baseline (fatal) Decreased risk mostly confined to users of 2: 10 years Schreinemachers & 12 688 US adults, 20 cases Gastric cancer Aspirin Last 30 days 0.93 (0.49-1.7) Everson (1994) 1971-87 (incidence)

Funkhouser & Sharp 12 688 US adults, 15 cases Oesophageal cancer Aspirin Last 30 days 0.10 (0.01-0.76) Multivariate estimate, also for (1995) 1971-87 alcohol use and smoking RR, relative risk; NS, not significant a ln parentheses, 95% confidence interval

vi;i "8... g: 1 5' IARC Handbooks of Cancer Prevention

Thun et al. (1993), in a study described on dispensed were linked to cancer records from

p. 52, found lower death rates from cancers of ho spi taIs and the local cancer registry. The the oesophagus and stomach among regular observed numbers of cancers were compared aspirin users (16 or more times per month in with the expected numbers, standardized for the past year) than in people who had never age and sex, derived from the entire cohort. used aspirin. The trend of decreasing risk with Three publications have summarized the more frequent aspirin use was statistically sig- screening findings for foIlow-up periods of up nificant for gastric cancer (p for trend = 0.002) to seven years (Friedman & Ury, 1980), nine and of borderline significance for oesophageal years (Friedman & Ury, 1983) and 15 years cancer (p = 0.054). Smoking, alcohol consump- (Selby et al., 1989). Among 2393 persons who tion, dietary consumption of fat and fruit, veg- received aspirin-phenacetin-caffeine-bu talbi tal etables and grains and obesity were adjusted for in combination, there was a significant in the analysis. (p .( 0.01) deficit of breast cancer (two observed, Schreinemachers and Everson (1994) found 9.6 expected) in the seven-year follow-up. No no difference in the number of newly diag- negative or positive association with use of this nosed cases of gastric cancer among partici- combination was reported in the lS-year fol- pants in the National Health and Nutrition low-up. Examination Survey who were followed from The incidences of cancers of the lung, blad- 1971 to 1987 (RR, 0.93; CI, 0.49-1.7; 30 cases). der, prostate and breast were similar among These authors did not consider oesophageal daily aspirin users and non-users in the study of cancer, but in another report of the same study, Paganini-Hil et aL. (1989). Funkhouser and Sharp (1995) found signifi- ln the previously described study of the inci- cantly fewer oesophageal cancers among peo- dence of cancer among Swedish patients with ple who used aspirin occasionally th an in non- rheumatoid arthritis (Gridley et aL., 1993), users (RR, 0.10; CI, 0.01-0.76), although this is women with this condition, who probably had based on only 15 cases. No cases of oesophageal prolonged exposure to NSAIDs, had reduced cancer were observed among regular aspirin rates of breast cancer (SIR, 0.79; Ci, 0.6-1.0). users. There was no evidence of protection from can- Garidou et al. (1996) conducted a small, hos- cers other than of the breast, colon and rectum pital-based case-control study in Greece. They and oesophagus. found that chronic intake of any analgesic was Thun et al. (1993) found no consistent dif- non-signifcantly inversely associated with ferences in the death rates of aspirin users and

both squamous-ceIl carcinoma (five cases; RR, non-us ers from cancers outside the digestive 0.6; CI, 0.2-1.9) and adenocarcinoma (four tract among over 600 000 US adults in the cases; RR, 0.5; CI, 0.2-1.6) of the oesophagus. American Cancer Society study. The death rates (The Working Group noted that chronic anal- were either not statisticaIly significantly differ- gesic use was not defined. Sorne controls may ent or were seen in one sex only, with no have used analgesics for long periods because of dose-response trend. Cancer sites that were chronic or recurrent injuries.) examined included buccal cavity and pharynx, respiratory system, breast (female), genital sys- 4.1.4 Studies of cancers other than in the tem, urinary system, lymphatic and haema-

digestive tract top oie tic systems and other or unspecified. The Aspirin was included in a hypothesis-generat- RR for breast cancer among women who report- ing cohort study designed to screen 215 drugs ed taking aspirin 16 or more times monthly was for possible carcinogenicity, which covered 0.88 (Ci, 0.62-1.2) in comparison with non- more than 140 000 subscribers enrolled users. between July 1969 and August 1973 in a pre- Schreinemachers and Everson (1994) report- paid medical care programme in northern ed significantly lower incidences among users

California (USA). Computer records of persons of aspirin than non-us ers for cancers of the to whom at least one drug prescription was trachea, bronchus and lung (RR, 0.68; Ci,

62 Aspirin

0.49-0.94; 72 cases in aspirin users, 91 cases in Publication bias. The Working Group was not non-us ers) and breast cancer in women (RR, aware (and did not think it plausible) that 0.70; CI, 0.50-0.96; 79 cases in aspirin users, informative studies have been excluded fram and 68 cases in non-users). the literature. ln a large, international, population-based, case-control study, salicylates were not associ- Screening/detection. It is possible that bleeding ated with renal-ceIl cancer (McCredie et aL., induced by NSAIDs including aspirin may le ad 1995). No dose-response relationship was to endoscopy and eadier detection and removal found. Moreover, the lack of association was of colorectal adenomas, resulting in a lower not altered by restricting analgesic use to that incidence of and death rates from colorectal five or 10 years before the year of diagnosis. cancer. Eadier detection of invasive cancer Egan et aL. (1996) found no association might also reduce mortality. This hypothesis between regular aspirin use and the incidence cannot, however, explain the lower prevalence of breast cancer in a cohort study of 89 528 and incidence of colorectal adenoma among registered US nurses in 1990. The analyses were aspirin users observed in several studies, which based on 2414 cases identified over 12 years of contradicts the hypothesis of screening bias. follow-up (RR, 1.0; CI,. 0.95-1.1). Rosenberg et al. (1991) reported no associations between Indications for usage. It is possible that the rea- regular use of aspirin and cancers of the sons why aspirin users take aspirin influence breast, lung, endometrium, ovary, testis or the risk for colorectal cancer. ln many of the urinary bladder or leukaemia, lymphoma or studies, the reasons for aspirin use are not weIl malignant melanoma in preliminary analyses of characterized. This uncertainty is particulady a case-control study of drug use in Boston, USA. apparent for long-term users, among whom the Harris et al. (1996) described a case-control putative protective effect appears to be most study of breast cancer and NSAID use in the marked. Nevertheless, two considerations reduce USA. They interviewed 511 women with newly this concern. First, the association is observed diagnosed breast cancer at one centre and 1534 in a variety of populations with different under- women who had undergone screening mam- lying morbidities. Second, the association is not mography. Use of any NSAID three or more observed with acetominophen. times weekly for at least one year was associat- ed with a reduced risk for breast cancer Lire-style factors potentially associated with (RR, 0.66; CI, 0.52-0.83). The risks were similar aspirin use and colorectal cancer. The Working for users of aspirin alone, ibuprofen al one and Group considered possible confounding by phys- aIl NSAIDs combined. The most heavily ical activity, diet, obesity and other lie-style exposed women, with regard to dose and dura- factors that potentially affect the risk for col- tion, had the lowest risk. (The Working Group orectal cancer. ln studies in which these factors noted the incomplete descriptions of the study were addressed, no dimunition of the associa- population, the participation rates and expo- tion was found, and no other known risk factor sure categories. An eadier report (Harris et al., is sufficiently strong to account for the association 1995) probably covered a subset of this study with aspirin. It is possible but implausible that and was therefore not considered separately.) unknown risk factors could be associated strong- ly enough with both aspirin use and the risk for .4.1.5 Issues in interpreting the evidence for colorectal cancer to account for the findings. prevention of colorectal cancer ln considering the epidemiological data on use Factors associated with aspirin intolerance. The of aspirin and risk for colorectal cancer, the possibilty that genetic or life-style factors asso- Working Group carefuIly considered the foIlowing ciated with intolerance to aspirin use could also sources of potential bias and confounding because be associated with risk for colorectal cancer was of their concern about the implications for colo- considered. The Working Group was unaware rectal cancer prevention in the general population. of any evidence to support this hypothesis.

63 lARC Handbooks of Cancer Prevention

Also, the small proportion of the general consecutive days, then given saline or population who are intolerant to aspirin makes 1,2-dimethylhydrazine (25 mg/kg bw) on days 4 this implausible. and 9 or were treated with 1,2-dimethylhy- drazine only. About half of the animaIs in aIl Exposure measurement. Information on the groups were kiled four weeks after the first effects of prolonged use of aspirin is available in administration of 1,2-dimethylhydrazine; the only a few studies; this is an important limita- rest were kiled after eight weeks, and colonie tion of the aggregated epidemiologieal data. ln aberrant crypt foci were quantified after most studies, measurement of aspirin use was methylene blue staining. When given both four based on self-reports relating to use a few years and eight weeks after the beginning of treat- before the onset of the studied end-point (ade- ment with 1,2-dimethylhydrazine, aspirin nomas or cancers). This is likely to be a mis- caused a significant (60%) decrease in the num- classified surrogate for long-term aspirin use; ber of foci (p ~ 0.01-0.001). ln addition, the however, non-differential misClassifieation numbers of larger foci (with three or more aber- would have the effect of minimizing any true rant crypts per focus) were signifieantly lower effect of aspirin. DifferentiaI misclassifieation (70% reduction; p ~ 0.01) at both times in leading to a spurious association is conceivable aspirin-treated rats. only in the case-control studies, but the Groups of 14 seven-week-old male Fischer Working Group concluded that this was unlike- 344 rats were given subcutaneous injections of ly to explain the observed findings. The Group aspirin at doses of 0.2 and 0.4 mg/kg diet (200 also considered the biological plausibilty of an and 400 ppm) for 35 days. Azoxymethane in association between aspirin use and colorectal saline (15 mg/kg bw) was given on days 7 and cancer, given the short interval between report- 14 of the experiment. Control rats were inject- ed exposure and outcome. Two interpretations ed with saline only. AlI rats were kiled on day are compatible with a causal association: recent 35, and aberrant crypt foci were quantified after aspirin use is a good surrogate for long-term methylene blue staining. At the doses used, use, and/or aspirin has a fairly rapid effect on aspirin did not inhibit either the number of cancer prevention. ln view of the evidence that aberrant crypt foci or the number of crypts per duration of exposure is important - and that a focus (Pereira et aL., 1994). reduced risk for colorectal cancer may indeed ln a similar experiment, 20 adult male be achieved, at least in part, through preven- Fischer 344 rats received subcutaneous injec- tion of adenomas - the Working Group recog- tions of azoxymethane at a dose of 15 mg/kg nized that the interpretation of a causal associ- bw once per week for two weeks. Rats were then ation depends on the assumption that reported randomized to diets containing 0, 0.2 or recent aspirin use is a good surrogate for long- 0.4 g/kg (200 or 400 ppm) aspirin; these doses term use. There was no independent evidence represented 40 and 80% of the maximum toI er- to support or refute this assumption. ated dose (MTD; see General Remarks) of aspirin determined in the same laboratory. 4.2 Experimental models 1 Azoxymethane had induced about 170 aberrant 4.2.1 Experimental animaIs crypt foci by eight weeks. Aspirin at either dose suppressed the formation and progression of (a) Colon foci to foci of multiple aberrant crypts Short-term studies. Aspirin was evaluated for its (p ~ 0.05), although the degree of inhibition abilty to reduce the incidence and growth of was greater at 400 than 200 ppm (Wargovich et aberrant crypt foci in the rat colon (Mereto et al., 1995). aL., 1994). Forty-eight male Sprague-Dawley rats were treated with either aspirin (10 mg/kg bw Long-term studies. These studies are summa- per day) by intragastrie administration for 12 rized in Table 7.

1 ln this section, the concentrations of aspirin in the diet are given in the units used by the authors of the study and in square brack- ets-- as ppm, to allow ready comparison of studies. 64 Table 7. Results of experiments on the chemopreventive activity of aspirin on colon carcinogenesis in male rats Strain Carcìnogen, dose and Aspirin, dose, route and Tumour incidence Tumour multiplicity Reference route of administration duration of administration (% animais with tumours) (tumours/tumour-bearing animal) Control Aspirin Control Aspirin Sprague-Dawley DMH, 30 mg/kg bw 10 mg/kg bw per day, 50 17 1. 0 1 .0 Craven & DeRubertis intragastrically, once subcutaneously, (1992) - 1 and + 1 week

DMH, 30 mg/kg bw 10 mg/kg bw per day, 42 42 1.2 1.0 intragastrically, once subcutaneously, 2 + 36 weeks

Wistar DMH 30 mg/kg bw, 5 mg/kg bw per day 100 100 NR NR Davis & Patterson (1994) subcutaneously 18 times, 30 mg/kg bw per day 100 50 weekly 60 mg/kg bw per day 100 25 intragastrically, 18 weeks

Fischer 344 AOM, 15 mg/kg bw, 200 ppm 78 53 1.7 0.80 Reddy et al. (1993) subcutaneously, twice, 400 ppm 78 47 1.7 0.70 weekly - 2 to + 50 weeks in the diet DMH, 1,2-dimethylhydrazine; AOM, azoxymethane; NR, not reported

v.~ '"... ~ 1 S' IARC Handbooks of Cancer Prevention

Groups of 12-20 male Sprague-Dawley rats, semisynthetic diet containing 1.75 g/kg methio- 21 days of age, were given subcutaneous injec- nine, 0 mg/kg choline and 0.11 mmol/kg tions of aspirin at 10 mg/kg bw per day one phosphatidylcholine, was examined in male week before and one week after a single dose of Fischer 344 rats. The levels of aspirin in the diet 1,2-dimethylhydrazine at 30 mg/kg bw by intra- were 0.1, 0.2, 0.4 or 0.8% (1000, 2000, 4000 or gastric administration or were given aspirin four 8000 ppm). The duration of the study was weeks after administration of 1,2-dimethylhy- 30 weeks. Administration of aspirin at the two drazine up to the end of the experiment at 36 higher concentrations reduced the develop- weeks. A 66% reduction in the incidence of ment of preneoplastic and neoplastic nodules 1,2-dimethylhydrazine- induced adenocarcino- in the liver (p 0( 0.05-0.001). ln the groupfed mas was seen in rats receiving aspirin for one 0.4% aspirin the number of y-glutamyl week before and after the carcinogen, but transpeptidase-positive nodules per square cen- aspirin had no effect on the tumour response timetre was reduced from 1.7 in the group on when given four weeks after the carcinogen control diet to 0.20, and the size of the nodules (Craven & DeRubertis, 1992). (The Working was decreased from 4.82 to 0.39 mm2. No nod- Group noted the small numbers of animaIs per ules were seen in the group given the diet con- group.) taining 0.8% aspirin (Denda et al.i 1994). ln a similar study, groups of 16 male Male Fischer 344 rats, six to eight weeks of Wistar rats, two months old, received daily age, were fed a commercial di et and hepatocel- doses of aspirin at 0, 5, 30 or 60 mg/kg bw by lular carcinomas were induced in all animaIs by intragastric administration for 18 weeks. initiation with an intraperitoneal injection of One-half of each group also received weekly 200 mg/kg bw N-nitrosodiethylamine and injections of 30 mg/kg bw 1,2-dimethylhy- selection by feeding 0.002% 2-acetylaminoflu- drazine for 18 weeks. Aspirin at aIl doses orene for two weeks and giving a single intra- progressively reduced the number of tumours gastric intubation of 1 mg/kg bw carbon tetra- (p 0( 0.03) and the percentage of tumours chloride. Aspirin, mixed in the diet and admin- ¿ 5 mm in diameter (p 0( 0.03). At the two istered at a concentration of 0.75% (7500 ppm) higher doses, aspirin significantly reduced the one week later, decreased the multiplicity of incidence of tumours (p 0( 0.03-0.01) (Davis & hepatocellular carcinomas from 4.08 to 2.21 (p Patterson, 1994). (The Working Group noted 0( 0.01). No significant differences in incidence the small number of animaIs per group.) were observed (Tang et al., 1993). ln a further study, groups of 48 male Fischer ln an initiation-promotion model of hepato- 344 rats, five weeks old, were fed diets contain- carcinogenesis, nine male Fischer 344 rats were ing 0,200 ppm (40% MTD) or 400 ppm (80% given a single intraperitoneal injection of 200 MTD) aspirin. Two weeks later, 36 rats per mg/kg bw N-nitrosodiethylamine; after two group were given subcutaneous injections of weeks of recovery, the animaIs received the 15 mg/kg bw azoxymethane once weekly for basal diet supplemented with 0.05% phenobar- two weeks; the other 12 rats per group were bital for 10 weeks and were then kiled. Another treated with the vehicle only. After 52 weeks on group also received aspirin in the diet at a their respective dietary regimens, aIl rats were concentration of 0.75 or 1.0% (7500 or 10000 necropsied, and aIl tumours were subjected to ppm). Aspirin treatment significantly retarded histopathological examination. At both dietary the body-weight gain and reduced the average concentrations, aspirin reduced the incidence, food intake throughout the experiment; it also multiplicity and size of azoxymethane-induced reduced the number and percent of areas of the colon adenocarcinomas (p 0( 0.5-0.01) (Reddyet liver occupied by y-glutamyl transpeptidase- al., 1993). positive foci in a dose-dependent manner (p 0( 0.01) but did not appreciably influence the (b) Liver average size of foci (Denda et al., 1989). The chemopreventive effect of aspirin on hepa- Groups of 14-16 male Fischer 344 rats tocarcinogenesis induced by a choline-deficient received a choline-deficient, L-amino acid-defined

66 Aspirin diet or the same diet containing 0.1 or 0.2% N-nitrosobutyl( 4-hydroxybutyl)amine in weeks (1000 or 2000 ppm) aspirin for 12 and 30 weeks, 2-10; a diet containing aspirin at 1 g/kg (1000 at which time the surviving animaIs were kiled. ppm) in weeks 1-20 and water ad libitum for By 12 weeks, the number and areas of the liver 32 weeks; or a diet containing aspirin at 1 g/kg staining for y-glutamyl transferase- positive foci (1000 ppm) in weeks 1-20, drinking-water were decreased in a dose-dependent manner by containing the nitrosamine at 0.05% during aspirin (p -( 0.05-0.01), and by 30 weeks, the weeks 2-10 and then basal diet and water for numbers and percent area of the liver occupied the remainder of the 32 weeks. Aspirin signif- by nodules staining for glutathione S-transferase icantly reduced (p -( 0.05) the incidence of car- placental form were also decreased dose-depen- cinogen-induced urinary bladder tumours: 8 dently (p -( 0.05-0.01) (Endoh et al., 1996). of 32 rats treated with the nitrosamine devel- oped bladder tumours, whereas only 1 of 32 (c) Urínary bladder rats treated with carcinogen plus aspirin devel- ln a study in B6D2F1 mice, the MTD for aspirin oped a bladder tumour (Klän et aL.1 1993). was first determined in a preliminary experi- ment for dose selection and dietary tolerance (d) Pancreas and found to be 1000 mg/kg diet (1000 ppm). Groups of 20 outbred female Syrian golden Groups of 75 male mice, five to six weeks of hamsters, five weeks old, received five weekly age, then received weekly oral doses of 7.5 mg doses of 10 mg/kg bw N-nitrosobis(2-oxo- N-nitrosobutyl( 4-hydroxybutyl)amine in etha- propyl)amine by subcutaneous injection; one nol:water (ratio not given) or vehicle only for group of 19 hamsters was also given aspirin eight weeks (total dose, 60 mg/mouse). Aspirin (purity, 99.5%) from weeks 6 to 32 (time of ter- was administered in the diet at doses of 400 minal kil). A control group of 30 hamsters was and 800 ppm (representing 40 and 80% of the given tap-water. Aspirin treatment had no MTD) beginning one week before the first dose effect on body-weight gain. Neither the reduc- of nitrosamine and continuing until termi- tion in the incidence of pancreatic tumours, nation of the study at 24 weeks. The terminal from 20/28 to 10/19, nor the reduction in the body weights and survival were not reduced by multiplicity of pancreatic adenocarcinomas, inclusion of aspirin in the diet. The incidence from 1.3 to 0.84, was significant (Takahashi et of transitional-cell carcinomas in the urinary aL.1 1990). bladders of nitrosamine-treated mice (22/75) was similar to that in mice treated with the car- 4.2.2 ln-vitro models cinogen plus aspirin (22/73) (Rao et aL.1 1996). No data were available to the Working Group. Groups of 32 Fischer 344 rats received 2% N- (4-( 5-nitro-2- furyl)-2-thiazolyl) formamide in 4.3 Mechanisms of chemoprevention the diet with 0.5% aspirin (5000 ppm) for Most research into the mechanisms of the chemo- 12 weeks; aspirin was continued for one week, preventive action of aspirin has been centred and then the animaIs were given control di et around four areas that are thought to be related for 56 weeks. Aspirin significantly reduced the to the development of colorectal cancer: (i) incidence of urinary bladder carcinomas: in activation of carcinogens, (ii) cell proliferation, only 10 of 27 (37%) rats treated with aspirin (iii) apoptosis and (iv) immune surveilance. but in 18 of 21 (87%) rats treated with the These hypotheses are summarized in Figure 3. carcinogen only. Forestomach tumours, how- ever, were not seen in rats fed the carcinogen 4.3.1 Inhibiton of carcinogen activation alone but developed in 7 of 27 rats fed car- Cyclooxygenases (COX-L and COX-2)1 may cinogen plus aspirin (Murasaki et al.i 1984). be involved in the initiation of carcinogenesis Groups of 32 five-week-old male Wistar rats in three general ways: activation of carcinogens received basal diet for 32 weeks; basal diet for to DNA-binding forms, production of malon- 32 weeks with water containing 0.05% dialdehyde and formation of peroxyl radicals.

1 Used as synonyms for prostaglandin endoperoxide synthases (PGH synthases) 67 lARC Handbooks of Cancer Prevention

Figure 3. Proposed mechanisms of prevention of colon cancer by aspirin

Arachidonic acid

* cox

Prostaglandins

Subverted immune surveilance Ce" proliferation

* *

Carcinogenesis

Carcinogen activation Impaired apoptotic (COX) mechanisms

*Indicates stages at which carcinogenesis can be blocked. Some of the effects could be due to metabo- lites of aspirin, including salicylate.

Activation of carcinogens by COX is weIl Malondialdehyde is produced by the documented (reviewed by Eling et al., 1990), enzymic and nonenzymic breakdown of prosta- and it has also been demonstrated that aspirin glandin H and during lipid peroxidation can inhbit such processes (Krauss & Eling, (reviewed by Marnett, 1992). It is a directly 1985; Levy & Weber, 1992; Liu et al., 1995). An acting mutagen in bacterial and mammalian ilustrative example is the conversion of 2- systems and it is also carcinogenic in rats. aminofluorene to a DNA-binding product by Aspirin and other NSAIDs inhibit the forma- both COX isozymes. This conversion is inhibited tion of malondialdehyde only via the break- by aspirin. down of prostaglandin Hz.

68 Aspirin

Minchin et aL. (1992) demonstrated in an cancer ceIl lines in vitro, but conflcting find- enzyme-free system in vitro that aspirin directly ings are reported for aspirin. Shiff et al. (1996) activa tes several N-hydroxyarylamines by found that although indomethacin, naproxen O-acetylation. and piroxicam induced apoptosis in HT-29 cells, aspirin at 1500 llmol/litre did not. Three methods were used to detect apoptosis: DNA 4.3.2 Inhibiton of cell prolieration laddering on agarose gel electrophoresis, An indirect pathway by which aspirin could fluorescent-activated ceIl sorting to detect sub- inhibit the proliferation of colonocytes is diploid peaks based on DNA content and inhibition of the proliferative effect of prosta- acridine orange staining to highlight cellular glandins. This effect, which requires acetyla- morphological changes such as DNA condensa- tion of COX by aspirin, has been documented tion. EIder et al. (1996), however, demonstrated only in cultured colon cancer cells. The plausi- a convincing, dose-dependent apoptotic bility of this idea rests on the already men- response of HT-29 colon cancer ce Us to tioned observations that colon tumours pro- salicylate and a similar response in transformed duce increased amounts of prostaglandin E2, adenoma ceIls but not in aIl adenoma ceIllines. colon adenomas and carcinomas overexpress Acridine orange staining of floating cells was COX and mice lacking both the Apc and Cox-2 used to quantify apoptosis. EIder et al. used genes have 90% fewer intestinal tumours than concentrations up to 5 mmol/litre but did those lacking only Apc. detect an effect at 1500 llmol/ltre, equivalent Aspirin induced a concentration-dependent to the concentration used by Shiff et al. The reduction in the proliferation rate of HT-29 latter group tested aspirin, whereas EIder et al. human colon cancer cells. This effect was tested salicylate, which is more appropriate, accompanied by distinctive morphological since it is the predominant pharmacological changes in these ceIls. Of greater interest, metabolite in patients on long-term aspirin aspirin altered the distribution of HT-29 cells in treatment. the various phases of the cell cycle in a non- liear, concentration-dependent fashion at con- centrations starting at i mmol/ltre (Shiff et aI.i 4.3.4 Immune surveilance 1996). The role of aspirin in immune surveilance is Salicyclic aCid, the metabolite of aspirin, also uncertain, as is the central idea that immune inhibited the growth of human colorectal surveilance is important in carcinogenesis. The tumour cell lines at concentrations of role of aspirin in immune surveilance has been 1-5 mmol/litre (EIder et aL.1 1996). The addressed both directly and indirectly in ceIl inhibitory effect was greater against carcinoma culture systems. The finding that colon cancers and adenoma ceIl lines transformed in vitro con tain elevated levels of prostaglandin E2 than against adenoma ceIllines. Accumulation (Rigas et al.i 1993) prompted studies of the of many ce Ils in the GolGi cell cycle phase role of this compound in regulation of the and apoptosis were also noted. It is doubtful expression of classes 1 and II HLA antigens in that the inhibition of cell proliferation in SW1116 colon cancer ceIls. Prostaglandin E2 these studies was due to a reduction in down-regulated the expression of the class II prostaglandin production (Hanif et al.i 1996). antigen HLA-DR in SWI116 cells in a concen- (The Working Group noted that as the typical tration- and time-dependent manner. The concentrations in humans in vivo would be effect of aspirin at 100-200 llmol/litre was less than 1 llmol/litre, the physiological sig- reversible and specific (Arvind et al.i 1995). nificance of these in-vitro observations Other eicosanoids such as prostaglandin F2a remains in doubt.) and leukotriene B 4 had no such effect. The reduction of HLA-DR by prostaglandin E2 4.3.3 Apoptosis was accompanied by reduced mRNA levels of Most NSAIDs can induce apoptosis in colon HLA-DRa and reduced transcription of the -- 69 lARC Handbooks of Cancer Prevention

corresponding gene. (HLA-DRa is one of the 5. Other Beneficiai Effects two genes that code for the heterodimeric HLA- DR protein). ln contrast, the expression of HLA 5.1 Antiplatelet effects class 1 genes was not affected. An additional 5.1.1 Background study by the same group confirmed that Aspirin is widely used to prevent myocardial prostaglandin, E2, prostaglandin F2a and infarct, thrombotic stroke and death from leukotriene B4 did not affect the expression vascular events in populations at high risk for of MHC class 1 antigens in SW1116 and HT-29 vascular conditions. Randomized trials have human colon adenocarcinoma ceUs. Further- confirmed the efficacy of aspirin in secondary more, 16, 16-dimethyl prostaglandin E2, a prevention in patients with documented coro- stable analogue of prostaglandin E2, did not nary, cerebral or peripheral vascular disease. affect their expression in mice, even when The absolute benefits are smaIler for healthy treated with a colon carcinogen (Feng et al.i people, however, and the net improvement less 1996). certain. This section covers the mechanism The effect of aspirin on the expression of whereby aspirin inhibits platelet aggregation, class II antigens was also assessed from a how aspirin differs mechanisticaUy from other different viewpoint (Arvind et al., 1996). NSAIDs and from non-NSAID antiplatelet Aspirin induced a several-fold increase in the drugs and what is known currently about the expression of HLA-DR in HT-29 human colon lowest effective dose. adenocarcinoma ceUs, which do not normaIly express these antigens. These effect was accom- 5.1.2 Mechanism panied by increased steady-state mRNA levels Aspirin inhibits platelet aggregation and of HLA-DRa and an increased transcription rate thrombosis by permanently inactivating of the gene. The study clearly established a COX-l in platelets (Moncada & Vane, 1979). transcriptional effect of aspirin on an HLA class Irreversible acetylation of the hydroxyl group II gene, suggesting a potentiaUy important of a single serine residue essentiaUy stops immunological effect of this versatile com- platelet thromboxane A2 production for the pound. This finding is consistent with results 7-10-day life of the platelet. Unlike nucleated showing up-regulation of MHC expression in ceUs, platelets cannot resynthesize COX-l. rats after treatment with piroxicam (Rigas et al., Aspirin is a more potent inhibitor of platelet

1994). thromboxane production th an other NSAIDs Several studies (reviewed by Rumore et al.i because it binds covalently, rather than 1987) have demonstrated that aspirin induces reversibly, to COX-l (Patrono, 1994). The interferon, decreases the antibody response, mechanism by which aspirin inhibits platelet inhibits antigen-antibody interactions, alters aggregation and prevents clot propagation dif- T-lymphocyte functions and alters leukocyte fers fundamentaUy from that of various recent- migration. ly developed antiplatelet drugs, which block Nitric oxide synthesized by inducible the binding of fibrinogen to receptors on the nitric oxide synthase has been implicated as a platelet membrane but do not inhibit COX or mediator of inflammation. Aspirin and salicy- the production of platelet thromboxane late at milimolar concentrations have been (CAPRIE Steering Committee, 1996; Cohen, reported to inhibit induction of inducible 1996). nitric oxide synthase in murine macrophages activated by lipopolysaccharide (Amin et al.i 5.1.3 Secondary prevention in populations at 1995; Brouet & Ohshima, 1995) and in neona- high risk for cardiovascular events tal rat cardiac fibroblasts treated with interfer- Prophylactic aspirin therapy is known to on-y and tumour necrosis factor-a (Farivar & reduce the risk for vascular thrombosis in high- Brecher, 1996). risk populations (Antiplatelet Trialists' CoIlabo- ration, 1988, 1994a,b). A comprehensive

70 Aspirin

overview of 145 randomized trials, 50 involv- randomized trials of secondary prevention have ing aspirin alone, found aspirin to be beneficial shown aspirin to be effective in preventing in high-risk settings: patients with acute thrombosis at doses of 75 mg/day (RISC Group, myocardial infarct, those with a past history of 1990; SALT CoIlaborative Group, 1991; Juul- myocardial infarct or clinical cerebrovascular Moller et al.i 1992; Lindblad et aL.1 1993). One disease, those with a past history of stroke or study indicated that a dose as low as transie nt ischaemic attack and those with vari- 30 mg/day may be protective (Dutch TIA Trial ous other vascular problems (including unsta- Study Group, 1991). The theory that very low ble angina, stable angina, a history of vascular doses of aspirin might be as effective and less surgery, angioplasty, atrial fibrilation, valvular toxic than higher doses is biologicaIly plausible disease and peripheral vascular disease). Most because aspirin inhibits platelet thromboxane of the trials involved daily doses of 75-325 mg A2 production almost completely (Patrono, aspirin (Antiplatelet Trialists' Collaboration, 1994). The efficacy of doses lower than 325 mg 1994b). every other day has not yet been tested in ran- ln absolute terms, the benefit of aspirin is domized trials in the context of primary pre- greatest in patients with acute myocardial vention. infarct, among whom 38 vascular events were prevented per 1000 patients treated for 5.2 Alzheimer disease only about one month. Similar benefits Mc Geer et al. (1996) recently reviewed 17 epi- were seen for patients with prior myocardial demiological studies of the use of NSAIDs and infarct, prior stroke, transient ischaemic steroids as possible protective factors against atack or other 'high risk' cardiovascular Alzheimer disease. Five of six case-control stud- conditions, although longer treatment (16-33 ies in which ¡ arthritis' was used as a surrogate months) was required to obtain them. Much for use of NSAIDs or steroids and one of two in smaller benefits were observed in primary which rheumatoid arthritis was examined prevention trials, with four vascular events reported a reduced risk for Alzheimer disease prevented in 1000 patients over an average of associated with those diagnoses (combined data 62 months of therapy (Antiplatelet Trialists' for arthritis, RR, 0.56; Ci, 0.44-0.70). Collaboration, 1994; Hirsh et aL.1 1995). ln three other studies of patients with rheuma- toid arthritis, Alzheimer disease was noted to be 5.1.4 Primary prevention in populations at uncommon. The summary measure of risk average risk for cardiovascular events in three addition al case-control studies of the Among men in the general population, pro- use of NSAIDs and risk for Alzheimer disease was phylactic aspirin administration reduces the 0.50 (0.34-0.72) as a group; similarly, steroids incidence of non-fatal myocardial infarct but were associated with a summary odds ratio of has not yet been demonstrated to reduce over- 0.66 (0.43-0.99) in four case-control studies. aIl mortality from cardiovascular disease (Hirsh ln nearly aIl of the reviewed studies, the et aL.1 1995). diagnosis of Alzheimer disease was made clini- cally, usuaIly by a neurologist, so that attempts 5.1.5 Lowest effective dose for prevention of were made to exclu de vascular and other cardiovascular events in high-risk dementias. ln aIl of these studies, information populations on use of aspirin was obtained retrospectively, The optimal dose of aspirin for long-term pro- so that recaIl bias or change in use of aspirin phylactic cardiovascular therapy is unknown. precipitated by the disease itself cou Id not be ln the randomized trials reviewed by the reliably excluded. Antiplatelet Trialists' Collaboration (1994b), daily doses of 75-150 mg seemed to be as effec- 5.3 Reproductive outcomes tive as higher doses in preventing vascular Combined analyses of aIl randomized trials of events, although the statistical power to examine antiplatelet therapy in the possible prevention this issue was limited. Several well-designed of pregnancy-induced hypertension have been .. 71 rARC Handbooks of Cancer Prevention published (CLASP CoIlaborative Group, 1994; Sibai et aL., 1993; Viinikka et aL., 1993; CLASP ECPPA CoIlaborative Group, 1996). Most of the Collaborative Group, 1994; ECPPA Colla- trials were of aspirin (50-150 mg/day), but a borative Group, 1996). The RRs associated with few were of aspirin with dipyridamole. When use of aspirin were in the range 0.5-1.0. A sig- the results of aIl the trials were taken together, nificant effect was found only in the relatively antiplatelet therapy was associated with a small trial of Uzan et aL. (1991). reduction of 23% in the incidence of pre- A combined analysis of antiplatelet therapy eclampsia (ECPPA CoIlaborative Group, 1996). in the prevention of perinatal mortality was The results are heterogeneous, however, and presented by the CLASP Collaborative Group when the small trials (including fewer than 200 (1994) and was subsequently updated by the women) are excluded, the apparent reduction ECPPA Collaborative Group (1996). This analy- is 17%. AIl of the trials that found strong sis suggested a 1% (standard deviation, 10) effects of antiplatelet therapy on the preven- reduction in the incidence of perinatal mortal- tion of pre-eclampsia were very smaIl, and at ity associated with antiplatelet therapy. Data least as many women are known to have been from the trials in which at least 200 women randomized in other small but unpublished tri- were enroIled suggested a 1% (standard devia- als (CLASP Collaborative Group, 1994). If some tion, 10) increase in perinatal mortality associ- smaIl trials with unpromising results were not ated with antiplatelet therapy. published, the available results from the small Shapiro et al. (1976) examined the relation- trials would give a biased estimate of the effects ship between perinatal mortality and reported of antiplatelet therapy, but the large trials would aspirin use at any time during pregnancy in a not. The findings of the analysis of the data from multicentre cohort study of 41 337 women the large trials are consistent with this assumption. whose pregnancies lasted at least seven months. ln five of the larger trials included in these Data on drug use were recorded at each antena- combined analyses, information on pre-term tal visit and were confirmed for most women by delivery was presented (Hauth et al., 1993; the attending physician or by review of the hos- Italian Study of Aspirin in Pregnancy, 1993; pital or clinical record. The women were divided Sibai et al., 1993; CLASP Collaborative Group, into 1515 who were heavily exposed, 24 866 1994; ECPPA CoIlaborative Group, 1996). No with intermediate exposure and 14 956 who noteworthy effect of aspirin (50 or 60 mg/day) were not exposed. Heavy exposure was defined on preterm delivery was observed; however, in as use for at least eight days per month for at the large trial of the CLASP Collaborative least six lunar months. There were 371 (2.5%) Group (1994), the absolute risks of preterm perinatal deaths in the unexposed group, 548 delivery differed substantiaIly between the cat- (2.2%) in the group with intermediate exposure egories of women studied. Among about 8000 and 38 (2.5%) in the group with heavy expo- women entered for prophylactic reasons, only sure. Thus, there was no association between one-fifth of the placebo group had pre-term perinatal mortality and level of exposure to delivery, and the absolute benefit appeared to aspirin. be about two fewer preterm deliveries per 100 women aIlocated aspirin. Among just over 6. Carcinogenicity 1000 women entered for therapeutic reasons, two-fifths of the placebo group had preterm 6.1 Humans delivery, and the absolute benefit appeared to 6.1.1 Renal cancer be about 5 per 100. Paganini-Hil et aL. (1989) reported signif- ln some of the trials of the use of low doses cantly more hospitalizations from renal can- of aspirin in the prevention of pregnancy- cer among men who used aspirin daily than induced hypertension or pre-eclampsia, data among non-users in a cohort in a retirement on intrauterine growth retardation were pre- community followed up from 1981 through sented (Uzan et aL., 1991; Hauth et al., 1993; 1987 (RR, 6.3; CI, 2.2-17; nine exposed cases, Italian Study of Aspirin in Pregnancy, 1993; six unexposed). Only three cases of renal

72 Aspirin cancer were observed among exposed women 6.1.3 Childhood cancer (RR, 2.1; 0.53-8.5) in the initial report. After ln some case-control studies of childhood 3.5 additional years of follow-up, the statistical- cancer, data on recalled aspirin use during ly significant excess remained in male but not pregnancy was obtained by interviewing the female aspirin users (Paganini-Hil, 1995). No mothers. ln a study of 188 cases of leukaemia information was available in this study on the and 93 controls with other cancers and a sec- duration of aspirin use, past use of phenacetin ond control group of people hospitalized for or current exposure to other analgesics. . reasons other than cancer (Manning & Carroll, Aspirin use was not associated with cancers 1957), the RR for leukaemia associated with of the urinary system in the large American reported use of aspirin was 1.5 (CI, 0.87-2.5), in Cancer Society cohort (Thun et al.i 1993) nor comparison with controls with other cancers with renal cancer in the two largest trials of and 2.3 (Ci, 1.1-.4.8) in comparison with the aspirin in the primary prevention of heart dis- other control group. ease (Henne kens et al.i 1990). Steineck et aL. ln single studies, no significant association (1995) found an increased risk for transitional- was found between reported aspirin use during ceIl urothelial cancer among people who report- pregnancy and brain tumours (Preston-Martin ed acetaminophen use (1.6, 1.1-2.3) but not et al.i 1982), neuroblastoma (Schwartzbaum, aspirin use (0.7; 0.5-1.0) in a population-based 1992) or rhabdomyosarcoma (Grufferman et case-control study of 325 cases and 393 contraIs. al.i 1982) in the offspring. (The Working Group noted that a major limitation of the studies that show aspirin to 6.2 Experimental animais be associated with urinary tract cancers is No data were available to the Working Group. the inabilty to control for past use of phenacetin. A number of the studies did not distinguish between renal-cell and renal pelvic cancer.) 7. Other Toxic Effects Ross et al. (1989) also found aspirin use to be associated with cancer of the renal pelvis and 7.1 Adverse effects ureter in a population-based case-control study 7.1.1 Humans of 187 cases from the Los Angeles Tumor Registry and 187 neighbourhood controls (RR (a) Upper gastrointestinal tract toxicity among nonsmokers, 5.0, 1.7-14); the associa- AIl NSAIDs, including aspirin, cause a dose- tion with renal pelvis cancer was confined to dependent increase in the incidence of upper women. ln a large-scale study in Minnesota, gastrointestinal toxic effects, ranging in severity USA, no relationship was found between renal- from dyspepsia to gastrointestinal haemorrhage, ceIl carcinoma and regular use or duration of ulceration and perforation. The severity and use of aspirin (Chow et al.i 1994). frequency of these complications vary greatly with the dose and duration of use. Aspirin is 6.1.2 Haematopoietic malignancies the only NSAID for which substantial data exist ln the studies of rheumatoid arthritis patients on the toxicity of both prolonged use of low doses in Finland and Sweden (see p. 51), the inci- and exposure to anti-inflammatory doses. dence of haematopoietic malignancies was about twice that of the general population Toxicity of high doses. At high anti-inflamma- (Isomäki et al.i 1978; Gridley et al.i 1993). ln tory doses of aspirin (? 2400 mg daily), the study of Gridley et aL. (1993), described on gastrointestinal bleeding and ulceration p. 511 there was an increased risk for lym- become important individual and public health phomas (SIR, 2.0; CI, 1.5-2.6). (The Working problems. ln several randomized trials of Group noted that the underlying rheumatoid cardiovascular disease and aspirin use, patients arthritis and other treatment could account receiving 1 g of aspirin per day had an inci- for differences in lymphoma risk in this dence of six episodes of haematemesis per study. J 10 000 person-months of treatment (Aspirin

73 rARC Handbooks of Cancer Prevention

Myocardial Infarction Study Research Group, Aspirin may also increase the risk for haem- 1980). The incidence during the three-year orrhagic stroke (Hirsh et al., 1995). ln both the treatment period was two times higher than British doctors study (Peto et al., 1988) and the that of untreated patients. The incidence of US Physicians' Health Study (Steering Committee upper gastrointestinal tract ulcers (per 10 000 of the Physicians' Health Study Research patient-months of treatment) was 9.7 in Group, 1989), statistically insignificant increas- patients treated with 972-1500 mg aspirin es in total stroke incidence were reported in daily (Coronary Drug Project Research Group, healthy men treated with aspirin. Ten stroke 1976; Britton et aL., 1987; Ehresmann et al., deaths were observed in the US Physicians 1977; Hess et al., 1985; Fields et al., 1978; Study among people treated with aspirin, ver- Lemak et aL., i 986) and 2.1 in the group sus seven in the placebo group (RR, 1.4; Ci, receiving placebo in the US Physicians' Health 0.54-3.9). The incidence of non-fatal disabling Study (Steering Committee of the Physicians' stroke was higher among British doctors treated Health Study Research Group, 1989). The with aspirin (19 per 10 000 man-years) than in absolute rates in these trials may not be gen- the placebo group (7.4 per 10 000; P ~ 0.05). eralizable to the general population because The total stroke incidence was not increased in people with ulcers were excluded from the an observational study of aspirin use among study, but they indicate that gastric toxicity healthy US nurses (Manson et al., 1991). The due to anti-inflammatory doses of aspirin is a net effect of aspirin prophylaxis is consistently serious problem. Gastric toxicity due to use of beneficial in populations at high risk for NSAIDs, including aspirin, by rheumatoid ischaemic stroke who have already experienced arthritis patients has been estimated to cause a cerebrovascular event or symptoms 240 000 hospitalizations and 2600 deaths per (Antiplatelet Trialists' Collaboration, 1994b). year in the USA (Fries et al., 1991). Ishaemic and haemorrhagic strokes cannot be reliably separated in many of the trials of Toxicity of low doses. Among men in the US aspirin in secondary prevention. Physicians' Health Study who received either placebo or 325 mg aspirin every other day for (c) Blood pressure five years, the incidence of haematemesis or ln a meta-analysis of 50 randomized, placebo- melaena was approximately 1.5 times higher controlled trials, short-term treatment with than that in the controls. This corresponds to aspirin appeared to have no demonstrable about i 9 episodes of major gastrointestinal effect on blood pressure, in contrast to many bleeding attributable to 100 000 pers on- other NSAIDs Oohnson et al., 1994). months of aspirin treatment. ln a trial in the United Kingdom in which some 2400 pers ons (d) Reye syndrome were randomized to receive 300 or 1200 mg Reye syndrome is an acute condition charac- of aspirin daily or placebo, the RR for upper terized by non-inflammatory encephalopathy gastrointestinal tract haemorrhage in people and liver injury. This extremely rare syndrome at 300 mg daily was 3.3 (1.2-9.0) in comparison has been reported primarily, although with those on placebo (Slattery et al., 1995). not exclusively, in children (Sullvan-Bolyai & Corey, 1981). A review of six case-control (b) Non-gastrointestinal bleeding, including studies from the USA - four published before haemorrhagic stroke 1981 and two subsequent studies - designed A dose-dependent increase in the risk for serious specifically to address methodological flaws blood loss requiring transfusion was observed in the eadier studies, supported the role of in the combined data from 34 randomized tri- use of aspirin during a period of antecedent als (Antiplatelet Trialists' CoIlaboration, 1994b, ilness (Hurwitz, 1989). A seventh case-control Appendix 1; Table 8). Aspirin at doses of 75 mg study from the United Kingdom further daily increases the risk for non-fatal extracere- supports this association (HaIl, 1990). braI bleeding requiring transfusion.

74 Aspirin

Table 8. Incidence of non-fatal extracerebral bleeding requiring transfusion according to aspirin dose in 34 randomized clinical trials

Aspirin dosea Person-years of No. of people Per 100 000 treatment years (mg/day) treatment Incidence 95% Ci Placebo 95 591 75 0.54 0.42-0.67 75-170 62 863 63 0.81 0.63-1.0 300-500 26 134 41 1.1 0.75-1.4 1200-1500 6590 20 2.2 1.2-3.0 From Antiplatelet Trialists' Collaboration (1994b) a Reflects actual dose used in trials; therefore, scale not continuous

Since 1980, publicity and advice has been fol- condition can be precipitated by any current- lowed by a marked decline (at least 50%) in ly available NSAID. Symptoms begin within aspirin use among children in the USA. This 15 min to 4 h (usually 1 h) after ingestion, decline was accompanied by a drastic reduction and may include rhinorrhoea, conjunctival in the reported number of cases of Reye syn- irritation, scarlet flushing of the head and drome in children, notably those over five years neck and severe, even life-threatening asth- old. At these ages, the problems in the differen- ma. The respiratory symptoms can continue tial diagnosis of metabolic disorders and Reye beyond discontinuation of NSAID use syndrome that may occur with younger chil- (Szczeklik, 1994). dren are unlikely (Hurwitz, 1989). Therefore, the consistent positive association between (f) Nephrotoxícíty Reye syndrome and aspirin use observed in The relationship between chronic use of anal- case-control studies is supported by a temporal gesics, most notably phenacetin, and chronic association between the use of aspirin in ch il- renal failure has been recognized for over 30 dren and the occurrence of the syndrome. years. Although epidemiological studies have Controlled studies of aspirin use and Reye consistently found an increased risk for chron- syndrome are confined to the USA and the ic renal failure associated with phenacetin use United Kingdom. Few children with Reye syn- and prolonged use of mixtures of analgesics, drome who were exposed to aspirin have been the findings with regard to aspirin have been reported from other countries. Among 20 chil- inconsistent. Two large case-control studies of dren with Reye syndrome reported over a 10- end-stage renal disease (Pernerger et aL.1 1994) year period in Australia when paediatric and early chronic renal failure (Sandler et al.i aspirin use of aspirin was low, prior exposure 1989) and one cohort study with a 20-year to aspirin was found in only one child foIlow-up (Dubach et al.i 1991) reported no (Orlowski et al.i 1987). ln a series of 15 chil- excess risk for chronic renal failure in associa- dren with Reye syndrome in Germany, three tion with aspirin use. ln another large had been exposed to aspirin (Gladtke & case-control study (Pommer et al.i 1989), an Schausiel, 1987). It remains unknown whether increased risk for chronic renal disease was aspirin-associated Reye syndrome has occurred associated with aspirin used in combination outside the USA and the United Kingdom. with other analgesics, but not when used as a single agent. ln a further large case-control (e) Asthma study, the RR was 2.5 (Ci, 1.2-5.2) for chronic Approximately 10% of adults with asthma renal failure associated with regular aspirin use develop acute, idiosyncratic bronchoconstric- alone (Morlans et al.i 1990); however, in this tion after ingesting aspirin or other NSAIDs study, the probabilty that the association was (Fischer et al.i 1994; Staton & Ingram, 1996). confounded by prior use of phenacetin-con- Often called 'aspirin-sensitive' asthma, this taining compounds could not be excluded

7S rARC Handbooks of Cancer Prevention

completely. At doses of 1-2 g/day, aspirin may MaternaI bleeding around the time of delivery decrease urate excretion, increase plasma urate Hertz-Picciotto et al. (1990) reviewed studies of concentrations and potentiaIly precipitate clin- the association between taking aspirin late ICal gout. At higher doses, aspirin either does in pregnancy and maternai haemostatic not affect urate excretion or lowers it abnormalities. Clinically observable effects on (Goodman Gilman et al., 1990). As aspirin maternaI haemostasis were seen at an average inhibits the effects of urICosuric agents, its use dose of 1500 mg/day or more. Platelet dysfunc- in patients treated with these agents is not tion was observed at lower doses, such as advised (Editions du Vidal, 1995). 60 mg/ day. ln a randomzed trial of the use of 60 mg of aspirin per day, no noteworthy differ- (g) Reproductive and developmental effects ence in the incidence of antepartum haemor- rhage, other than abruptio placentae or Abruptio placentae. ln a randomized controlled post-partum bleeding of 500 ml or more, was trial, Sibai et aL. (1993) found an increased inci- observed in comparison with women given dence of abruptio placentae among women placebo (CLASP CoIlaborative Group, 1994). who received 60 mg of aspirin per day over that A significantly higher percentage (4%) of of women who received placebo (Table 9). This women aIlocated to aspirin received blood was not a primary outcome of the trial, nor transfusions after delivery th an women indeed of any other trial (Hauth et al., 1995), as allocated placebo (3.2%), independently of no evidence of an increase in the incidence of differences in the occurrence or degree of abruptio placentae was found in randomized post-partum haemorrhage. No effect of aspirin trials in which at least 200 women were on maternai bleeding complications was enrolled. The increased risk found by Sibai et al. observed in other large trials (Italian Study of (1993) may be a chance observation or due to a Aspirin in Pregnancy, 1993; Sibai et al., 1993; low incidence of the disorder in the placebo Viinikka et al., 1993; ECPPA CoIlaborative group in that trial (Hauth et aL., 1995). Group, 1996).

Table 9. Use of low doses of aspirin and abruptio placentae: data fram randomized trials in which at least 200 women were enrolled

Dose of aspirin No. of women Abruptio placentae RR 95% cia Reference (mg per day) Aspirin Placebo Aspirin Placebo No. % No. %

60 1485 1500 11 0.7 2 0.1 5.6 1.2-25 Sibai et al. (1993) 150 156b 74 7b 4.5 6 8.1 0.6 0.2-1.6 Uzan et al. (1991)

60 302 302 3c 1.0 2C 0.7 1.5 0.3-8.9 Hauth et al. (1993) 50 561 471d 7C 1.2 9C 1.9 0.7 0.2-1.7 Italian Study of Aspirin in Pregnancy (1993) 50 97 100 oc oc Undefined Viinikka et al. (1993) 60 4659 4650 86 1.8 71 1.5 1.2 0.9-1.7 CLASP Collaborative Graup (1994) 60 476 494 5 1.1 7 1.4 0.7 0.2-2.3 ECPPA Collaborative Graup (1996) a Calculated by the Working Graup b Some women received 225 mg/day diprimadole c Data fram Hauth et al. (1995) d No treatment

76 Aspirin

Neonatal haemostatic abnormaliies. There is a Congenital abnormalities were not found to consistent association between bleeding in the be associated with aspirin use during the first newborn and maternaI exposure to aspirin at 14 days of pregnancy (Nelson & Forfar, 1971) or analgesie or antipyretie doses late in pregnancy during the first trimester (Weatherall & (Hertz-Pieciotto et aL., 1990). Such abnormalities Greenberg, 1979). may include intracranial haemorrhage, partieu- ln a comparison of prescriptions for 764 lady in preterm babies and those with a low mothers whose children had a defect of the birth weight. central nervous system with those of an ln a large randomized trial of 60 mg/day equal number of mothers of control babies, aspirin or placebo, fewer intraventricular haem- aspirin use for the three months before the orrhages were reported among babies born to last menstrual period and for the first trimester women aIlocated aspirin (0.7%) than among of pregnancy was not associated with increased those in the placebo group (0.9%); this risk (Winship et al., 1984). This finding was difference was not statistically signifieant corroborated for aH congenital defects in a (CLASP CoIlaborative Group, 1994). No signifi- similar study of prescribed analgesics (Hil et aL., cant differences in fetal or neonatal deaths 1988), and by McDonald (1994) for use of any attributed to haemorrhage or in the incidence analgesie during the first trimes ter. of other neonatal haemorrhages were seen, and The study of Rothman et aL. (1979) was no differences in the incidence of fetal bleeding designed to investigate the relationship complications were observed in other large between exposure to exogenous sex hormones trials of low doses of aspirin (Italian Study of and congenital heart disease. A total of 460 Aspirin in Pregnancy, 1993; Sibai et aL., 1993; cases was ascertained among infants born in Viinikka et aL., 1993; ECPPA CoHaborative Massachusetts, USA, du ring the period Group, 1996). 1973-75. Most of the cases were ascertained from a programme designed to provide Preterm constriction of the ductus arteriosus. special care to infants born in New England During fetallife, the patency of the ductus arte- with serious congenital heart disease, the riosus is maintained by prostaglandins, while diagnosis being determined by cardiac catheter- COX inhibitors constriet it. As aspirin inhibits ization, surgery or, ultimately, autopsy. COX, it has been postulated that maternaI use The remaining cases were ascertained from of aspirin late in pregnancy may lead to preterm death certifieates. The control series comprised constriction of the ductus arteriosus, leading to 1500 births selected randomly from aH births abnormalities in pulmonary vasculature that in Massachusetts during the study period. would promote pulmonary hypertension in the At the end of each year, questionnaires were newborn. Few data are available, however, as sent to the mothers of control infants, abnormalities of pulmonary vasculature are not and cases were identified from the specialized easy to diagnose, even at routine autopsy care programme. Mothers of cases identified (Hertz-Picciotto et al., 1990). from death certificates were interviewed by telephone. Data were obtained on 390 cases Congenital anomalies. Studies of the association (85% of those eligible) and 1254 controls between maternaI aspirin use in the first (89%). The RR associated with aspirin trimester and congenital anomalies are summa- consumption at about the time the pregnancy rized in Table 10. The studies are difficult began was 1.3 (one-tailed p = 0.02). to compare because of differences in the defini- The authors noted that information about tion and characterization of anomalies. The use of non-hormonal drugs was obtained only statistically signifieant increases associated from an open-ended questionnaire and there- with reported aspirin use were for congenital fore may have been subject to some heart defects (Rothman et al., 1979; Zieder & recaIl bias. For the cases in which a specifie Rothman, 1985) and for orofacial clefts (Saxén, diagnosis was known, reported medieation 1975). was compared for the major diagnostic

..77 ~ 1 1 ;;n:; :: p) :: 0- 0' 0 "" Table 1 O. Association between maternai aspirin use in the first trimester and congenital malformations 1 ,.~ np) Area and period of Cases Controls or cohort Aspirin Prevalence of Association with aspirin Reference :: study use in controls n Typea No. Type No. Source Method of Contrast RR 95% Ci ..(' assessing useb 'V ('.. UK, South Wales, CNS 279 Population 279 Any IR, MR 17 Any versus 1.6c 1.1-2.4 Richards (1969) ('.. 1964-66 CVS 100 100 15 none :: 0.8c 0.4-1.9 M- Ali 173 173 13 õ' :: MSK 152 152 14 2.2c 1.3-3.9 Ali 833 833 14 1.8c 1.0-3.3 1.7c 1.3-2.2 UK, Scotland (3 Major 175 Hospital 916 Any 0, Pres 3 Any versus 1.2 0.6-2.5 Nelson & Forfar maternity units over 2 Minor 283 2 none 1.7 1.0-2.9 (1971 ) years) Ali 458 5 1.5 0.9-2.4

Finland, 1967-71 ICP 232 Population 226 Any (salicy- lA, IR 6 Any versus no ne 1.9 0.9-3.8 Saxén (1975) ICL(P) 232 230 lates) 5 4.5 2.3-8.6 CLP 599 590 6 2.5 1.6-3.7

USA, multicentre, CNS 266 Cohort 50 282 Any lA 30d Heavye versus 0.81 Sione et al. (1976) 1959-65 CVS 404 no ne 0.9f MSK 395 RT 218 1.01 GI 301 1.0f Major 1393 1.2' 0.9f 0.8-1.1

USA, Massachusetts, CVS 390 Population 1254 Any 0 169 Any versus none 1.3 1.0-1. Rothman et al. 1973-75 (1979)

UK, England and Serioush 836 General 836 Prescribed MR 1.3 Any versus none 1.7 0.7-4.2 Weatherall & Wales population Greenberg (1979)

UK, England and CNS 764 General 764 Prescribed MR 0.4 Any versus none 2. 0.6-16 Winship et al. (1984) Wales, 1971 population Table 10 (contd) Area and period of Cases Contrais or cohort Aspirin Prevalence study Association with aspirin Reference Type of use in Typea No. No. Source Method of Contrast RR 95% Ci assessing useb controls USA, Massachusetts, CVS 298 Population 738 Any IR, MR 1980-83 9 Any versus 1.4 1.0-2.0 Zierler & Rothman (1985) no ne

UK, England and CLP 676 Population 676 Prescribed MR 4 Any versus 1.3 0.8-2.1 Hill et al. (1988) Wales, 1983-84 LRD 115 115 analgesics 4 none 0.6 0.1-2.5 USA and Canada, CVS 1381 Other i 6966 Any IR 27 multicentre, 1976-86 Any versus 0,9 0.8-1.1 Werler et al. (1989) none Canada, Montreal, Major 787 Hospital 787 Any IR 17 Any versus 1.1 1987-94 Minor 2386 2386 analgesic none 1.3 McDonald (1994) a CNS, central nervous system; CVS, cardiovascular system; Ali, alimentary system (including orofacial c1efts): MSK, musculoskeletal system; ICP, cleft palate without other anomaly; ICL(P), c1eft lip ;¡ palate without other anomaly; CLP, ail orofacial c1efts, with or without anomalies of other systems; RT, respiratory tract (including orofacial c1efts); LRD, limb reduction defects b IR, maternai interview after delivery of index child; MR, review of medical records; Q, questionnaire; Pres, prescription information; lA, maternai interview at antenatal c1inic visit C Crude unmatched analysis of matched data d Drug use: prevalence of heavy use, 10% e Defined as taken for at least eight days during at least one of the first four lunar months f Adjusted for range of potentially confounding variables 9 ln periconceptional period h 23% had neural tube defects, 7% Iimb malformations, 49% oral c1efts and 21 % other serious malformations i 90% confidence interval

'";: ~ 1 '9... Ëï lARC Handbooks of Cancer Prevention categories. The RR for transposition of the Greater Boston and Philadelphia, USA, and great arteries associated with use of aspirin was south-eastern Ontario, Canada, during the peri- 3.3 (90% CI, 1.7-6.6, based on 12 exposed od 1976-86 and in five counties in Iowa, USA, cases) . in 1983-85. Data on medications taken for Zierler and Rothman (1985) carried out a various indications were obtained by maternaI further study of severe congenital heart disease interview. Cases with identified syndromes that and maternaI use of medications in early included cardiac abnormalities such as Down pregnancy in Massachusetts during the period syndrome and Holt-Oram syndrome, were

1980-83. Congenital heart disease was cons id- excluded. More than 80% of cases and 80% of ered to be severe if the diagnostic and controls (mothers of infants with non-cardiac therapeutic procedures included cardiac malformations) participated. No association catheterization or surgery during the first year was seen between reported aspirin use during of life, or if death occurred before the first the first trimester and total cardiac defects. ln birthday. Controls were randomly selected addition, no association was apparent for spe- from birth certificates fied in Massachusetts. cific defects, comprising aortic stenosis, coarc- MaternaI interviews were completed for 298 tation of the aorta, hypoplastic left ventricle, cases (68% of those potentiaIly eligible) and transposition of the great arteries or conotrun- 738 controls (79% of those eligible). A positive cal defects. association was found with reported aspirin No association between use of aspirin and use during the first trimester (RR, 1.4; 90% anomalies of the cardiovascular system was CI, 0.95-2.0). The most frequently reported found in a case-control study in South Wales, indications for aspirin use were fever, cold United Kingdom (Richards, 1969), or in a mul- and flu symptoms. The mothers of affected ticentre cohort study in the USA (Slone et aI.i children reported use of aspirin for control- 1976). The latter study is the only one in which ling fever more often than mothers of con- information relevant to the investigation of a troIs. Confounding by maternaI ilness did possible dose-response relationship was avail- not account for the relationship with aspirin. able. Another analysis of the data coIlected in

Because of con cern about potential recall bias, the latter study related to specific types of con- the authors also considered information on genital anomaly (Heinonen et aI.i 1977). The exposure from obstetric records. The RR RRs, adjusted for hospital of delivery, were 2.4 sis, 1.5 associated with use of aspirin was 2.4 (eight exposed cases) for aortic steno (95% CI, 0.6-10). (The Working Group noted (seven exposed cases) for transposition of the that information on aspirin obtained over the great arteries, 2.1 (17 exposed cases) for coarc- counter wou Id be unlikely to be recorded in tation of the aorta and 3.0 (eight exposed cases) obstetric records, and that no information for the tetralogy of FaIlot. was given on the numbers of cases and con- A case-control study of orofacial clefts in troIs exposed according to these records.) Finland during the period 1967-71, in which When the data on specific types of cardiac information on exposure was obtained prospec- anomalies among the cases were analysed, the tively from prenatal clinic records and retro- RR, adjusted for use of other drugs, reported spectively by interview by the midwife during symptoms and laboratory reports of infec- the mother's first visit to the maternity weUare tion, were 2.4 (90% CI, 0.9-6.4) for aortic centre after delivery, suggested a positive steno sis; 3.1 (1.2-8.0) for coarctation of the association with maternaI exposure to salicylates aorta; 3.2 (1.3-7.5) for hypoplastic left ventri- (Saxén, 1975). This was largely accounted for cIe and 1.7 (0.9-3.7) for transposition of the by exposure during the first trimester. (The great arteries. Working Group noted that, as positive associa- Werler et aL. (1989) analysed data from an tions were also seen with use of other antipyret- on-going surveilance case-control study of ic analgesics, opiates (mainly codeine) and peni- birth defects in relation to exposure to drugs cillins, confounding by pyrexia may have and other environ mental factors in centres in occurred.)

80 Aspirin

No association between the prevalence of disorders. ln addition, there was no difference orofacial clefts and aspirin use during the first between the groups in terms of the gross or fine trimester was found in the multicentre cohort motor and language development of the child study in the USA (Heinonen et al.i 1977). RRs (Parazzini et al.i 1994). greater than 3 were associated with any expo- FoIlow-up of children born to women in sure to aspirin during the first trimes ter and the the trial of the CLASP Collaborative Group prevalence of rachischisis or cranioschisis, situs (1994) was restrieted initially to children in inversus or dextrocardia, other adrenal the United Kingdom and Canada (CLASP syndromes, abnormal hands and fingers and Collaborative Group, 1995). Thus, 4168 chil- misceIlaneous foot abnormalities. Multivariate dren in the United Kingdom were assessed at analyses were not carried out for specifie 12 months from information provided by gen- defects, and these observations may be chance eral practitioners and 4365 children in the findings. No elevation in risk was found for the United Kingdom and Canada were assessed at broader categories of anomalies considered in 18 months from responses to a questionnaire the analysis of aspirin categorized by degree of by their parents. The response rate at 12 exposure (Slone et aL.1 1976; Heinonen et al.i months was 89% and that at 18 months, 86%. 1977). There were no differences between the groups ln two of the randomized trials of use of low in the frequency of hospital visits during the doses of aspirin during pregnancy, information first 18 months of life for motor defieits, on foIlow-up of the offspring was reported developmental delay, respiratory probleils or (Parazzini et al.i 1994; CLASP Collaborative bleeding. ln addition, there were no differ- Group, 1995). No difference in the frequency of ences in the proportion of children whose congenital anomalies was found. height or weight was below the third centie, in the frequency of abnormal gross motor, fine Morbidity la ter in childhood. ln two cohort studies, motor or language development or in the the relationship between use of aspirin during prevalence of abnormal sleep patterns, and pregnancy and the IQ of the offspring was there were no differences in feeding problems, investigated (Hertz-Pieciotto et aL.1 1990). ln one mood, behaviour, hearing, vision or respira- of these, use of aspirin at least seven times per tory symptoms. week was associated with a 10-point lower me an IQ for girls and 1.3-point lower mean IQ 7.1.2 Experimental animaIs for boys at the age of four. Use of aspirin was (a) Gastrointestinal tract toxicity also related to attention decrement. The credi- It has been shown in animal models that bilty of these findings may be strengthened by aspirin is harmful to the gastric mucosa and is the lack of association between use of aceta- associated with irritation, ulceration and bleed- minophen (paracetamol) and either IQ or ing of the stomach (Kauffman, 1989). These attention decrement (Streissguth et al.i 1987). studies have indieated two broad mechanisms No association between aspirin use and IQ at by whieh aspirin causes gastrie mucosal dam- the age of four was observed in a multieentre age: one related to inhibition of COX activity cohort study in the USA (Klebanoff & Berendes, and the other independent of the effect of 1988). aspirin on COX. An 18-month follow-up of children born to women participating in the Italian Study of Gastric toxicity due to COX inhibition. Aspirin Aspirin and Pregnancy (1993) was undertaken makes the gastric mucosa more susceptible by postal questionnaire. Information was to injury, inhibits mucus and bicarbonate secre- obtained on 427 children (72%) of the women tion, alters the physiochemieal nature of given aspirin and 361 (73%) of those who mucus, stimulates fundic but not antral received no treatment. No difference between 3H-thymidine incorporation and makes the the groups was apparent in height, weight, res- epithelial surface less hydrophobic (reviewed by piratory, hearing or vision problems or other Kauffman, 1989). -- 81 lARC Handbooks of Cancer Prevention

Aspirin given intravenously or intragastrical- (Levet aL., 1972). The damage was more pro- ly at 60 mg/kg bw per h to rats inhibited COX nounced after one than four weeks, suggesting activity and caused macroscopic mucosal adaptation to repeated administration of injury; these two effects were well correlated aspirin. Electron microscopic evaluation of the (Konturek et aL., 1981). Exogenous prosta- gastric mucosa of mice exposed to glandin Ez and IZ completely prevented this 20 mmol/litre aspirin in 1, 10 or 100 mmol/litre mucosal injury. ln addition, dose-response Hei for 8 min showed many lysed and exfoliat- studies with lower doses of aspirin showed a sig- ed surface epithelial ce lis and swellng and dis- nificant correlation between COX inhibition ruption of all cells, with enlarged nuclei and and mean ulcer area. Further support for the clumped nuclear chromatin (Fromm, 1976). hypothesis that reduction of endogenous Davenport (1967) demonstrated that the gastric prostaglandins predisposes the mucosa to mucosal barrier of rats is lost after exposure to injury comes from studies in which rabbits were either aspirin or salicylic acid. Both drugs immunized with prostaglandin Ez-thyro-globu- increase the proton flux into the mucosa and lin conjugate (OIson et aL., 1985; Redfern et al., cause a drop in potential difference, a sensitive 1987), which resulted in the production of cir- measure of epithelial integrity. The back-diffu- culating prostaglandin Ez antibodies. sion of protons leads to cellular acidification Gastrointestinal ulcers occurred as early as six and altered ceIlular metabolism. Studies in rats weeks after the beginning of immunization. (Rowe et aL., 1987) and rabbits (Fromm & Kolis, These observations support the notion that 1982) suggest, however, that aspirin and sali- endogenous prostaglandins are important for cylic acid damage the mucosa equally, but only the maintenance of mucosal defence and that after the gastric luminal pH has been lowered to their inhibition is an important mechanisms of 1.0. Guinea-pig gastric mucosa perfused with 2 aspirin-induced mucosal injury. mmol/litre aspirin at pH 4 showed a fall in

trans mu cos al potential, a reduction in ATP con- Gastric toxicity independent of COX inhibition. ln tent and acid secretion and an increase in pro- most of the studies described below, the similar- ton back-diffusion (Ohe et al., 1980). These ity of the effects of aspirin and salicylic acid was observations suggest that one action of aspirin used to deduce that the mechanism of action of is to damage the energy metabolism of mucosal aspirin is not via COX inhibition, since salicylic ceIls, causing cell death with resultant back-dif- acid is a less efficient COX inhibitor (MitcheIl et fusion of protons. aL., 1994). As aspirin is rapidly deacetylated to Membrane transport mechanisms are also salicylic acid in cells, the half-life of aspirin in affected by salicylates. Observations on rabbit interstitial fluid and serum after oral administra- antral mucosa exposed to aspirin or salicylic tion is short. Salicylic acid is, however, toxic to acid at low pH (Fromm, 1976; Kuo & Shanbour, ceIls and affects epithelial function. Salicylates 1976) suggest that salicylates inhibit active ion are associated with mucosal barrier injury, transport in the gastric mucosa, possibly through resulting in large net cation fluxes, hydrogen decreased ATP production as a result of either back-diffusion and a faIl in the transmucosal dif- enzyme inhibition or their uncoupling effect. ference in potential. The mucosal content of A TP is reduced by salicylic acid, affecting ion (b) Nephrotoxicity transport and increasing proton dissipation Aspirin causes a wide spectrum of renal damage from surface epithelial ceIls (reviewed by including nephrotic syndrome, acute interstitial Kauffman, 1989). nephritis, acute tubular necrosis, acute The effects of single and repeated doses of glomerulonephritis and nonspecific renal fail- aspirin have been examined by light and elec- ure (Clive & Stoff, 1984; Carmichael & Shankel, tron microscopy. The gastric mucosa of dogs 1985). showed dose-dependent epithelial damage and Chronic administration of aspirin at 120-500 haemorrhage into the lamina propria within mg/kg per day to rats over 18-68 weeks caused 4 h after intraluminal administration of aspirin renal papilary necrosis and decreased urinary

82 Aspirin

concentrating abilty (Burrell et al.i 1991; Thus, aspirin may initiate or promote neoplas- D'Agati, 1996); however, some investigators tic change by installng a long-term imbalance have been unable to induce renal papilary between cellular oxidative stress and antioxi- necrosis in other species or in rats at lower divid- dant defence. ed doses, as used in humans (Owen & Heywood, 1986). ln a variety of rat strains, administration (d) Ototoxicity of aspirin as a single high dose intravenously or Aspirin causes mild to moderate, temporary by gavage produced acute necrosis of the hearing loss in laboratory animaIs. The proximal tubules, rarely accompanied by renal deficit is detected behaviourally or electro- papilary necrosis in susceptible strains like physiologicaIly (Boettcher & Salvi, 1991). There homozygous Gunn rats (Axel sen, 1980; Mittman appear to be sorne species differences in suscep- et aL.1 1985). This strain of rat, which has an inac- tibilty to salicylate ototoxicity, presumably due tivating mutation in one glucuronyl transferase rel- in part to differences in the pharmacokinetics evant to äspirin, develops renal papilary necrosis of salicylates among species (Myers & after a single oral dose of aspirin (Axelsen, 1976). Bernstein, 1965; Gold & Wilpizeski, 1966; Eddy A study of administration of 500 mg/kg 14C_ et aL.1 1976). The hearing loss caused by aspirin aspirin to 3- and 12-month-old male rats showed is accompanied by supra-threshold changes in an age-dependent effect of aspirin on the kid- hearing, including a decrease in temporal inte- neys (Kyle & Kocsis, 1985). Aspirin induced gration, poorer frequency selectivity and poor- proximal tubular necrosis in the older animaIs er temporal resolution. The supra-threshold but only mild, nonspecific cellular changes in changes are not severe and appear to be quite the younger group. ln addition, the mitochon- variable among subjects. AnimaIs exposed to drial pathway for salicylurate synthesis was sig- both noise and aspirin have greater hearing loss nificantly inhibited in the older animaIs. These and cochlear damage than those exposed to noise findings suggest that mitochondrial injury alone (Eddy et al.i 1976; Carson et al.i 1989). plays an important role in the development of salicylate-induced proximal tubular necrosis. (e) Reproductive and developmental effects Reproductive effects. Administration of aspirin (c) Hepatotoxicity to adult male rats at a dose of one-tenth of the Aspirin-induced liver injury probably has an LDso value for six weeks was accompanied by a immunological basis, but neither the detailed decrease in the functional activity of spermato- mechanism nor the precise incidence rates are zoids. Repeated inhalation of a concentration of known. Studies in mice (Cai et al.i 1994, 1995) 25 mg/m3 for four months produced morpho- have demonstrated that long-term treatment logical changes in the spermatogenic epithe- with aspirin leads to increased proliferation of lium and abnormal antenatal development of hepatic peroxisomes. According to the oxida- the progeny (Vasilenko et aL.1 1979). tive stress hypothesis (Reddy & Lalwani, 1983), peroxisome prolieration results in excess for- Developmental toxicity. Congenital malforma- mation of hydrogen peroxide, which induces tions were induced in rats by salicylate poison- lipid peroxidation. ln fact, treatment of mice ing of the mother while the embryos were in (Cai et al.i 1995) and rats (Goel et al.i 1986) early stages of development (Warkany & Takacs, with aspirin induced a 1.3-fold increase in basal 1959). Among the defects produced were cran- hydrogen peroxide levels in liver homogenates. iorachischisis with well-preserved cerebral and It is possible that products of lipid peroxidation spinal nervous tissues. Other malformations interact with DNA, leading to adducts, DNA encountered were anencephaly, hydrocephaly, strand breaks and DNA-protein cross-linking facial clefts, gastroschisis and irregularities of (Vaca et aL.1 1988). the vertebrae and ribs. Long-term treatment of rats with peroxi- The doses of aspirin most commonly used in some proliferators like aspirin decreases the cel- animal models are 250-1000 mg/kg of maternaI lular antioxidant defenses (Glauert et al.i 1992). weight. ln aIl species, thes~ doses usuaIly cause

83 lARC Handbooks of Cancer Prevention

malformations in the surviving fetuses, 25-80% Doses of 250-1000 mg/kg of maternaI weight of which are affected. The malformations cause a high rate of embryo deaths and stil- include cleft lip and palate, hydrocephaly, gas- births in aIl animal species, and fetuses of rats troschisis and skeletal dysplasias (Lubawy & given 125 or 250 mg/kg bw per day of aspirin Burriss Garrett, 1977). ln mice, aspirin at high were shorter and weighed less than those from doses (500 mg/kg) over a 24-h period on days 8 control rats (Lubawy & Burriss Garrett, 1977). and 9 or 9 and 10 of gestation induces cleft lip When aspirin was co-administered with (Trasler, 1965). ethanol, as in a study in TO mice When rat embryos were cultured with (Padmanabhan et al., 1994), it signifcantly 100-300 mg/ml salicylic acid, decreases in reduced the rate of prenatal ethanol-induced crown-rump length, somite number and yolk mortality. Pre-administration of a low dose sac diameter are observed Ooschko et aL., 1993). (150 mg/kg bw) of aspirin reduced the ethanol- A significant increase in the prevalence of induced exencephaly, while a higher dose malformations is se en, including anomalies of (200 mg/kg bw) increased the incidence of this the eye, branchial arch and heart and an malformation. absence of forelimb buds. The neural tube is especiaIly vulnerable and frequently fails to 7.2 Genetic and related effects close. CeIlular and ultrastructural examination 7.2.1 Humans reveals extensive ceIl death in the neuroepithe- No data were available to the Working Group. lium, with a lesser effect on mesenchymal ceIls. It is likely that the extensive ceIl necrosis 7.2.2 Experimental models and blebbing in the developing neuroepi-theli- The results of tests for genetic and related um at the site of neural tube fusion effects in model systems are summarized in are involved in failed neurulation, while Table II and Figure 4. The genetic and related necrosis at other sites in the Cfanial neuro- effects of aspirin have been reviewed (Giri, epithelium is linked with intellectual and 1993). Aspirin induced DNA damage in Bacilus behavioural abnormalities. subtiis (Kawachi et al., 1980; Kuboyama & Fujii, Salicyclic acid, the product of aspirin hydrol- 1992) but not in Escherichia coli (King et al., ysis, is considered to be the causative agent in 1979) or in Salmonella typimurium tester strains teratogenicity associated with aspirin (Kimmel (Bruce & Heddle, 1979; King et aL., 1979; et aL., 1971; Koshakji & Schulert, 1973). Early Bartsch et al., 1980; Kawachi et al., 1980; studies (Goldman & Yakovac, 1963) showed that Oldhham et al., 1986; Jasiewicz & Richardson, the teratogenic action of salicylate compounds 1987; Kuboyama & Fujii, 1992). It did not occurs through maternally mediated metabolic induce sex-linked recessive lethal mutation in factors; however, more recent studies with Drosophila melanogaster or mutations in a host- fluorimetric techniques (Kimmel et aL., 1971) mediated assay (King et aL., 1979), and it did not

and culture in vitro (McGarrity et aL., 1981) indu ce mutation, cell transformation (Patierno demonstrated that aspirin has a direct effect in et aL., 1989), aneuploidy (Watanabe, 1982; the rat embryo in the absence of any maternaI Ishidate, 1988) or micronucleus formation (Dunn influence. et aL., 1987) in mammalian cells in vitro. Mixed The teratogenicity of aspirin may be mediat- results were reported for chromosomal aberra- ed via its obvious target, COX, and altered tions in mammalian cells in vitro (Meisner & prostaglandin synthesis (Vane, 1971), interfer- Inhorn, 1972; Kawachi et al., 1980; Watanabe, ence with oxidative phosphorylation (Bostrom 1982; Ishidate, 1988; Muller et aL., 1991). It et al., 1964) or altered biosynthesis of nucleic induced chromosomal aberrations (Kawachi et acids and proteins Oanakidevi & Smith, 1970). al., 1980) but not micronuclei (Bruce & Heddle, Alternative explanations include a direct effect 1979; King et al., 1979) in bone-marrow ceIls of of salicylic acid on cell membranes, particularly rodents treated in vivo. It did not induce sperm those close to the mesenchyme Ooschko et al., abnormalities in mice in vivo (Bruce & Heddle, 1993). 1979).

84 Aspirin

Table 11. Genetic and related effects of aspirin

End-Test- Test system Resultsa Doseb Reference - + point code (LED or HID) D BSD B. subtiis rec, differential toxicity + 0 0.00 Kawachi et al. (1980) D BSD B. subtiis rec, differential toxicity (+) 0 5000 Kuboyama & Fujii (1992) G SA5 S. typhimurium TA 1535, reverse mutation 250 Jasiewicz & Richardson (1987) G SA5 S. typhimurium TA 1535, reverse mutation 1800 King et al. (1979) G SA5 S. typhimurium TA1535, reverse mutation 250 Oldham et aL. (1986) G SA7 S. typhimurium TA1537, reverse mutation 250 Bruce & Heddle (1979) G SA7 S. typhimurium TA 1537, reverse mutation 250 Jasiewicz & Richardson (1987) G SA7 S. typhimurium TA1537, reverse mutation 1800 King et al. (1979) G SA7 S. typhimurium TA1537, reverse mutation 250 Oldham et al. (1986) G SA8 S. typhimurium TA 1538, reverse mutation 250 Jasiewicz & Richardson (1987) G SA8 S. typhimurium TA 1538, reverse mutation 1800 King et al. (1979) G SA8 S. typhimurium TA 1538, reverse mutation 250 Oldham et al. (1986) G SA9 S. typhimurium TA98, reverse mutation 250 Bruce & Heddle (1979) G SA9 S. typhimurium TA98, reverse mutation 250 Jasiewicz & Richardson (1987) G SA9 S. typhimurium TA98, reverse mutation o Kawachi et al. (1980) G SA9 S. typhimurium TA98, reverse mutation 1800 King et al. (1979) G' SA9 S. typhimurium TA98, reverse mutation 27 Kuboyama & Fujii (1992) G SA9 S. typhimurium TA98, reverse mutation 250 Oldham et al. (1986) G SAO S. typhimurium TA100, reverse mutation 180 Bartsch et al. (1980) G SAO S. typhimurium TA 100, reverse mutation 250 Bruce & Heddle (1979) G SAO S. typhimurium TA 100, reverse mutation 250 Jasiewicz & Richardson (1987) G SAO S. typhimurium TA 100, reverse mutation o Kawachi et al. (1980) G SAO S. typhimurium TA 100, reverse mutation 1800 King et al. (1979) G SAO S. typhimurium TA 100, reverse mutation 27 Kuboyama & Fujiì (1992) G SAO S. typhimurium TA 100, reverse mutation 250 Oldham et al. (1986) G ECK E. coli K 12, forward or reverse mutation 1800 King et al. (1979) G DMX D. melanogaster, sex-linked recessive lethal mutation - 0 1800 King et al. (1979) G GIA Mutation, other animal cells in vitro - 0 3000 Patierno et al. (1989) M MIA Micronucleus test, animal cells in vitro - 0 3600 Dunn et al. (1987) C CIC Chromosomal aberration, Chinese hamster cells + 0 0.00 Ishidate (1988) in vitro C CIC Chromosomal aberration, Chinese hamster cells + 0 15.6 Ishidate (1988) in vitro C CIC Chromosomal aberration, Chinese hamster cells - + 0.00 Kawachi et al. (1980) in vitro C CIC Chromosomal aberration, Chinese hamster cells - 0 1800 Muller et al. (1991) in vitro A AIA Aneuploidy, animal cells in vitro 1500 Ishidate (1988) T TCM Cell transformation, C3H10T1/2 cells in vitro - 0 3000 Patierno et al. (1989) C CHF Chromosomal aberration, human fibroblasts in vitro - 0 250 Meisner & Inhorn (1972) C CHL Chromosomal aberration, human lymphocytes in vitro + 0 75 Watanabe (1982) A AIH Aneuploidy, human cells in vitro - 0 300 Watanabe (1982) H HMM Host-mediated assay, microbial cells - 0 180 King et al. (1979) M MVM Micronucleus formation, mice in vivo - 0 1000 Bruce & Heddle (1979) M MVM Micronucleus formation, mice in vivo - 0 360 King et al. (1979) C CBA Chromosomal aberration, animal bone marrow in vivo + 0 0.00 Kawachi et al. (1980) P SPM Sperm morphology, mice in vivo - 0 1000 Bruce & Heddle (1979) Definitions of the abbreviations and terms used are given in Appendix 1. a ln the absence H and presence (+) of an exogenous metabolic activation system; +, positive; (+), weakly positive; -, nega- tive; 0, not done . b Lowest effective dose (LED) or highest ineffective dose (HID), expressed as flg/ml for in-vitro studies and as mg/kg body weight per day for in-vivo studies .. 85 ~ 1 Figure 4. Profile of genetic and related effects of aspirin s; n:: ~:: :: 0. 00' 0 ""7: 1 1 1 B i: ~ !: ( H D r: L 1 15:: (" ..ro ..'- ro -: ro ::.. 6 õ' ::

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PROKARYOTES LOWER EUKAR. PLANTS ANIMALlHUMAN lN ViVO INSECTS 1 ANIMAL CELLS lN VITRO Aspirin

8. Summary of Data Ove raIl, the observational epidemiological studies cover more than 18 000 cases of colo- rectal cancer and more than 2000 cases of ade- 8.1 Chemistry, occurrence and human nomatous polyps. The studies differ in design, exposure location, population and motivating hypothe- Aspirin has been used for nearly a century as an sis. ln 12 studies (four cohort and eight analgesic, anti-inflammatory and antipyretic case-control) out of 13 that assessed the risk for agent. It is used in the treatment of rheuma- colorectal cancer, there was a reduced risk asso- tism, fever and related conditions; it is also CIated with sustained aspirin use. ln nine of used in the prevention of arterial and venous these 12 studies, the reduction in risk was sta- thrombosis. The doses of aspirin usuaIly used tistically significant, with relative risks of vary according to the therapeutic indication. 0.4-0.6 in regular users in comparison with Low doses (75-300 mg/day) are conventionally non-users. ln aIl six studies on adenomatous used in the prophylaxis of cardiovascular dis- colorectal polyps (two cohort and four ease; daily doses up to 5 gare used in the treat- case-control), there was a reduction in risk with ment of pain and fever. Doses up to 8 g three or aspirin use, which was statisticaIly significant four times daily are used in the management of in four of them. ln addition, two studies on rheumatic complaints. ln view of its ready patients with rheumatoid arthritis showed a availability, low cost and efficacy in a wide significant reduction in colorectal cancer inci- range of conditions, aspirin consumption is dence in comparison with general population rates. common and widespread. While information on the duration of treatment and dose of aspirin that are necessary 8.2 Metabolism and kinetics for prevention is limited, the prophylactic Aspirin is rapidly hydrolysed to salicylic aCId in effect appears to increase with increasing dura- the intestinal waIl, liver and erythrocytes. Aspirin tion of use. is absorbed rapidly after oral administration. The observational studies are sufficiently Both aspirin and salicylate are partiaIly bound to large, taken together, and consistent, despite proteins, espeCIally albumin. Salicylate reaches theìr diversity, that chance alone cannot the synovial fluid, the cerebrospinal fluid, saliva, explain their results. The Working Group breast milk and the fetus. Hydrolysis of aspirin to considered several possible problems in the salicylate in the plasma occurs with a half-lie of interpretation of the evidence, including 15-20 min. Salicylate is removed by renal elimi- publication bias, detection bias, bias due to nation and formation of metabolites. The hydrol- indications for use of aspirin, genetic predispo- ysis of aspirin is not altered by concurrent admin- siton, other confounding factors and problems istration of other drugs. in the measurement of aspirin use. There is no obvious bias or confounding that could explain 8.3 Cancer-preventive effects the findings. Collectively, the published obser- 8.3.1 Humans vational studies provide consistent evidence that aspirin may inhibit one or more stages in (a) Colorectal cancer the development of colorectal cancer. Most of the data on aspirin and colorectal can- The negative findings in the randomized US cer come from epidemiological studies of the Physicians' Health Study neither support nor disease in the general population. ln several stud- convincingly refute the aspirin-colorectal ies, use of aspirin was not separated from use of cancer prevention hypothesis. Factors that cou Id other non-steroidal anti-inflammatory drugs. obscure protection by aspirin against colorectal Relevant data are also available with respect to polyps or cancer in this trial include its short dura- adenomatous colorectal polyps, which are tion (randomized aspirin treatment being stopped thought to be precursor lesions for colorectal after a mean of five years) and the smaIl number cancer. ln a few studies, adenomatous and of cases of cancer expected. hyperplastic polyps were not distinguished.

87 IARC Handbooks of Cancer Prevention

(b) Gastric cancer 8.3.3 Mechanism of action Two population-based cohort studies addressed Aspirin can irreversibly inhibit cyclooxygenas- use of aspirin and gastric cancer. ln the larger es, which may be involved in the initiation of of these, a statistically significant inverse trend carcinogenesis in three general ways: activa- for gastric cancer was found with aspirin use. tion of carcinogens to DNA-binding forms, ln one of two other population-based cohort production of malondialdehyde and formation studies of similar size and design, in which a of peroxyl radicals. diagnosis of rheumatoid arthritis was used as a Aspirin at high concentrations reduces the proxy for exposure to non-steroidal anti- proliferation rate of cultured human colon cancer inflammatory drugs, rheumatoid arthritis was ceIls, alters their distribution in the various phas- associated with a significantly lower risk for es of the ceIl cycle, increasing the proportion of gastric cancer. ln the other study, no such rela- ceIls in Go or G i phase, and can induce apoptosis. tionship was found. Non-cyclooxygenase-dependent mechanisms have been described that could play a role in its (c) Oesophageal cancer chemopreventive effects. Three studies addressed the relationship between aspirin use and oesophageal cancer. 8.4. Other beneficial effects One of these studies demonstrated a statistical- Prophylactic aspirin therapy has been proven ly significant inverse relationship. in large, reliable, randomized trials to reduce by about 25% the risk for myocardial infarct, (d) Breast cancer stroke and vascular death in people with No consistent association has been observed pre-existing cardiovascular conditions. The between use of aspirin and the occurrence of absolute benefits are greatest for patients with cancer of the breast in women. The larger acute myocardial infarct and are smaller studies generaIly found no association, but in patients with conditions posing a less acute a reduced risk was reported in two of six risk. Two randomized trials of healthy people cohort studies and in one of two case-control did not show any benefit of aspirin in studies. preventing deaths from circulatory disease. Although studies of clinicaIly diagnosed (e) Cancers at other sites Alzheimer disease and non-steroidal anti-inflam- No reduction in the risks for cancers of the matory drugs consistently suggest a 50% lung, bladder, prostate, buccal cavity, pharynx reduction in risk, the temporal relationship or genital system or melanoma was found to be between such exposure and disease development associated with aspirin use in the few studies in or progression has not been convincingly demon- which results were reported for cancers at these strated. sites. 8.5 Carcinogenicity 8.3.2 Experimental animaIs 8.5.1 Humans Aspirin had chemopreventive activity in two Many large-scale epidemiological studies have of three studies in rat models in which colonic been conducted of aspirin use and cancer. aberrant crypt foci were used as the end-point. There is no consistent evidence of an increased ln three studies with rat models of colon cancer, risk for cancer at any specific site. administration of aspirin significantly reduced the incidence and (in one case) the size of 8.5.2 Experimental animaIs colon tumours. Aspirin inhibited hepatocar- No data were available to the Working Group. cinogenesis in four studies in rat models. ln a single study in mice, aspirin was ineffective in 8.6 Toxic effects inhibiting carcinogenesis in a urinary bladder 8.6.1 Humans

mode l, but it inhibited bladder carcinogenesis Aspirin causes a dose-dependent increase, with in rats. no known lower threshold, in the incidence of

88 Aspirin upper gastrointestinal toxicity, including 9. Recommendations for Research dyspepsia, gastrointestinal haemorrhage, oesophageal and gastric erosion, perforation Definitive evidence for chemopreventive activ- and death. Low doses (40 mg) of aspirin inhib- ity nominaIly requires data from appropriately it platelet aggregation and can increase the risk designed randomized trials. ln practiee, the dura- for non-fatal bleeding requiring transfusion. tion that is necessary for aspirin to exert the The risk for haemorrhagic stroke may also be sought-after effect may, for practieal purposes, increased by relatively low doses. A positive preclude the execution of the necessary ran- association has been observed between use of domized trials. Rather, it may be necessary to aspirin in children and Reye syndrome. Aspirin rely upon observational studies. Such studies can precipitate or aggravate asthma. MaternaI can be performed using existing databases, and exposure to high but not low doses of aspirin this possibilty merits high priority. prior to delivery has consistently been associat- Adenomatous polyps may be perceived as ed with bleeding in the mother and the new- biomarkers for the probable development of born. colorectal cancer; however, confidence in this perception is progressively increased as the rela- 8.6.2 Experimental animaIs tionship between these lesions and the later Aspirin is harmful to the gastric mucosa and stages of colorectal cancer is more fully under- can result in irritation, ulceration and bleeding stood. It is important, therefore, that studies of in the stomach. Aspirin induces a wide these biomarkers include, where possible, spectrum of renal damage. ln rats, it causes monitoring of subsequent disease develop- papilary necrosis and decreased urinary ment. concentrating abilty or acute necrosis of the Cohort studies on sporadic cancer are need- proximal tubules. Susceptibilty to the nephro- ed, with prospective evaluation of aspirin use toxicity of aspirin appears to be age-dependent. over long periods of time - 10 or more years. ln mice, long-term treatment with aspirin is ln addition, the Group identified the need associated with proliferation of hepatic for clinieal trials of aspirin use for the preven- peroxisomes. High doses of aspirin cause tion of recurrent or primary sproadic adeno- mild to moderate temporary hearing loss, mas, of colorectal adenomas in patients with accompanied by changes in suprathreshold familal predisposition and of recurrent col- hearing, including a decrease in temporal inte- orectal cancer after surgi cal treatment of a first gration, poorer frequency selectivity and poor- case. er temporal resolution. The Working Group was aware that certain Congenital malformations can be induced in trials are in progress, apart from published rats after administration of aspirin at high data cited in this volume. Obviously, the doses to dams while the embryos are in early results of such trials wil influence current stages of development, leading to a variety of evaluations of NSAIDs as cancer-preventive anomalies. There is a clear correlation between agents. The knowledge that trials are in ingestion of aspirin and congenital malforma- progress mitigates against specifie recommen- tions, but these adverse effects occur at doses dations for future trial design; however, one far in excess of those likely to be encountered matter that necessitates attention is determi- in the therapeutic setting. nation of the lowest dose of aspirin necessary Aspirin induced chromos omal aberrations in for effective chemopreventive activity. This Chine se hamster cells and in human lympho- parameter should be a specific con cern in the cytes in vitro in one study. It induced chromo- design of future trials and/or observational somal aberrations in the bone marrow of rats studies. treated in vivo in one study.

89 IARC Handbooks of Cancer Prevention

10. Evaluation1 can be shown to be of greater benefit in reduc- ing cancer in human populations th an its pos- 10.1 Cancer-preventive activity sible off-setting toxicity. Detailed consideration 10.1.1 Humans of the total benefits in the prevention of cancer There is limited evidence in hum ans that aspirin and other diseases in contrast to toxicity wil reduces the risk for colorectal cancer, based on be required before use of aspirin for the pre- the finding of a consistent moderate reduction vention of cancer in humans, particularly in in risk in observational studies. IndividuaIly, asymptomatic populations, can be recom- none of the potential sources of bias or con- mended. founding provides a reasonable explanation for the reduction in risk for colorectal cancer that has been reported; however, the possible 11. References cumulative effect of these issues, although not quantifiable, cannot be excluded. Therefore, AI-Badr, A.A. & Ibrahim, S.E. (1981) Simultaneous the Working Group concluded that bias and quantitative analysis of aspirin, phenacetin and confounding could not be ruled out with rea- caffeine in pharmaceutical preparations by pro- sonable confidence. ton magnetic resonance spectrometry. Zbl. Pharm. Pharrakother. Laboratoriumsdiagn., 120, 1251-1254 10.1.2 Experimental animaIs Ali, B. & Kaur, S. (1983) Mammalian tissue acetyl- There is suffcíent evidence for the cancer-pre- salicylic acid esterases. Identification, distribution ventive activity of aspirin in experimental ani- and discrimination from other esterases. J. maIs. This evaluation is based on models of Pharmacol. exp. Ther., 226, 589-594 cancers of the colon and liver. Amer, M.M., Wanbi, A.M. & Aboul-Eialah, M.K. 10.2 Overall evaluation (1978) DifferentiaI spectrophotometric analysis of aspirin in some pharmaceutical preparations. Epidemiological studies in hum ans provide limited evidence for the cancer-preventive activ- Bull. Fac. Pharm. Cairo Univ., 15, 311-323 ity of aspirin, based on over 20 observational Amin, A.R., Vyas, P., Attur, M., Leszczynska-Piziak,

studies (both cohort and case-control), which J. Pate l, I.R., Weissmann, G. & Abramson, S.B. show a moderately reduced risk for colorectal (1995) The mode of action of aspirin-like drugs: cancer in people using aspirin regularly, and an Effect on inducible nitric oxide synthase. Proc. indication of greater reduction in risk with pro- natl Acad. Sei. USA, 92, 7926-7930 longed use. ln experimental animal models, Antiplatelet Trialists' Collaboration (1988) there is suffcíent evidence for the prevention of Secondary prevention of vascular disease by pro- colon cancer by aspirin. Aspirin is toxic, espe- longed antiplatelet treatment. Br. med. J., 296, ciaIly at high doses, but beneficial effects for 320-331 humans have been demonstrated at relatively Antiplatelet Trialists' Collaboration (1994a) The low doses, especially a reduction in the risk for aspirin papers. Aspirin benefits patients with vas- myocardial infarct and thrombotic stroke in cular disease and those undergoing revascularisa- populations with pre-existing disease. These tion. Br. med. J., 308, 71-72 findings indicate the need for more detailed research on cancer prevention, including con- Antiplatelet Trialists' Collaboration (1994b) troIled trials with different regimens of aspirin, Collaborative overview of randomised trials of including dose, route of administration, fre- antiplatelet therapy 1: Prevention of death, quency and duration, and different cohorts, in myocardial infarction, and stroke by prolonged an endeavour to determine whether aspirin antiplatelet therapy in various categories of patients. Br. med. ¡., 308, 81-106

1 For definitions of the italicized terms, see the Preamble, pp. 12-13. .. 90 Aspirin

Aonuma, S., Kohama, U. & Fujimoto, S. (1982) Boettcher, EL. & Salvi, R.j. (1991) Salicylate oto- Studies on aspirin derivatives with very little side- toxicity: Review and synthesis. Am. J. Otolaryngol., effects. II. Absorption, distribution, excretion and 12, 33-47 metabolism of tritium-Iabeled aspirin-isopropylan- Bostrom, H., Berntsen, K. & Whitehouse, M.W. tipyrine (AIA) in rats. J. Pharmacobiodyn., 5, 252-258 (1964) Biochemical properties of anti-inflamma- Arvind, P., Papavassilou, E.D., Tsioulias, G.J., tory drugs. II. Sorne effects on sulphate-35S Lovelace, c.I.P., Duceman, B. & Rigas, B. (1995) metabolism in vivo. Biochem. Pharmacol., 13, PGE2 down-regulates the expression of HLA-DR 413-420 antigen in human colon adenocarcinoma cell Briggs, D.E, Coutts, R.T. & Walter, L.j. (1977) A lines. Biochemistry, 34, 5604-5609 note of the bioavailabilty of five Canadian brands Arvind, P., Qiao, L., Papavassilou, E.D., Goldin, of acetylsalicylic acid tablets. Cano 1. Pharmacol. E., Koutsos, M.I. & Rigas, B. (1996). Aspirin and Sei., 12, 23 aspirin-like drugs indu ce the expression of HLA- Britton, M., Helmers, C. & Samuelsson, K. (1987) DR in HT29 colon adenocarcinoma cells. Int. 1. High-dose acetylsalicylic acid after cerebral infarc- Oncol., 52, 237-245 tion - A Swedish co-operative study. Stroke, 18, Aspirin Myocardial Infarction Study Research 325-334 Group (1980) A randomized controlled trial of Brouet, 1. & Ohshima, H. (1995) Curcumin, an aspirin in persons recovered from myocardial anti-tumour promoter and anti-inflammatory infarction. 1. Am. med. Assoc.i 243, 661-669 agent, inhibits induction of nitric oxide synthase Asymbekova G.U., Banartsev, P.D., Ochan, TB., in activated macrophages. Biochem. biophys. Res. Rozenfeld, B.Ye., Sariyev, A.K., Folomeyeva I.Yu. & Commun., 206, 533-540 Pavlovich, S.v. (1995) Pharmacokinetics and phar- Brouwers, j.R.B.j. & De Smet, P.A.G.M. (1994) macodynamics of aspirin prophylactic doses in Pharmacokinetic-pharmacodynamic drug interac- pregnant females at high risk placental insuffi- tions with nonsteroidal anti-inflammatory drugs. ciency. Exp. clin. Pharmacol., 58, 35-39 Clin. Pharmacokinet., 27, 462-485 Axelsen, R.A. (1976) Analgesic-induced renal pap- Bruce, W.R. & Heddle, lA. (1979) The mutagenic ilary necrosis in the Gunn rat: The comparative activity of 61 agents as determined by the nephrotoxicity of aspirin and phenacetin. J. micronucleus, Salmonella, and sperm abnormali- Pathol., 120, 145-150 tyassays. Cano J. genet. Cytol., 21, 319-334 Axelsen, R.A. (1980) Nephrotoxicity of mild anal- Budavari, S., ed. (1989) The Merck Index, Rahway, gesics in the Gunn strain of rat. Br. 1. clin. NJ, Merck & Co., p. 870 Pharmacol., 10, 309S-312S Burrell, J.H., Yong, J.L. & Macdonald, G.j. (1991) Bansal, P. & Sonnenberg, A. (1996) Risk factors of Analgesic nephropathy in Fischer 344 rats: colorectal cancer in inflammatory bowel disease. Comparative effects of chronic treatment with Am. J. Gastroenterol., 91, 44-48 either aspirin or paracetamol. Pa th 0 logyi 23, Bartsch, H., Malaveile, c., Camus, A.-M., Martel- 107-114 Planche, G., Brun, G., Hautefeuile, A., Sabadie, Cai, Y., Sohlenius, A.-K., Andersson, K., Sundberg, N., Barbin, A., Kuroki, T, Drevon, c., Piccoli, C. & C. & DePierre, J.W. (1994) Effects of acetylsalicylic Montesano, R. (1980) Validation and comparative acid on parameters related to peroxisome prolier- studies on 180 chemicals with S. typhimurium ation in mouse liver. Biochem. Pharmacol., 47, strains and V79 Chinese hamster cells in the pres- 2213-2219 ence of various metabolizing systems. Mutat. Res., 76, 1-50 Cai, Y., Appelkvist, E.-L. & DePierre, j.W. (1995) Hepatic oxidative stress and related defences dur- Bochner, E, Graham, G.G., Cham, E., Imhoff, ing treatment of mice with acetylsalicylic acid and D.M. & Haavisto, TM. (1981) Salicylate metabo- other peroxisome proliferators. J. Biochem. lite kinetics after several salicylates. Clin. Toxicol.i 10, 87-94 Pharmacol. Ther.i 30, 266-275 - 91 lARC Handbooks of Cancer Prevention

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