Editorial 385

Coffee and risk: an update Carlo La Vecchiaa,b and Alessandra Tavania

European Journal of Cancer Prevention 2007, 16:385–389 Correspondence to Professor Carlo La Vecchia, Istituto di Ricerche Farmacologiche ‘Mario Negri’, via Eritrea 62, 20157 , Italy Tel: + 39 02 3901 4527; e-mail: [email protected] a‘Mario Negri’ Institute for Pharmacological Research and bInstitute of Medical Statistics and Biostatistics, , Milan, Italy

Introduction years. Most papers allowed for several potential con- The possible relationship between coffee and cancer risk founding risk factors, but multivariate analyses did not has been extensively considered in epidemiological substantially modify the results. studies. The main cancer sites of interest are colorectal and liver on one side, for which inverse relationships have A biological interpretation of the potential inverse been reported, and bladder and pancreas on the other association between coffee and large bowel cancer has side, for which direct relationships have been suggested. been related to reductions of cholesterol, bile acid and Available evidence on these sites will be reviewed here, neutral sterol secretion in the colon by coffee, as bile together with a brief mention of other relevant cancer acids are promoters of colon carcinogenesis (Potter, sites. Focus will be on data published after 1990; that is, 1992). This would also be consistent with the association after Monograph 51 of the International Agency for being stronger for (or restricted to) colon rather than for Research on Cancer on Coffee (IARC, 1991). rectal cancer. Furthermore, coffee intake increases colonic motility, which has been inversely related to colon cancer Colorectal cancer risk by influencing the exposure to colonic carcinogens The 1990 IARC Working Group (IARC, 1991) concluded (Brown et al., 1990). Coffee beans also contain several that in humans ‘there is some evidence of an inverse phenolic compounds with antioxidant properties [such as relationship between coffee drinking and cancer of the caffeic acid and chlorogenic acid (Daglia et al., 2000; large bowel’. Anese and Nicoli, 2003)] and diterpenes (such as cafestol and kahweol) with anticarcinogenic activity (Cavin et al., 2002). The literature from 1990 to 2005 on the relationship between coffee, decaffeinated coffee and colorectal cancer risk is summarized here. At least four cohort Liver cancer (total number of cases: 1694) and nine case–control Several data on a potentially favourable effect of coffee on studies (7555 cases) analysed colon cancer, four cohort liver function and liver diseases have accumulated over (568 cases) and four case–control studies (2704 cases) the last two decades. These span from liver enzymes, to analysed rectal cancer, and six case–control studies cirrhosis and to hepatocellular carcinoma (HCC), and (854 cases) analysed colorectal cancer combined (Tavani therefore constitute a continuous spectrum not only of and La Vecchia, 2000, 2004; Michels et al., 2005). For epidemiological data, but also of biological and clinical colon cancer, most case–control studies found risk evidence. estimates below unity; the results are less clear for cohort studies. No consistent relationship emerged for Coffee consumption, in fact, has been inversely related to rectal cancer. Decaffeinated coffee was not related to g-glutamyltransferase and alanine aminotransferase activ- either colon or rectal cancer in one cohort and three case– ity in studies from Norway, Italy, Finland, France, Japan control studies (Tavani and La Vecchia, 2004). One and the United States. Such inverse relationships were cohort study found an inverse relationship for decaffei- particularly strong in high-risk individuals, including nated coffee only (Michels et al., 2005). heavy alcohol drinkers (La Vecchia, 2005). Coffee drinking has also been inversely related to the risk of Various possible reasons exist for the apparent inverse cirrhosis in studies from North America and Europe association between coffee intake and colon cancer risk (La Vecchia, 2005). observed in case–control but not in cohort studies. One of these is the presence of some bias or residual confound- Cirrhosis is a major correlate of HCC, and the relationship ing in case–control studies. Any obvious methodological between coffee drinking and the risk of primary liver bias, however, is unlikely to account for the consistent cancer has been examined in at least six studies. An results in different countries and settings. Likewise, Italian case–control study based on 151 cases of HCC major publication bias is unlikely, as negative results on reported a multivariate relative risk (RR) of 0.78 for the issue have also attracted interest over the last few drinkers of three or more cups of coffee per day,

0959-8278 c 2007 Lippincott Williams & Wilkins 386 European Journal of Cancer Prevention 2007, Vol 16 No 5 compared with noncoffee drinkers (La Vecchia et al., in six other studies. As smoking is an important risk 1989). In a Greek case–control study (Kuper et al., 2000), factor for bladder cancer, lifelong nonsmokers were also including 333 cases, the age and sex-adjusted RR was 0.7 considered separately to obtain information on the for drinkers of Z 20 cups of coffee per week compared potential distorting effect of tobacco. Some relation with with that of nondrinkers. The combined analysis of the coffee was still observed, although it was less clear, two studies gave a RR of 0.7 [95% confidence interval possibly because of smaller numbers. (CI): 0.5–1.0] for three or more cups per day (Gallus et al., 2002). After the publication of the IARC Monograph, at least four cohort (Mills et al., 1991; Chyou et al., 1993; In another Italian case–control study of 250 cases (Gelatti Stensvold and Jacobsen, 1994; Zeegers et al., 2001a) et al., 2005), compared with noncoffee drinkers, the RRs and 13 case–control studies (Clavel and Cordier, 1991; were 0.8 for drinkers of one to two cups per day, 0.4 for Nomura et al., 1991; D’Avanzo et al., 1992; Kunze et al., those of three to four cups and 0.3 for drinkers of five or 1992; Escolar Pujolar et al., 1993; McGeehin et al., 1993; more cups per day. Vena et al., 1993; Momas et al., 1994; Brown et al., 1995; Bruemmer et al., 1997; Donato et al., 1997; Pohlabeln et al., In a prospective study of 334 cases from Japan, 1999; Geoffroy-Perez and Cordier, 2001) provided in- individuals who consumed coffee on a daily basis had formation on coffee and bladder cancer. lower HCC risk than those who almost never drank coffee (RR = 0.49, 95% CI: 0.36–0.66). The risk decreased with Three cohort studies found moderately increased risk of the amount of coffee consumed (compared with non- bladder cancer in coffee drinkers, in the absence of a drinkers, the RR for one to two cups per day = 0.52; for dose–risk relationship. In the Californian Seventh-Day three to four cups per day = 0.48; for five or more cups Adventists’ cohort, which included 52 cases, the smoking- per day = 0.24) (Inoue et al., 2005). A pooled analysis of adjusted RR was 1.99 (nonsignificant) for two or more two other Japanese studies including a total of 117 cases cups of coffee per day compared with noncoffee drinkers, gave a RR of 0.58 (95% CI: 0.36–0.96) for drinkers of one with a stronger relation in never smokers (Mills et al., or more cups per day compared with never drinkers 1991). In a cohort of Japanese-Americans living in Hawaii (Shimazu et al., 2005). In another cohort investigation, (including 92 cases), a high consumption of coffee the Japan Collaborative Cohort Study for Evaluation of nonsignificantly increased risk (Chyou et al., 1993), and, Cancer Risk (JACC Study), including 258 cases, the in a Norwegian cohort of 43 000 men and women, the RR multivariate RR was 0.83 (95% CI: 0.54–1.25) for for drinkers of seven or more cups of coffee per day was occasional and 0.50 (95% CI: 0.31–0.79) for regular 1.5 in men (based on 40 cases) and 2.4 in women (based (one or more cups per day) coffee drinkers. The inverse on 13 cases) (Stensvold and Jacobsen, 1994). In the relationship was similar in men and women, and in those Netherlands cohort study based on 569 cases, the RR for without and with a history of liver disease (Kurozawa an increment of one cup of coffee per day was 1.03 in men et al., 2005). and 0.84 in women (Zeegers et al., 2001a).

The favourable effect of coffee consumption on HCC In a pooled analysis of 10 European studies restricted to may be due to its inverse relationship with cirrhosis, but 564 nonsmokers, there was no excess risk in coffee allowance for clinical history of cirrhosis did not totally drinkers (odds ratio: 1.0) (Sala et al., 2000). Another meta- account for the inverse association. Given its effects on analysis, which included three cohort and 34 case–control liver enzymes and cirrhosis, and the weight of epidemio- studies, estimated that coffee consumption increased logical evidence, coffee appears therefore to have a real urinary tract (mainly bladder) risk by approxi- effect in reducing the risk of HCC, as suggested also by mately 20%: the RR, adjusted for age, sex and smoking, data on rodents (Tanaka et al., 1990). Various components was 1.18 (95% CI: 1.03–1.36) for coffee and 1.18 (95% CI: of coffee have been related to such a favourable effect, 0.99–1.40) for decaffeinated coffee (Zeegers et al., including caffeine, coffee oils kahweol or cafestol, and 2001b). antioxidant substances from coffee beans, but no definite evidence is available. Thus, the large amount of epidemiological data on coffee and bladder cancer risk allows one to exclude a strong Bladder cancer association. It is not clear whether the moderate The IARC Monograph 51 evaluated 22 studies published association reported in many studies is causal. The major before 1990 (IARC, 1991). Of these, 16 found moderately potential confounding factor is cigarette smoking, which increased RRs of bladder cancer in coffee drinkers is related to both coffee consumption and bladder cancer compared with nondrinkers; in seven of these, the risk; however, misclassification of smoking status or association was significant and in three there was also residual confounding are unlikely to completely explain evidence of a dose–risk relation. No relation was observed the association. Other possible sources of residual Coffee and cancer risk La Vecchia and Tavani 387 confounding include diet or occupational exposure to Other cancers bladder carcinogens, although the similar associations The IARC Monograph 51 included data on coffee and found in men and women suggest that occupation is gastric cancer from five case–control studies (IARC, unlikely to be a major confounder. 1991). No evidence of association was found in any of them. More recently, a Norwegian cohort study observed Pancreatic cancer no association between coffee intake and gastric cancer risk (RR 0.5 in men and in women, not significant, based In the early 1980s, a case–control study from North on 78 cases) (Stensvold and Jacobsen, 1994). A cohort America showed a direct association between coffee study of Japanese residents in Hawaii, including 108 consumption and pancreatic cancer risk (MacMahon et al., cases, found that men who drank one cup of coffee per 1981). Overall, 21 case–control studies on pancreatic day had an elevated risk of gastric cancer compared with cancer relationship were reviewed in the IARC Mono- noncoffee drinkers (RR = 2.5) (Galanis et al., 1998). No graph 51 (IARC, 1991). Among them, 10 found moderate association between coffee drinking and gastric cancer positive associations, which were weaker after allowance risk was found in four case–control studies: a Spanish for smoking, and the remaining studies found no study based on 354 cases (Agudo et al., 1992), a Swedish association. study based on 338 cases (Hansson et al., 1993), a Japanese one based on 893 cases (Inoue et al., 1998) and a The results of at least seven cohort studies have been Polish study based on 464 cases (Chow et al., 1999). Thus, published after the IARC Monograph 51 (IARC, 1991). it is now clear that coffee is unlikely to have any major No association emerged in a cohort of 17 633 American effect on gastric carcinogenesis. men (RR 0.9 for intake of seven or more cups per day, based on 56 cases) (Zheng et al., 1993); in a Norwegian Six studies providing data on cancers of the oral cavity, cohort of 43 000 men and women (RR 0.6 in men for pharynx and oesophagus were considered in the IARC seven or more cups per day and 1.2 in women for more monograph (IARC, 1991). No evidence of association than six cups per day, based on 26 and 13 cases, with coffee consumption was found in any of them. Since respectively) (Stensvold and Jacobsen, 1994); in a cohort then, at least one cohort (Stensvold and Jacobsen, 1994) of nearly 14 000 residents of a retirement community and five case–control studies (La Vecchia et al., 1990; from the United States (RR 0.88 for four or more cups per Franceschi et al., 1991; Pintos et al., 1994; Bundgaard et al., day, based on 65 cases) (Shibata et al., 1994); in the 1995; Castellsague et al., 2000) found no association for Health Professionals’ Follow-up Study (RR 0.37 for more these cancers, whereas a case–control study based on 749 than three cups of coffee per day and 0.99 for cases of oral and pharyngeal cancer and 395 of oesopha- decaffeinated coffee, based on 130 cases) (Michaud geal cancer from Italy (Tavani et al., 2003) found that risk et al., 2001); in the Nurses’ Health Study (RR 0.88 for approximately halved in the highest quintile compared more than three cups of coffee per day and 0.85 for with the lowest quintile of coffee intake. decaffeinated coffee, based on 158 cases) (Michaud et al., 2001) and in the Japan collaborative cohort study for evaluation of cancer risk, where no trend in risk with With relevance to breast cancer, of the seven case–control number of cups emerged (Lin et al., 2002). Conversely, in studies considered in the IARC monograph (IARC, the Iowa Women’s Health Study cohort on nearly 34 000 1991), none found an association with coffee consump- women and including 66 incident cases of pancreatic tion (IARC, 1991). More recently, three cohort and four cancer, the RR was 2.15 for drinkers of more than 17.5 case–control studies, including an Italian one with nearly cups of coffee per week. The association was not 6000 cases (Tavani et al., 1998), found no association significant in never smokers (Harnack et al., 1997). (Tavani and La Vecchia, 2000, 2004).

Most case–control studies published after the IARC Likewise, no consistent relationship was observed be- monograph found no significant association between tween coffee, ovarian, laryngeal, lung, prostate, cervical, coffee and pancreatic cancer risk (Tavani and La Vecchia, endometrial and thyroid cancers, Hodgkin’s and non- 2000, 2004), and one study found an inverse association Hodgkin lymphomas, sarcoma, multiple myeloma and (Bueno de Mesquita et al., 1992). skin melanoma (Tavani et al., 2003; Naldi et al., 2004; Tavani and La Vecchia, 2004). It is possible therefore that any relationship between coffee and pancreatic cancer is not causal but explainable Conclusions through selection or recall bias, residual confounding with The large amount of epidemiological data on bladder cigarette smoking (the major recognized risk factor for cancer allows one to exclude a strong association with pancreatic cancer) or other sources of confounding. In any coffee intake, and the lack of dose–response relation does case, a strong association between coffee and pancreatic not support causality. Likewise, an association between cancer can now be excluded. coffee and pancreatic cancer risk can now be excluded. 388 European Journal of Cancer Prevention 2007, Vol 16 No 5

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