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Role of paan chewing and dietary habits in cervical carcinoma in Chennai, India

Role of paan chewing and dietary habits in cervical carcinoma in Chennai, India Epidemiology British Journal of Cancer (2003) 88, 1388 – 1393 & 2003 Cancer Research UK All rights reserved 0007 – 0920/03 $25.00 www.bjcancer.com Role of paan chewing and dietary habits in cervical carcinoma in Chennai, India 1 ,2 2 3,6 1 4 2 T Rajkumar , S Franceschi* , S Vaccarella , V Gajalakshmi , A Sharmila , PJF Snijders , N Munoz , 4 5 CJLM Meijer and R Herrero 1 2 Cancer Institute (WIA), 18 Sardar Patel Road, Adyar, Chennai 600 020, India; International Agency for Research on Cancer, 150 cours Albert Thomas, 3 4 F-69372 Lyon, cedex 08, France; Epidemiological Research Center, Chennai 600 010, India; Free University Medical Center, Postbus 7057, NL – 1007 ´ ´ MB Amsterdam, the Netherlands; Proyecto Epidemiologico Guanacaste, Costa Rican Foundation for Health Sciences, San Jose, Costa Rica Non-viral factors contribute to human papillomavirus (HPV)-related cervical carcinogenesis. We investigated the role of paan chewing and dietary habits among 205 women with invasive cervical cancer (ICC) and 213 age-matched control women in Chennai, India. Odds ratios (OR) and 95% confidence intervals (CI) were computed by means of unconditional multiple regression, taking into account major correlates of ICC risk. Paan chewing showed a dose-dependent direct association with ICC (OR for X5 paan day ¼ 4.0; 95% CI 1.2–13.3). Among dietary habits, the highest vs lowest intake tertile for vegetables and fruit was associated with an OR of 0.5 (95% CI 0.2–1.0). Low education level and low body weight were also risk factors for ICC, but they did not account for the associations of paan chewing and low vegetable and fruit intake. In the analyses restricted to HPV-positive cases and controls, the inverse association with vegetable and fruit intake was confirmed. Conversely, the adverse influence of paan chewing on ICC risk seemed to be attributable to a higher prevalence of cervical HPV infection in women who chewed. British Journal of Cancer (2003) 88, 1388–1393. doi:10.1038/sj.bjc.6600902 www.bjcancer.com & 2003 Cancer Research UK Keywords: paan chewing; vegetables; fruit; body mass index; cervical cancer Infection with oncogenic types of human papillomavirus (HPV) polymerase chain reaction (PCR)-based assays for HPV-DNA has been established as the central cause of invasive cervical cancer detection became available. They were, hence, not able to take the (ICC) (Bosch et al, 2002). The probability of developing strong effect of HPV infection into account. preinvasive and invasive cervical neoplasias is relatively low, given We, therefore, explored the role of paan chewing and dietary habits in ICC aetiology in Chennai (formerly Madras), Southern that between 10 and 50% of sexually active women have been India, one of the areas with the highest ICC incidence rates (38.9/ found to carry cervical HPV infection (Bosch et al, 2002) and this 100 000; Parkin et al, 1997) worldwide, by means of a case–control probability depends upon other factors acting in conjunction with study that could allow carefully for HPV infection. HPV. Cigarette smoking is associated with an approximately two- fold increase in the risk of ICC (Szarewski and Cuzick, 1998; Plummer et al, 2001), even in studies where stratification and adjustment for HPV infection and individual sexual habits MATERIALS AND METHODS excluded the possibility that smoking was a surrogate marker for This study is part of an international case–control study of ICC such variables (Plummer et al, 2001). No information exists on and HPV coordinated by the International Agency for Research on whether smokeless tobacco (e.g. in some paan chewing) is also Cancer (IARC) (Mun˜oz et al, 2002). Between June 1998 and May associated with ICC (IARC, 1985). 1999, 222 women with a diagnosis of ICC were interviewed at the Several studies have shown that low vegetable and fruit intake Cancer Institute in Chennai, Southern India. On account of the (La Vecchia et al, 1988; Herrero et al, 1991) and low serum levels of high burden of ICC cases at the Cancer Institute, the first woman various micronutrients (Potischman et al, 1991; Giuliano et al, to be newly diagnosed with cervical cancer in each working day 1997; Wideroff et al, 1998; Schiff et al, 2001; Sedjo et al, 2002) are was asked to participate in the study and informed consent was associated with a moderate increase in the risk of invasive and obtained. Inclusion criteria were: (1) histological confirmation of preinvasive cervical tumours. Most studies on dietary habits and ICC diagnosis, (2) no previous cancer treatment, and (3) lack of ICC were conducted, however, before the most sensitive, physical or mental impairments that would have made the interview impossible. In all, 17 women were excluded based on the revision of histological report: two had no neoplastic lesions, *Correspondence: Dr S Franceschi, Unit of Field and Intervention 14 women had cervical intraepithelial neoplasia (CIN) I or II, one Studies, International Agency for Research on Cancer, 150 cours Albert had carcinoma in situ. Among 205 eligible ICC cases, the Thomas, F-69372 Lyon ce´dex 08, France; E-mail: franceschi@iarc.fr distribution by FIGO stage was the following: stage 1: 10.2%; stage Formerly at Cancer Institute – WIA. 2: 44.9%; stage 3: 38.5%; stage 4: 6.3%. Squamous-cell carcinoma Received 19 December 2002; revised 14 February 2003; accepted 14 was diagnosed in 193 cases and adenocarcinoma/adenosquamous February 2003 carcinoma in 12. In all, 12 cancer cases refused to provide cervical Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al samples, although they were willing to be interviewed, leaving a HPV type-specific oligoprobes for the HPV types described above total of 193 cervical cancer patients with cervical exfoliated cells (Jacobs et al, 1995). available for HPV testing. Finally, E7 open-reading frame type-specific PCR assays for 14 Control women were identified at the Cancer Institute among in- high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, patients and visitors of patients other than women with cervical 68) (Walboomers et al, 1999) were applied to five ICC case cancer, and were frequency matched by age with ICC cases within specimens that were positive for b-globin but negative for HPV 5 years age groups. Exclusion criteria for control women included: DNA by GP5+/GP6+ PCR. Reamplification of specimens with E7 (1) a diagnosis of anogenital tract cancers (i.e. cervix, vagina, was not done among control women, since integration of HPV vulva, anal canal), cancer of the breast, endometrium, ovary or DNA in the cellular genoma, and, therefore, loss or disruption of colon, benign genital tumours and tobacco-related diseases (e.g. HPV L1 open-reading frame should not be found in women coronary heart disease, lung cancer or chronic bronchitis); (2) a without cervical cancer (Walboomers et al, 1999). history of hysterectomy or cervical conisation; and, as for ICC cases, (3) physical or mental problems. A total of 179 visitors and Statistical analyses 37 in-patients were thus contacted. Of the eligible 216 controls, three declined to participate in the study and three refused to have To estimate the risk of cervical cancer associated with various HPV a gynaecological examination. Thus, a sample of exfoliated cells types and the other risk factors, we calculated odds ratios (ORs) from the cervix was available for 210 control women. and 95% confidence intervals (CIs) by unconditional logistic regression. The ORs were adjusted for age and area of residence (Chennai and out of Chennai), education level, occupation, marital Data and specimen collection status, age at first marriage (which nearly always coincided with age at first sexual intercourse), number of pregnancies and Each participant was administered a standardised questionnaire husband’s extramarital affairs, as indicated in the Tables. Only on socioeconomic status, sexual behaviour, reproductive history, 4.9% of cases and 1.4% of control women reported more than one contraceptive practices, smoking habits, genital hygiene, history of lifetime sexual partner and zero cases and 1.4% of control women sexually transmitted infections and cervical cytological screening. reported oral contraceptive use. Therefore, these two variables Questions on weekly consumption of 21 foods or food groups, and were not included in the models. Approximate tertiles of weight, summary questions on overall consumption of all vegetables and height, body mass index (BMI, weight kg/height, m ), and intake of fruits were included. Information on height (cm) at time of foods or food groups were computed based on the combined interview and weight (kg) 2 years before interview was self- distribution of cases and controls. Tests for linear trend were reported. Two trained female interviewers administered the performed assigning an increasing score for each level of questionnaire to all case and control women in the hospital. categorical variables. Scores were then fitted into the model as a After the interview, each consenting woman had a pelvic continuous variable. In order to elucidate the influence of HPV examination performed by a gynaecologist, who took two cervical infection, major analyses were repeated: (1) among all cases and scrapes with two Ayre spatulas and one endocervical brush. A controls, (2) among HPV-positive vs HPV-negative control Papanicolaou smear was prepared, and the remaining cells were women, and (3) among HPV-positive cases vs HPV-positive eluted in phosphate-buffered saline (PBS), pelleted in PBS control women only. (2000 r.p.m. for 20 min at room temperature), and then stored at 701C. A punch biopsy sample from the tumour (cases only) and a 10-ml sample of peripheral blood were also collected and stored at RESULTS 701C. The study was approved by the ethical review committees of the Table 1 shows the distribution of 205 cases of cervical carcinoma IARC in Lyon and the Cancer Institute in Chennai. and 213 control women according to selected characteristics. Only one case was found to be HPV-DNA negative and the OR for HPV- DNA positivity was 388. The vast majority of HPV infections Detection of HPV DNA involved high-risk HPV types and no cases and 11 control women To analyse the quality of target DNA, beta (b)-globin gene-specific were infected only with low-risk types (data not shown). Cervical primers were used. b-Globin-negative and HPV-negative samples cancer cases reported a lower education level than control subjects (i.e. two ICC cases and 26 control women) were considered (OR¼ 2.7 for no education vs secondary school or more). inadequate and excluded from HPV-related analyses, thus leaving Approximately half of the cases and controls combined reported 191 invasive cancer cases (179 squamous-cell carcinoma cases and to work in agriculture, and farmers showed an OR of 4.3 compared 12 adeno/adenosquamous carcinoma cases) and 184 control with housewives. Being a widow or divorced rather than currently women with adequate HPV-DNA results. married (OR¼ 8.1), having had X5 vs 1–2 pregnancies (OR¼ 5.0), The presence of HPV DNA in cervical cells was assessed using and reporting that one’s husband had had (or probably had) general primer-mediated GP5+/6+ PCR. Polymerase chain-reac- extramarital affairs (OR¼ 7.0) were associated with significantly tion positivity was assessed by means of hybridisation of PCR increased risk of cervical cancer (Table 1). products in an enzyme immunoassay (EIA) using two HPV In respect to paan chewing habits, 18.5% of cancer cases oligoprobe cocktails that together detect the following 36 HPV and 7.0% of control women reported to be ever chewers (OR¼ 2.3; types: HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 6, 11, 95% CI: 1.0–5.3) (Table 2). The majority of chewers used paan 26, 34, 40, 42, 43, 44, 53, 54, 55, 57, 61, 70, 71 (equivalent to with tobacco. No substantial difference in the ORs was found CP8061), 72, 73, 81 (equivalent to CP8304), 82 (IS39 and MM4 according to the presence of tobacco in paan. Women who subtypes), 83 (equivalent to MM7), 84 (equivalent to MM8) and CP reported to chew five or more paans per day showed a more 6108. Probes and procedures used for EIA detection are described elevated OR (4.0; 95% CI: 1.2–13.3) than women who reported less elsewhere (Jacobs et al, 2000). In addition, HPV-positivity was than 5 paans per day (1.4; 95% CI: 0.5–4.1) (w for trend¼ 5.08, assessed by low-stringency Southern blot analysis of PCR products P¼ 0.02). Two cases and no controls reported to have ever smoked with a cocktail probe of HPV-specific DNA fragments. Subse- (Table 2). quently, GP5+/6+ PCR was repeated on positive samples in The mean weight was 52 and 54 kg among cases and controls, triplicate to generate sufficient products for further typing. After respectively. Women who weighted less than 50 kg had an OR of pooling these PCR products, typing was performed using EIA and 1.9 compared with women who weighted 55 kg or more (w for & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology Epidemiology Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 1 The distribution of 205 cases of cervical carcinoma and 213 controls with corresponding odds ratios (OR) and 95% confidence intervals (CI) by selected characteristics (Chennai, 1998–1999) No. No. Cases % Controls % OR (95% CI) Age (years) o45 70 34.1 73 34.3 F 45 – 49 44 21.5 44 20.6 F X50 91 44.4 96 45.1 F Human papilloma-virus DNA Negative 1 0.5 133 72.3 1 Positive 190 99.5 51 27.7 387.7 (82.2 – 7443.8) Education High 22 10.7 62 29.1 1 Primary 22 10.7 48 22.5 1.42 (0.59 – 3.43) None 161 78.5 103 48.4 2.69 (1.25 – 5.79) w for trend 7.53; P=0.006 Occupation Housewife 34 16.6 99 46.5 1 Farmer 140 68.3 74 34.7 4.33 (2.30 – 8.15) Other 31 15.1 40 18.8 1.52 (0.70 – 3.32) Marital status Married 143 69.8 201 94.4 1 Widow 55 26.8 12 5.6 8.11 (3.57 – 18.43) Separated-divorced 7 3.4 0 0.0 Age at first marriage/cohabiting (years) X21 20 9.8 36 16.9 1 19 – 20 39 19.0 41 19.3 1.23 (0.48 – 3.14) 17 – 18 53 25.9 69 32.4 0.76 (0.32 – 1.84) 15 – 16 45 22.0 32 15.0 0.74 (0.28 – 1.95) o15 48 23.4 35 16.4 0.80 (0.31 – 2.10) w for trend 0.92; P=0.337 Number of pregnancies o3 34 16.6 70 32.9 1 3 – 4 85 41.5 90 42.3 3.06 (1.54 – 6.10) X5 86 42.0 53 24.9 4.99 (2.37 – 10.49) w for trend 17.26; Po0.001 Husband’s extramarital affairs No 58 28.6 156 73.6 1 Uncertain/yes 145 71.4 56 26.4 6.99 (4.08 – 12.00) a b Some strata do not add up to the total because of missing values. Estimates from unconditional regression equations, including terms for age and area of residence, education, occupation, marital status, age at first marriage, number of c d pregnancies and husband’s extramarital affairs. Reference category. Including prostitutes. trend¼ 3.72, Po0.06). A nonsignificant inverse association was vs never OR¼ 2.4) and vegetable and fruit intake (summary found also for height (OR for o1.51 vs 41.54 m ¼ 1.7; w for question) (highest vs lowest intake tertile OR¼ 0.5) were trend¼ 2.56, P¼ 0.11). associated with ICC risk. In the analyses restricted to HPV- Table 3 shows ORs by intake tertile of selected foods or food positive women, however, only the association with low vegetable groups and cervical cancer. Significant inverse associations and fruit intake (OR¼ 0.4) was confirmed, even if it became of emerged for pulses (OR in the highest vs lowest intake tertile¼ 0.4) borderline statistical significance. Conversely, paan chewing was and bananas (OR¼ 0.3). The inverse associations with intake of not related to ICC risk among HPV-positive women but showed a fresh tomatoes, carrots, cruciferae and other citrus fruit were hint of direct association with HPV infection among control not statistically significant. There was no indication that the women. consumption of green vegetables, apples or pears, rice, milk, yogurt, egg, fish, meat, cakes or desserts and various oils affected ICC risk. A direct association was found for the intake of bread DISCUSSION (OR¼ 2.0). Table 4 shows the associations between ICC and paan chewing, This is the first report of an association between paan chewing and BMI and overall vegetable and fruit intake according to the fully cervical cancer. The topic is of interest in the light of the well- adjusted model in three different types of comparisons (see established association between ICC and tobacco smoking Statistical Analyses). Among all study women, paan chewing (ever (Szarewsky and Cuzick, 1998). The mechanisms involved in the British Journal of Cancer (2003) 88(9), 1388 – 1393 & 2003 Cancer Research UK Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 2 The distribution of 205 cases of cervical carcinoma and 213 controls with corresponding odds ratios (OR) and 95% confidence intervals (CI) by chewing and smoking habits, weight and height (Chennai, 1998–1999) No. No. Cases % Controls % OR (95% CI) Chewing habit Never 167 81.5 198 93.0 1 Ever 38 18.5 15 7.0 2.30 (1.00 – 5.34) Type of paan Without tobacco 10 4.9 6 2.8 2.64 (0.71 – 9.75) With tobacco 28 13.6 9 4.2 2.13 (0.78 – 5.86) No of paan/day o5 16 7.8 9 4.2 1.42 (0.49 – 4.14) X5 22 10.7 6 2.8 4.00 (1.20 – 13.33) w for trend 5.08; P=0.02 Smoking habit Never 203 99.0 213 100.0 1 Ever 2 1.0 0 0.0 N (0.28 –N) Weight (kg) X55 58 28.7 86 40.4 1 50 – 54 79 39.1 75 35.2 1.56 (0.84 – 2.88) p49 65 32.2 52 24.4 1.92 (0.98 – 3.75) w for trend 3.72; P=0.06 Height (cm) X155 63 31.2 83 39.0 1 151 – 154 59 29.2 66 31.0 1.14 (0.59 – 2.20) p150 80 39.6 64 30.0 1.69 (0.89 – 3.23) w for trend 2.56; P=0.11 a b Some strata do not add up to the total because of missing values. Estimates from unconditional regression equations, including terms for age and area of residence, education, occupation, marital status, age at first marriage, number of pregnancies and husband’s extramarital affairs. Reference category. tobacco-cervical cancer link are not well understood, but some of apparent adverse effect of weight and BMI must be interpreted them (e.g. high concentration of nicotine, cotinine and tobacco- with caution, as it may be a consequence rather than a risk factor specific nitrosamines in cervical mucus, impairment of immune for cervical cancer. The findings on height, although not function, accumulation of free radicals, etc, Szarewsky and Cuzick, statistically significant, point to a possible influence of nutritional deficiencies in childhood and adolescence that might have 1998) may not require tobacco burning. Aqueous extracts of betel quids and arecanuts that are generally used to make paan prevented some women from attaining their full height. Unfortu- produced carcinomas of the cheek pouch and fore-stomach of nately, the reliability of self-reported weight and height in India is rodents after subcutaneous or intragastric administration (IARC, unknown. 1985). Chewing is common among women in South-East Asia and Our present evaluation of dietary habits also has limitations, the South Pacific Islands (IARC, 1985) where cervical cancer rates since we have been using a short frequency questionnaire that are very high (Parkin et al, 1997), and, in Southern India, paan included 21 indicator foods or food groups only and we did not chewing has been found to account for 87% of oral cancer in explore serving size. Furthermore, the questionnaire had not been women (Balaram et al, 2002). validated in India, and it was especially difficult to capture any In addition to paan chewing, low education, occupation in association with staple foods like rice, which are eaten daily by farming, low weight and low intake of vegetables and fruit were the majority of the population, and with food groups which risk factors for cervical cancer in our study. An excess of cervical are eaten rarely (e.g, apples or pears and citrus fruit) or as cancer among low socioeconomic class women is one of the most ingredients of complex recipes (e.g, meat, green vegetables). consistent findings of epidemiological studies on this tumour No reliable translation into specific macro- and micronutrients (Schiffman et al, 1996). Although the socioeconomic gradient in has been possible, but in the summary questions on overall intake cervical cancer is now chiefly attributed to a lack of adequate of all vegetables and fruit, ICC cases did report a significantly screening, it has been present long before the spread of lower intake than control women, in agreement with findings Papanicolaou smears in developed countries and must have of some previous reports (La Vecchia et al, 1988; Herrero et al, explanations other than screening in our study since only one 1991). woman (a case) in Chennai reported to have ever had a The greatest challenge in the interpretation of our findings is, Papanicolaou smear. however, to rule out the possibility that the observed associations A possible correlate of low social class is poor nutritional status. with paan chewing and low vegetable and fruit intake are not mere The inverse relation we found between ICC risk and vegetable and correlates of sexual habits and, most important, HPV infection. fruit intake, after allowing for education level and occupation, may These associations were somewhat weakened, but were still support this possibility. Although we tried to obtain a woman’s statistically significant after adjustment for their possible mutual weight 2 years before cancer diagnosis or interview (controls), the confounding effect and for all the major correlates of ICC risk in & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology Epidemiology Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 3 Odds ratios (OR) and corresponding 95% confidence intervals (CI) for cervical carcinoma according to approximate intake tertile of selected foods or food groups; 205 cases and 213 controls (Chennai, 1998–1999) Approximate intake tertile a,b OR (95% CI) Food or food group Servings (week) II III (highest) v for trend Fresh tomatoes (o3: 3–4; X5) 0.94 (0.33 – 2.71) 0.64 (0.25 – 1.66) 1.72; P=0.19 Green vegetables (0; o2; X2) 1.68 (0.75 – 3.73) 0.59 (0.22 – 1.59) 0.08; P=0.78 Cruciferae (o3; 3–4; X5) 0.75 (0.32 – 1.72) 0.73 (0.36 – 1.49) 0.63; P=0.43 Carrots (o3; 3–4; X5) 0.66 (0.28 – 1.58) 0.64 (0.31 – 1.35) 1.08; P=0.30 Pulses (o5; 5; X6) 0.74 (0.39 – 1.40) 0.38 (0.17 – 0.82) 5.86; P=0.02 Fruit juices (0; X1) 0.61 (0.18 – 2.11) F Apples or pears (0; X1) 0.90 (0.28 – 2.91) F Citrus fruit (o1; X1) 0.59 (0.25 – 1.40) F Bananas (o1; 1; X2) 0.77 (0.38 – 1.54) 0.30 (0.11 – 0.78) 5.63; P=0.02 Milk (o1; 1; X2) 0.98 (0.52 – 1.83) 0.67 (0.33 – 1.36) 1.21; P=0.27 Yoghurt (o1; 1–5; X7) 1.12 (0.61 – 2.06) 0.63 (0.30 – 1.31) 1.28; P=0.26 Bread (0; 0.5; X1) 1.68 (0.93 – 3.01) 2.04 (0.82 – 5.04) 4.15; P=0.04 Rice and pasta (o7; X7) 1.93 (0.57 – 6.47) F Maize (0; 40) 0.13 (0.01 – 1.64) F Eggs (0; o2; X2) 1.30 (0.52 – 3.24) 0.63 (0.19 – 2.04) 0.80; P=0.37 Fish (0; o1 X1) 1.24 (0.44 – 3.46) 1.28 (0.60 – 2.71) 0.36; P=0.55 Ham and salami (0; o1; X1) 1.94 (0.65 – 5.81) 1.47 (0.63 – 3.42) 1.28; P=0.26 Meat (0; o1; X1) 1.14 (0.39 – 3.36) 1.41 (0.59 – 3.37) 0.76; P=0.38 Cakes and desserts (0; X1) 1.94 (0.42 – 8.89) F Fat for seasoning (seed vs palm/coconut oil) 0.81 (0.30 – 2.17) F Fat for cooking (seed vs palm/coconut oil) 0.92 (0.36 – 2.37) F a b Reference category is at the lowest intake tertile. Estimates from unconditional regression equations, including terms for age, area of residence, education, occupation, marital status, age at first marriage, number of pregnancies and husband’s extramarital affairs. Table 4 Odds ratios (OR) and corresponding 95% confidence intervals (CI) according to selected characteristics among all cases and controls; controls only, by HPV DNA; and HPV DNA-positive cases and controls only (Chennai, 1998–1999) All Controls HPV+ Cases vs controls HPV+ vs HPV Cases vs controls Ca/Co OR (95% CI) HPV+/ OR (95% CI) Ca/Co OR (95% CI) Chewing habit Never 167/198 1 45/126 1 154/4 1 Ever 38/15 2.36 (0.99 – 5.60) 6/7 2.12 (0.56 – 8.02) 36/6 1.06 (0.27 – 4.10) BMI X23.3 51/86 1 14/59 1 50/14 1 21.5 – 23.3 75/63 1.66 (0.85 – 3.25) 19/35 2.21 (0.86 – 5.67) 71/19 1.04 (0.30 – 3.53) o21.5 76/64 1.63 (0.83 – 3.21) 18/39 2.03 (0.81 – 5.04) 66/18 1.04 (0.32 – 3.42) w for trend 1.88; P=0.17 2.28; P=0.13 0.00; P=0.95 Vegetable and fruit intake (servings week ) o6 76/42 1 10/23 1 67/10 1 6 77/83 0.68 (0.34 – 1.33) 19/55 0.83 (0.28 – 2.40) 74/19 0.88 (0.26 – 3.03) X7 52/88 0.48 (0.24 – 0.98) 22/55 0.86 (0.30 – 2.43) 49/22 0.37 (0.11 – 1.22) w for trend 4.10; P=0.04 0.05; P=0.82 3.05; P=0.08 Estimates from unconditional regression equations, including terms for age, area of residence, occupation, marital status, age at first marriage, number of pregnancies, husband’s extramarital affairs and all listed variables. HPV=human papillomavirus. Ca=cases. Co=controls our study. HPV infection was found in all but one case and 28% of cases and HPV-positive controls can help to elucidate whether controls, and it involved, in the vast majority of women, high-risk these influence chiefly the acquisition and persistence of HPV HPV types. infection or the progression from HPV infection into malignant The separate analysis of risk factors for HPV infection (among cervical lesions (Munoz et al, 2002). The comparison of ORs in control women only) and for cervical cancer among HPV-positive Table 4 suggests that low intake of vegetables and fruit is unrelated British Journal of Cancer (2003) 88(9), 1388 – 1393 & 2003 Cancer Research UK Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al to HPV infection, but is directly associated with ICC risk among Unfortunately, the subgroup analyses in our study are based on HPV-positive women. These findings are in agreement with small numbers of women and have very broad confidence those of Wideroff et al (1998) and Sedjo et al (2002), who reported intervals. However, the analyses restricted to HPV-positive women no association between intake of various vitamins and support the possibility that low intake of vegetables and fruit HPV infection. Paan chewing showed some, although nonsignifi- contributes to the progression from HPV infection to cervical cant, association with the prevalence of HPV infection cancer. With respect to paan chewing, either its adverse effect on among controls, but no association with ICC risk among HPV- cervical cancer is real and, possibly, mediated by a decreased positive women. A case–control study from the United Kingdom ability of women who chew to clear HPV infection, or the habit of (Deacon et al, 2000) showed that tobacco smoking was associated chewing is a surrogate marker for increased HPV exposure. 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Jacobs MV, de Roda Husman AM, van den Brule AJC, Snijders PJF, Meijer Sedjo RL, Inserrra P, Abrahamsen M, Harris RB, Roe DJ, Baldwin S, CJLM, Walboomers JMM (1995) Group-specific differentiation between Giuliano AR (2002) Human papillomavirus persistence and nutrients high- and low-risk human papillomavirus genotypes by general primer- involved in the methylation pathway among a cohort of young women. mediated PCR and two cocktails of oligonucleotide probes. J Clin Cancer Epidemiol Biomark Prev 11: 353–359 Microbiol 33: 901–905 Szarewski A, Cuzik J (1998) Smoking and cervical neoplasia: a review of the Jacobs MV, Walboomers JM, Snijders PJ, Voorhorst FJ, Verheijen RH, evidence. J. Epidemiol Biostat 3: 229–256 Fransen-Daalmeijer N, Meijer CJ (2000) Distribution of 37 mucosotropic Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah HPV types in women with cytologically normal cervical smears: the age- KV, Snijders PJF, Peto J, Meijer CJLM, Mun˜oz N (1999) Human related patterns for high-risk and low-risk types. Int J Cancer 87: 221– papillomavirus is a necessary cause of invasive cervical cancer world- 227 wide. J Pathol 189:12–19 La Vecchia C, Decarli A, Fasoli M, Parazzini F, Franceschi S, Gentile A, Wideroff L, Potischman N, Glass AG, Greer CE, Manos MM, Scott DR, Negri E (1988) Dietary vitamin A and the risk of intraepithelial and Burk RD, Sherman ME, Wacholder S, Schiffman M (1998) A invasive cervical neoplasia. Gynecol Oncol 30: 187–195 nested case–control study of dietary factors and the risk of Mun˜oz N, Franceschi S, Bosetti C, Moreno V, Herrero R, Smith J, Shah KV, incident cytological abnormalities of the cervix. Nutr Cancer 30: Meijer CJLM, Bosch FX for the IARC Multicentric Cervical Cancer Study 130–136 & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Role of paan chewing and dietary habits in cervical carcinoma in Chennai, India

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Springer Journals
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Copyright © 2003 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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10.1038/sj.bjc.6600902
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Abstract

Epidemiology British Journal of Cancer (2003) 88, 1388 – 1393 & 2003 Cancer Research UK All rights reserved 0007 – 0920/03 $25.00 www.bjcancer.com Role of paan chewing and dietary habits in cervical carcinoma in Chennai, India 1 ,2 2 3,6 1 4 2 T Rajkumar , S Franceschi* , S Vaccarella , V Gajalakshmi , A Sharmila , PJF Snijders , N Munoz , 4 5 CJLM Meijer and R Herrero 1 2 Cancer Institute (WIA), 18 Sardar Patel Road, Adyar, Chennai 600 020, India; International Agency for Research on Cancer, 150 cours Albert Thomas, 3 4 F-69372 Lyon, cedex 08, France; Epidemiological Research Center, Chennai 600 010, India; Free University Medical Center, Postbus 7057, NL – 1007 ´ ´ MB Amsterdam, the Netherlands; Proyecto Epidemiologico Guanacaste, Costa Rican Foundation for Health Sciences, San Jose, Costa Rica Non-viral factors contribute to human papillomavirus (HPV)-related cervical carcinogenesis. We investigated the role of paan chewing and dietary habits among 205 women with invasive cervical cancer (ICC) and 213 age-matched control women in Chennai, India. Odds ratios (OR) and 95% confidence intervals (CI) were computed by means of unconditional multiple regression, taking into account major correlates of ICC risk. Paan chewing showed a dose-dependent direct association with ICC (OR for X5 paan day ¼ 4.0; 95% CI 1.2–13.3). Among dietary habits, the highest vs lowest intake tertile for vegetables and fruit was associated with an OR of 0.5 (95% CI 0.2–1.0). Low education level and low body weight were also risk factors for ICC, but they did not account for the associations of paan chewing and low vegetable and fruit intake. In the analyses restricted to HPV-positive cases and controls, the inverse association with vegetable and fruit intake was confirmed. Conversely, the adverse influence of paan chewing on ICC risk seemed to be attributable to a higher prevalence of cervical HPV infection in women who chewed. British Journal of Cancer (2003) 88, 1388–1393. doi:10.1038/sj.bjc.6600902 www.bjcancer.com & 2003 Cancer Research UK Keywords: paan chewing; vegetables; fruit; body mass index; cervical cancer Infection with oncogenic types of human papillomavirus (HPV) polymerase chain reaction (PCR)-based assays for HPV-DNA has been established as the central cause of invasive cervical cancer detection became available. They were, hence, not able to take the (ICC) (Bosch et al, 2002). The probability of developing strong effect of HPV infection into account. preinvasive and invasive cervical neoplasias is relatively low, given We, therefore, explored the role of paan chewing and dietary habits in ICC aetiology in Chennai (formerly Madras), Southern that between 10 and 50% of sexually active women have been India, one of the areas with the highest ICC incidence rates (38.9/ found to carry cervical HPV infection (Bosch et al, 2002) and this 100 000; Parkin et al, 1997) worldwide, by means of a case–control probability depends upon other factors acting in conjunction with study that could allow carefully for HPV infection. HPV. Cigarette smoking is associated with an approximately two- fold increase in the risk of ICC (Szarewski and Cuzick, 1998; Plummer et al, 2001), even in studies where stratification and adjustment for HPV infection and individual sexual habits MATERIALS AND METHODS excluded the possibility that smoking was a surrogate marker for This study is part of an international case–control study of ICC such variables (Plummer et al, 2001). No information exists on and HPV coordinated by the International Agency for Research on whether smokeless tobacco (e.g. in some paan chewing) is also Cancer (IARC) (Mun˜oz et al, 2002). Between June 1998 and May associated with ICC (IARC, 1985). 1999, 222 women with a diagnosis of ICC were interviewed at the Several studies have shown that low vegetable and fruit intake Cancer Institute in Chennai, Southern India. On account of the (La Vecchia et al, 1988; Herrero et al, 1991) and low serum levels of high burden of ICC cases at the Cancer Institute, the first woman various micronutrients (Potischman et al, 1991; Giuliano et al, to be newly diagnosed with cervical cancer in each working day 1997; Wideroff et al, 1998; Schiff et al, 2001; Sedjo et al, 2002) are was asked to participate in the study and informed consent was associated with a moderate increase in the risk of invasive and obtained. Inclusion criteria were: (1) histological confirmation of preinvasive cervical tumours. Most studies on dietary habits and ICC diagnosis, (2) no previous cancer treatment, and (3) lack of ICC were conducted, however, before the most sensitive, physical or mental impairments that would have made the interview impossible. In all, 17 women were excluded based on the revision of histological report: two had no neoplastic lesions, *Correspondence: Dr S Franceschi, Unit of Field and Intervention 14 women had cervical intraepithelial neoplasia (CIN) I or II, one Studies, International Agency for Research on Cancer, 150 cours Albert had carcinoma in situ. Among 205 eligible ICC cases, the Thomas, F-69372 Lyon ce´dex 08, France; E-mail: franceschi@iarc.fr distribution by FIGO stage was the following: stage 1: 10.2%; stage Formerly at Cancer Institute – WIA. 2: 44.9%; stage 3: 38.5%; stage 4: 6.3%. Squamous-cell carcinoma Received 19 December 2002; revised 14 February 2003; accepted 14 was diagnosed in 193 cases and adenocarcinoma/adenosquamous February 2003 carcinoma in 12. In all, 12 cancer cases refused to provide cervical Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al samples, although they were willing to be interviewed, leaving a HPV type-specific oligoprobes for the HPV types described above total of 193 cervical cancer patients with cervical exfoliated cells (Jacobs et al, 1995). available for HPV testing. Finally, E7 open-reading frame type-specific PCR assays for 14 Control women were identified at the Cancer Institute among in- high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, patients and visitors of patients other than women with cervical 68) (Walboomers et al, 1999) were applied to five ICC case cancer, and were frequency matched by age with ICC cases within specimens that were positive for b-globin but negative for HPV 5 years age groups. Exclusion criteria for control women included: DNA by GP5+/GP6+ PCR. Reamplification of specimens with E7 (1) a diagnosis of anogenital tract cancers (i.e. cervix, vagina, was not done among control women, since integration of HPV vulva, anal canal), cancer of the breast, endometrium, ovary or DNA in the cellular genoma, and, therefore, loss or disruption of colon, benign genital tumours and tobacco-related diseases (e.g. HPV L1 open-reading frame should not be found in women coronary heart disease, lung cancer or chronic bronchitis); (2) a without cervical cancer (Walboomers et al, 1999). history of hysterectomy or cervical conisation; and, as for ICC cases, (3) physical or mental problems. A total of 179 visitors and Statistical analyses 37 in-patients were thus contacted. Of the eligible 216 controls, three declined to participate in the study and three refused to have To estimate the risk of cervical cancer associated with various HPV a gynaecological examination. Thus, a sample of exfoliated cells types and the other risk factors, we calculated odds ratios (ORs) from the cervix was available for 210 control women. and 95% confidence intervals (CIs) by unconditional logistic regression. The ORs were adjusted for age and area of residence (Chennai and out of Chennai), education level, occupation, marital Data and specimen collection status, age at first marriage (which nearly always coincided with age at first sexual intercourse), number of pregnancies and Each participant was administered a standardised questionnaire husband’s extramarital affairs, as indicated in the Tables. Only on socioeconomic status, sexual behaviour, reproductive history, 4.9% of cases and 1.4% of control women reported more than one contraceptive practices, smoking habits, genital hygiene, history of lifetime sexual partner and zero cases and 1.4% of control women sexually transmitted infections and cervical cytological screening. reported oral contraceptive use. Therefore, these two variables Questions on weekly consumption of 21 foods or food groups, and were not included in the models. Approximate tertiles of weight, summary questions on overall consumption of all vegetables and height, body mass index (BMI, weight kg/height, m ), and intake of fruits were included. Information on height (cm) at time of foods or food groups were computed based on the combined interview and weight (kg) 2 years before interview was self- distribution of cases and controls. Tests for linear trend were reported. Two trained female interviewers administered the performed assigning an increasing score for each level of questionnaire to all case and control women in the hospital. categorical variables. Scores were then fitted into the model as a After the interview, each consenting woman had a pelvic continuous variable. In order to elucidate the influence of HPV examination performed by a gynaecologist, who took two cervical infection, major analyses were repeated: (1) among all cases and scrapes with two Ayre spatulas and one endocervical brush. A controls, (2) among HPV-positive vs HPV-negative control Papanicolaou smear was prepared, and the remaining cells were women, and (3) among HPV-positive cases vs HPV-positive eluted in phosphate-buffered saline (PBS), pelleted in PBS control women only. (2000 r.p.m. for 20 min at room temperature), and then stored at 701C. A punch biopsy sample from the tumour (cases only) and a 10-ml sample of peripheral blood were also collected and stored at RESULTS 701C. The study was approved by the ethical review committees of the Table 1 shows the distribution of 205 cases of cervical carcinoma IARC in Lyon and the Cancer Institute in Chennai. and 213 control women according to selected characteristics. Only one case was found to be HPV-DNA negative and the OR for HPV- DNA positivity was 388. The vast majority of HPV infections Detection of HPV DNA involved high-risk HPV types and no cases and 11 control women To analyse the quality of target DNA, beta (b)-globin gene-specific were infected only with low-risk types (data not shown). Cervical primers were used. b-Globin-negative and HPV-negative samples cancer cases reported a lower education level than control subjects (i.e. two ICC cases and 26 control women) were considered (OR¼ 2.7 for no education vs secondary school or more). inadequate and excluded from HPV-related analyses, thus leaving Approximately half of the cases and controls combined reported 191 invasive cancer cases (179 squamous-cell carcinoma cases and to work in agriculture, and farmers showed an OR of 4.3 compared 12 adeno/adenosquamous carcinoma cases) and 184 control with housewives. Being a widow or divorced rather than currently women with adequate HPV-DNA results. married (OR¼ 8.1), having had X5 vs 1–2 pregnancies (OR¼ 5.0), The presence of HPV DNA in cervical cells was assessed using and reporting that one’s husband had had (or probably had) general primer-mediated GP5+/6+ PCR. Polymerase chain-reac- extramarital affairs (OR¼ 7.0) were associated with significantly tion positivity was assessed by means of hybridisation of PCR increased risk of cervical cancer (Table 1). products in an enzyme immunoassay (EIA) using two HPV In respect to paan chewing habits, 18.5% of cancer cases oligoprobe cocktails that together detect the following 36 HPV and 7.0% of control women reported to be ever chewers (OR¼ 2.3; types: HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 6, 11, 95% CI: 1.0–5.3) (Table 2). The majority of chewers used paan 26, 34, 40, 42, 43, 44, 53, 54, 55, 57, 61, 70, 71 (equivalent to with tobacco. No substantial difference in the ORs was found CP8061), 72, 73, 81 (equivalent to CP8304), 82 (IS39 and MM4 according to the presence of tobacco in paan. Women who subtypes), 83 (equivalent to MM7), 84 (equivalent to MM8) and CP reported to chew five or more paans per day showed a more 6108. Probes and procedures used for EIA detection are described elevated OR (4.0; 95% CI: 1.2–13.3) than women who reported less elsewhere (Jacobs et al, 2000). In addition, HPV-positivity was than 5 paans per day (1.4; 95% CI: 0.5–4.1) (w for trend¼ 5.08, assessed by low-stringency Southern blot analysis of PCR products P¼ 0.02). Two cases and no controls reported to have ever smoked with a cocktail probe of HPV-specific DNA fragments. Subse- (Table 2). quently, GP5+/6+ PCR was repeated on positive samples in The mean weight was 52 and 54 kg among cases and controls, triplicate to generate sufficient products for further typing. After respectively. Women who weighted less than 50 kg had an OR of pooling these PCR products, typing was performed using EIA and 1.9 compared with women who weighted 55 kg or more (w for & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology Epidemiology Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 1 The distribution of 205 cases of cervical carcinoma and 213 controls with corresponding odds ratios (OR) and 95% confidence intervals (CI) by selected characteristics (Chennai, 1998–1999) No. No. Cases % Controls % OR (95% CI) Age (years) o45 70 34.1 73 34.3 F 45 – 49 44 21.5 44 20.6 F X50 91 44.4 96 45.1 F Human papilloma-virus DNA Negative 1 0.5 133 72.3 1 Positive 190 99.5 51 27.7 387.7 (82.2 – 7443.8) Education High 22 10.7 62 29.1 1 Primary 22 10.7 48 22.5 1.42 (0.59 – 3.43) None 161 78.5 103 48.4 2.69 (1.25 – 5.79) w for trend 7.53; P=0.006 Occupation Housewife 34 16.6 99 46.5 1 Farmer 140 68.3 74 34.7 4.33 (2.30 – 8.15) Other 31 15.1 40 18.8 1.52 (0.70 – 3.32) Marital status Married 143 69.8 201 94.4 1 Widow 55 26.8 12 5.6 8.11 (3.57 – 18.43) Separated-divorced 7 3.4 0 0.0 Age at first marriage/cohabiting (years) X21 20 9.8 36 16.9 1 19 – 20 39 19.0 41 19.3 1.23 (0.48 – 3.14) 17 – 18 53 25.9 69 32.4 0.76 (0.32 – 1.84) 15 – 16 45 22.0 32 15.0 0.74 (0.28 – 1.95) o15 48 23.4 35 16.4 0.80 (0.31 – 2.10) w for trend 0.92; P=0.337 Number of pregnancies o3 34 16.6 70 32.9 1 3 – 4 85 41.5 90 42.3 3.06 (1.54 – 6.10) X5 86 42.0 53 24.9 4.99 (2.37 – 10.49) w for trend 17.26; Po0.001 Husband’s extramarital affairs No 58 28.6 156 73.6 1 Uncertain/yes 145 71.4 56 26.4 6.99 (4.08 – 12.00) a b Some strata do not add up to the total because of missing values. Estimates from unconditional regression equations, including terms for age and area of residence, education, occupation, marital status, age at first marriage, number of c d pregnancies and husband’s extramarital affairs. Reference category. Including prostitutes. trend¼ 3.72, Po0.06). A nonsignificant inverse association was vs never OR¼ 2.4) and vegetable and fruit intake (summary found also for height (OR for o1.51 vs 41.54 m ¼ 1.7; w for question) (highest vs lowest intake tertile OR¼ 0.5) were trend¼ 2.56, P¼ 0.11). associated with ICC risk. In the analyses restricted to HPV- Table 3 shows ORs by intake tertile of selected foods or food positive women, however, only the association with low vegetable groups and cervical cancer. Significant inverse associations and fruit intake (OR¼ 0.4) was confirmed, even if it became of emerged for pulses (OR in the highest vs lowest intake tertile¼ 0.4) borderline statistical significance. Conversely, paan chewing was and bananas (OR¼ 0.3). The inverse associations with intake of not related to ICC risk among HPV-positive women but showed a fresh tomatoes, carrots, cruciferae and other citrus fruit were hint of direct association with HPV infection among control not statistically significant. There was no indication that the women. consumption of green vegetables, apples or pears, rice, milk, yogurt, egg, fish, meat, cakes or desserts and various oils affected ICC risk. A direct association was found for the intake of bread DISCUSSION (OR¼ 2.0). Table 4 shows the associations between ICC and paan chewing, This is the first report of an association between paan chewing and BMI and overall vegetable and fruit intake according to the fully cervical cancer. The topic is of interest in the light of the well- adjusted model in three different types of comparisons (see established association between ICC and tobacco smoking Statistical Analyses). Among all study women, paan chewing (ever (Szarewsky and Cuzick, 1998). The mechanisms involved in the British Journal of Cancer (2003) 88(9), 1388 – 1393 & 2003 Cancer Research UK Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 2 The distribution of 205 cases of cervical carcinoma and 213 controls with corresponding odds ratios (OR) and 95% confidence intervals (CI) by chewing and smoking habits, weight and height (Chennai, 1998–1999) No. No. Cases % Controls % OR (95% CI) Chewing habit Never 167 81.5 198 93.0 1 Ever 38 18.5 15 7.0 2.30 (1.00 – 5.34) Type of paan Without tobacco 10 4.9 6 2.8 2.64 (0.71 – 9.75) With tobacco 28 13.6 9 4.2 2.13 (0.78 – 5.86) No of paan/day o5 16 7.8 9 4.2 1.42 (0.49 – 4.14) X5 22 10.7 6 2.8 4.00 (1.20 – 13.33) w for trend 5.08; P=0.02 Smoking habit Never 203 99.0 213 100.0 1 Ever 2 1.0 0 0.0 N (0.28 –N) Weight (kg) X55 58 28.7 86 40.4 1 50 – 54 79 39.1 75 35.2 1.56 (0.84 – 2.88) p49 65 32.2 52 24.4 1.92 (0.98 – 3.75) w for trend 3.72; P=0.06 Height (cm) X155 63 31.2 83 39.0 1 151 – 154 59 29.2 66 31.0 1.14 (0.59 – 2.20) p150 80 39.6 64 30.0 1.69 (0.89 – 3.23) w for trend 2.56; P=0.11 a b Some strata do not add up to the total because of missing values. Estimates from unconditional regression equations, including terms for age and area of residence, education, occupation, marital status, age at first marriage, number of pregnancies and husband’s extramarital affairs. Reference category. tobacco-cervical cancer link are not well understood, but some of apparent adverse effect of weight and BMI must be interpreted them (e.g. high concentration of nicotine, cotinine and tobacco- with caution, as it may be a consequence rather than a risk factor specific nitrosamines in cervical mucus, impairment of immune for cervical cancer. The findings on height, although not function, accumulation of free radicals, etc, Szarewsky and Cuzick, statistically significant, point to a possible influence of nutritional deficiencies in childhood and adolescence that might have 1998) may not require tobacco burning. Aqueous extracts of betel quids and arecanuts that are generally used to make paan prevented some women from attaining their full height. Unfortu- produced carcinomas of the cheek pouch and fore-stomach of nately, the reliability of self-reported weight and height in India is rodents after subcutaneous or intragastric administration (IARC, unknown. 1985). Chewing is common among women in South-East Asia and Our present evaluation of dietary habits also has limitations, the South Pacific Islands (IARC, 1985) where cervical cancer rates since we have been using a short frequency questionnaire that are very high (Parkin et al, 1997), and, in Southern India, paan included 21 indicator foods or food groups only and we did not chewing has been found to account for 87% of oral cancer in explore serving size. Furthermore, the questionnaire had not been women (Balaram et al, 2002). validated in India, and it was especially difficult to capture any In addition to paan chewing, low education, occupation in association with staple foods like rice, which are eaten daily by farming, low weight and low intake of vegetables and fruit were the majority of the population, and with food groups which risk factors for cervical cancer in our study. An excess of cervical are eaten rarely (e.g, apples or pears and citrus fruit) or as cancer among low socioeconomic class women is one of the most ingredients of complex recipes (e.g, meat, green vegetables). consistent findings of epidemiological studies on this tumour No reliable translation into specific macro- and micronutrients (Schiffman et al, 1996). Although the socioeconomic gradient in has been possible, but in the summary questions on overall intake cervical cancer is now chiefly attributed to a lack of adequate of all vegetables and fruit, ICC cases did report a significantly screening, it has been present long before the spread of lower intake than control women, in agreement with findings Papanicolaou smears in developed countries and must have of some previous reports (La Vecchia et al, 1988; Herrero et al, explanations other than screening in our study since only one 1991). woman (a case) in Chennai reported to have ever had a The greatest challenge in the interpretation of our findings is, Papanicolaou smear. however, to rule out the possibility that the observed associations A possible correlate of low social class is poor nutritional status. with paan chewing and low vegetable and fruit intake are not mere The inverse relation we found between ICC risk and vegetable and correlates of sexual habits and, most important, HPV infection. fruit intake, after allowing for education level and occupation, may These associations were somewhat weakened, but were still support this possibility. Although we tried to obtain a woman’s statistically significant after adjustment for their possible mutual weight 2 years before cancer diagnosis or interview (controls), the confounding effect and for all the major correlates of ICC risk in & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology Epidemiology Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al Table 3 Odds ratios (OR) and corresponding 95% confidence intervals (CI) for cervical carcinoma according to approximate intake tertile of selected foods or food groups; 205 cases and 213 controls (Chennai, 1998–1999) Approximate intake tertile a,b OR (95% CI) Food or food group Servings (week) II III (highest) v for trend Fresh tomatoes (o3: 3–4; X5) 0.94 (0.33 – 2.71) 0.64 (0.25 – 1.66) 1.72; P=0.19 Green vegetables (0; o2; X2) 1.68 (0.75 – 3.73) 0.59 (0.22 – 1.59) 0.08; P=0.78 Cruciferae (o3; 3–4; X5) 0.75 (0.32 – 1.72) 0.73 (0.36 – 1.49) 0.63; P=0.43 Carrots (o3; 3–4; X5) 0.66 (0.28 – 1.58) 0.64 (0.31 – 1.35) 1.08; P=0.30 Pulses (o5; 5; X6) 0.74 (0.39 – 1.40) 0.38 (0.17 – 0.82) 5.86; P=0.02 Fruit juices (0; X1) 0.61 (0.18 – 2.11) F Apples or pears (0; X1) 0.90 (0.28 – 2.91) F Citrus fruit (o1; X1) 0.59 (0.25 – 1.40) F Bananas (o1; 1; X2) 0.77 (0.38 – 1.54) 0.30 (0.11 – 0.78) 5.63; P=0.02 Milk (o1; 1; X2) 0.98 (0.52 – 1.83) 0.67 (0.33 – 1.36) 1.21; P=0.27 Yoghurt (o1; 1–5; X7) 1.12 (0.61 – 2.06) 0.63 (0.30 – 1.31) 1.28; P=0.26 Bread (0; 0.5; X1) 1.68 (0.93 – 3.01) 2.04 (0.82 – 5.04) 4.15; P=0.04 Rice and pasta (o7; X7) 1.93 (0.57 – 6.47) F Maize (0; 40) 0.13 (0.01 – 1.64) F Eggs (0; o2; X2) 1.30 (0.52 – 3.24) 0.63 (0.19 – 2.04) 0.80; P=0.37 Fish (0; o1 X1) 1.24 (0.44 – 3.46) 1.28 (0.60 – 2.71) 0.36; P=0.55 Ham and salami (0; o1; X1) 1.94 (0.65 – 5.81) 1.47 (0.63 – 3.42) 1.28; P=0.26 Meat (0; o1; X1) 1.14 (0.39 – 3.36) 1.41 (0.59 – 3.37) 0.76; P=0.38 Cakes and desserts (0; X1) 1.94 (0.42 – 8.89) F Fat for seasoning (seed vs palm/coconut oil) 0.81 (0.30 – 2.17) F Fat for cooking (seed vs palm/coconut oil) 0.92 (0.36 – 2.37) F a b Reference category is at the lowest intake tertile. Estimates from unconditional regression equations, including terms for age, area of residence, education, occupation, marital status, age at first marriage, number of pregnancies and husband’s extramarital affairs. Table 4 Odds ratios (OR) and corresponding 95% confidence intervals (CI) according to selected characteristics among all cases and controls; controls only, by HPV DNA; and HPV DNA-positive cases and controls only (Chennai, 1998–1999) All Controls HPV+ Cases vs controls HPV+ vs HPV Cases vs controls Ca/Co OR (95% CI) HPV+/ OR (95% CI) Ca/Co OR (95% CI) Chewing habit Never 167/198 1 45/126 1 154/4 1 Ever 38/15 2.36 (0.99 – 5.60) 6/7 2.12 (0.56 – 8.02) 36/6 1.06 (0.27 – 4.10) BMI X23.3 51/86 1 14/59 1 50/14 1 21.5 – 23.3 75/63 1.66 (0.85 – 3.25) 19/35 2.21 (0.86 – 5.67) 71/19 1.04 (0.30 – 3.53) o21.5 76/64 1.63 (0.83 – 3.21) 18/39 2.03 (0.81 – 5.04) 66/18 1.04 (0.32 – 3.42) w for trend 1.88; P=0.17 2.28; P=0.13 0.00; P=0.95 Vegetable and fruit intake (servings week ) o6 76/42 1 10/23 1 67/10 1 6 77/83 0.68 (0.34 – 1.33) 19/55 0.83 (0.28 – 2.40) 74/19 0.88 (0.26 – 3.03) X7 52/88 0.48 (0.24 – 0.98) 22/55 0.86 (0.30 – 2.43) 49/22 0.37 (0.11 – 1.22) w for trend 4.10; P=0.04 0.05; P=0.82 3.05; P=0.08 Estimates from unconditional regression equations, including terms for age, area of residence, occupation, marital status, age at first marriage, number of pregnancies, husband’s extramarital affairs and all listed variables. HPV=human papillomavirus. Ca=cases. Co=controls our study. HPV infection was found in all but one case and 28% of cases and HPV-positive controls can help to elucidate whether controls, and it involved, in the vast majority of women, high-risk these influence chiefly the acquisition and persistence of HPV HPV types. infection or the progression from HPV infection into malignant The separate analysis of risk factors for HPV infection (among cervical lesions (Munoz et al, 2002). The comparison of ORs in control women only) and for cervical cancer among HPV-positive Table 4 suggests that low intake of vegetables and fruit is unrelated British Journal of Cancer (2003) 88(9), 1388 – 1393 & 2003 Cancer Research UK Paan chewing and diet in cervical cancer in Chennai T Rajkumar et al to HPV infection, but is directly associated with ICC risk among Unfortunately, the subgroup analyses in our study are based on HPV-positive women. These findings are in agreement with small numbers of women and have very broad confidence those of Wideroff et al (1998) and Sedjo et al (2002), who reported intervals. However, the analyses restricted to HPV-positive women no association between intake of various vitamins and support the possibility that low intake of vegetables and fruit HPV infection. Paan chewing showed some, although nonsignifi- contributes to the progression from HPV infection to cervical cant, association with the prevalence of HPV infection cancer. With respect to paan chewing, either its adverse effect on among controls, but no association with ICC risk among HPV- cervical cancer is real and, possibly, mediated by a decreased positive women. A case–control study from the United Kingdom ability of women who chew to clear HPV infection, or the habit of (Deacon et al, 2000) showed that tobacco smoking was associated chewing is a surrogate marker for increased HPV exposure. 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Nutr Cancer 30: Meijer CJLM, Bosch FX for the IARC Multicentric Cervical Cancer Study 130–136 & 2003 Cancer Research UK British Journal of Cancer (2003) 88(9), 1388 – 1393 Epidemiology

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