Betel quid not containing tobacco and oral cancer: a report on a case-control study in Papua New Guinea and a meta-analysis of current evidence

Smoking and betel quid chewing are associated with increased risk of oral cancer but few studies have reported on associations in populations where betel quid does not contain tobacco. We conducted a case-control study in Papua New Guinea and a systematic review. Our case-control study recruited 143 cases with oral cancer and 477 controls. We collected information on smoking and betel quid chewing. Current smoking was associated with an increased risk of oral cancer with an adjusted odds ratio (OR) for daily smokers of 2.63 (95% confidence intervals (95% CI) 1.32, 5.22) and amongst heaviest smokers of 4.63 (95% CI 2.07, 10.36) compared to never-smokers. Betel chewing was associated with increased risk of oral cancer with an adjusted OR for current chewers of 2.03 (95% CI 1.01, 4.09) and in the heaviest chewers of 2.47 (95% CI 1.13, 5.40) compared to nonchewers. The OR in those who both smoked tobacco and chewed betel quid was 4.85 (95% 1.10, 22.25), relative to those who neither smoked nor chewed. The systematic review identified 10 previous studies that examined risk of oral cancer associated with betel quid chewing that controlled for smoking in populations where betel quid did not contain tobacco. In studies that reported results for non-smokers the combined OR was 2.14 (95% CI 1.06, 4.32) in betel quid chewers and in studies that adjusted for smoking the combined OR was 3.50 (95% CI 2.16, 5.65) in betel quid chewers. Preventive efforts should discourage betel quid chewing as well as smoking.     

Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan

The effects of betel nut chewing, smoking and alcohol on the occurrence of leukoplakia and its malignant transformation to oral carcinoma were quantified in a leukoplakia cohort (n = 435) from one medical centre between 1988 and 1998 in Taiwan. Sixty oral carcinomas were ascertained in this cohort. A case-control study within the leukoplakia cohort was used to study, risk factors. Using the Weibull survival model, the incidence of malignant transformation of leukoplakia was shown to increase with follow-up years. After adjustment for other relevant risk factors, betel nut chewing (adjusted odds ratio (OR) = 4.59; 95% confidence interval (CI) 1.25-16.86) remained a significant risk factor for malignant transformation. Results from the case-control study showed that the adjusted odds ratios for betel nut chewing and smoking on the occurrence of leukoplakia were 17.43 (95% CI 1.94-156.27) and 3.22 (95% CI 1.06-9.78), respectively. Similar findings were observed when daily frequency and duration were taken into account. This implies that cessation of smoking may reduce by 36% leukoplakia cases, while elimination of betel nuts may prevent 62% of leukoplakia and 26% of malignant transformation to oral carcinoma in the underlying population.     

Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta‐analysis with implications for cancer control

We conducted a random‐effects meta‐analysis of 50 publications assessing the relationship between oral/oropharyngeal cancer and chewing betel quid, with (BQ+T) or without added tobacco (BQ‐T), a common practice in many parts of Asia and globally among Asian immigrants. Exposure‐response, by daily amount and years of BQ chewed, was assessed using spline models. Attributable fractions (PAF%) were calculated to estimate the public health impact if BQ were no longer chewed. The meta‐relative risk (mRR) for oral/oropharyngeal cancer in the Indian subcontinent was 2.56 (95%CI, 2.00–3.28; 15 studies) for BQ‐T and 7.74 (95%CI, 5.38–11.13; 31 studies) for BQ+T; in Taiwan, China, the mRR for BQ‐T was 10.98 (95%CI, 4.86–24.84; 13 studies). Restricting to studies that adjusted for tobacco and alcohol use had only a small effect on the risk estimates. For BQ+T in the Indian subcontinent, the mRR was much higher in women (mRR, 14.56; 95%CI, 7.63–27.76) than in men. Exposure‐response analyses showed that the risk of oral/oropharyngeal cancer increased with increasing daily amount and duration (years) of chewing BQ in India and Taiwan, China. Roughly half of oral cancers in these countries could be prevented if BQ were no longer chewed (PAF% = 53.7% for BQ‐T in Taiwan, China; PAF% = 49.5% for BQ+T in India). We demonstrate that betel quid chewing, with or without added tobacco, increases the risk of oral/oropharyngeal cancer in an exposure‐dependent manner, independently of tobacco and alcohol use. Further work is needed to explain the higher risks associated with chewing BQ‐T in Taiwan, China.     

The precancer risk of betel quid chewing,tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan

In areas where the practise of betel quid chewing is widespread and the chewers also often smoke and drink alcohol, the relation between oral precancerous lesion and condition to the three habits is probably complex. To explore such association and their attributable effect on oral leukoplakia (OL) and oral submucous fibrosis (OSF), a gender-age-matched case-control study was conducted at Kaohsiung, southern Taiwan. This study included 219 patients with newly diagnosed and histologically confirmed OL or OSF, and 876 randomly selected community controls. All information was collected by a structured questionnaire through in-person interviews. A preponderance of younger patients had OSF, while a predominance of older patients had OL. Betel quid chewing was strongly associated with both these oral diseases, the attributable fraction of OL being 73.2% and of OSF 85.4%. While the heterogeneity in risk for areca nut chewing across the two diseases was not apparent, betel quid chewing patients with OSF experienced a higher risk at each exposure level of chewing duration, quantity and cumulative measure than those who had OL. Alcohol intake did not appear to be a risk factor. However, cigarette smoking had a significant contribution to the risk of OL, and modified the effect of chewing based on an additive interaction model. For the two oral premalignant diseases combined, 86.5% was attributable to chewing and smoking. Our results suggested that, although betel quid chewing was a major cause for both OL and OSF, its effect might be difference between the two diseases. Cigarette smoking has a modifying effect in the development of oral leukoplakia.     

Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis

Although several studies have found overexpression of epidermal growth factor receptor (EGFR) proteins EGFR and Her-2 in head and neck cancers, the clinical relevance of the finding varies. We examined the expression and clinical association of these molecules with oral squamous cell carcinoma in an area where betel chewing is prevalent. EGFR and Her-2 proteins were measured in 59 paired (grossly normal and cancer) tissues by an enzyme immunoassy method. The cutoff value for gene overexpression was defined as the level of mean expression in normal tissue plus two s.d. A total of 59% of the patients consumed alcohol, 90% smoked tobacco, and 90% chewed betel quid. Of the patients assayed, 34 (58%) and 24 (41%) had EGFR and Her-2 overexpression, with average 3.5- and 1.5-fold elevations. EGFR overexpression has been shown to be statistically associated with T stage, N stage, overall TMN stage, primary tumour depth, lymph node extra-capsular spread, and poor survival. Her-2 overexpression, however, did not demonstrate a similar association with clinicopathological parameters or therapeutic outcome. On multivariant analysis, EGFR overexpression (P=0.041) and N stage (P=0.024) were the only independent factors for overall survival. These results indicate that the molecular targeting therapy to EGFR may be a treatment for oral cavity cancer in the betel quid-chewing prevalent area.     

Oral carriage of yeasts in two villages in Papua New Guinea

Oral swabs were taken from 194 subjects in two villages in Papua New Guinea. Yeasts were isolated from 103 (53.1%) individuals of which 41 (21.1%) were Candida albicans. A wide variety of other yeasts were also identified.     

Geographical Distribution of Subjects Seropositive for Human T-Cell Leukemia Virus Type 1 in Papua New Guinea

Of 1471 sera collected from 1986 to 1989 in Papua New Guinea (PNG), 2.2% were found to be positive for anti-HTLV-1 antibody by successive particle agglutination and immunofluorescence tests. The seropositive rate varied in different provinces and was higher in the coastal areas of the main island and in neighboring small islands than in the highlands of PNG. The frequency of HTLV-1 infection of children was higher, but the age-dependent increase in antibody positivity, generally observed in other HTLV-1 endemic areas of the world, was not clear in PNG. No difference was observed in antibody prevalence in males and females in this study.     

Tobacco (Kretek) Smoking,Betel Quid Chewing and Risk of Oral Cancer in a Selected Jakarta Population

Purpose: This study aimed to determine the association between tobacco consumption (kretek) and betel quidchewing with oral cancer risk. Materials and Methods: A total of 81 cases of oral cancers were matched with162 controls in this hospital-based study. Information on sociodemographic characteristics and details of riskhabits (duration, frequency and type of tobacco consumption and betel quid chewing) were collected. Associationbetween smoking and betel quid chewing with oral cancer were analysed using conditional logistic regression.Results: Slightly more than half of the cases (55.6%) were smokers where 88.9% of them smoked kretek. Afteradjusting for confounders, smokers have two fold increased risk, while the risk for kretek consumers and thosesmoking for more than 10 years was increased to almost three-fold. Prevalence of betel quid chewing among casesand controls was low (7.4% and 1.9% respectively). Chewing of at least one quid per day, and quid combinationof betel leaf, areca nut, lime and tobacco conferred a 5-6 fold increased risk. Conclusions: Smoking is positivelyassociated with oral cancer risk. A similar direct association was also seen among betel quid chewers.     

Cytotoxic Effects of Betel Quid and Areca Nut Aqueous Extracts on Mouse Fibroblast,Human Mouth-Ordinary-Epithelium 1 and Human Oral Squamous Cell Carcinoma Cell Lines

Background: Betel quid chewing is more common among the older generation in rural areas of Malaysia. Oral cancer in Asia has been associated with the habit of chewing betel quid and areca nut. Objective:  This study aims to investigate the cytotoxic effects of betel quid and areca nut extracts on the fibroblast (L929), mouth-ordinary-epithelium 1 (MOE1) and oral squamous cell carcinoma (HSC-2) cell lines. Methods: L929, MOE1 and HSC-2 cells were treated with 0.1, 0.2 and 0.4 g/ml of betel quid and areca nut extracts for 24, 48 and 72 h. MTT assay was performed to assess the cell viability. Results: Both extracts, regardless of concentration, significantly reduced the cell viability of L929 compared with the control (P<0.05). Cell viability of MOE1 was significantly enhanced by all betel quid concentrations compared with the control (P<0.05). By contrast, 0.4 g/ml of areca nut extract significantly reduced the cell viability of MOE1 at 48 and 72 h of incubation. Cell viability of HSC-2 was significantly lowered by all areca nut extracts, but 0.4 g/ml of betel quid significantly increased the cell viability of HSC-2 (P<0.05). Conclusion: Areca nut extract is cytotoxic to L929 and HSC-2, whereas the lower concentrations of areca nut extract significantly increased the cell viability of MOE1 compared to the higher concentration and control group. Although betel quid extract is cytotoxic to L929, the same effect is not observed in MOE1 and HSC-2 cell lines. Further investigations are needed to clarify the mechanism of action.     

HTLV-I, HIV-I, and Hepatitis B and C Viruses in Western Province, Papua New Guinea: A Serological Survey

Seven hundred and twenty-three serum samples from individuals in 13 Gidra-speaking villages in Western Province, Papua New Guinea were tested for evidence of infection with human T- lymphotropic virus type I (HTLV-I), human immunodeficiency virus type I (HIV-I), hepatitis B virus (HBV) and hepatitis C virus (HCV). No samples were positive for antibodies to HIV-I. Antibodies to HTLV-I were found in 13 samples (1.8%), HBV surface antigens (HBsAg) were found in 86 samples (11.9%), and antibodies to HCV were found in 30 samples (4.1%). Six (46.2%) of 13 HTLV-I positive samples were positive for HCV or HBsAg. The seropositive rate varied in different villages and the incidence of HTLV-I and HCV was higher in coastal and riverine areas than inland.     

Bidi smoking and oral cancer: a meta-analysis

Several epidemiological studies suggest that bidi smoking increases the risk of oral cancer. No systematic review, however, has been reported to examine how consistent the evidence is across the studies. We undertook a meta-analysis of epidemiological studies investigating the relationship between bidi smoking and oral cancer. Primary studies were identified through a computerized literature search of Medline. Articles abstracted were all epidemiological studies published as original articles in English during 1966-2002 that included quantitative information on bidi smoking and oral cancer. Summary odds ratios (OR) were calculated based on random effects model. A total of 12 case-control studies used for this meta-analysis provided the summary estimates of OR of bidi smoking for oral cancer compared to that of non-smokers. An increased risk of oral cancer was found for bidi smokers compared to never smokers (OR = 3.1, 95% confidence interval [CI] 2.0-5.0) whereas no significant pattern of risk was found for cigarette smokers (OR = 1.1, 95% CI = 0.7-1.8). There was substantial heterogeneity in the pooled OR estimate. Our results clearly indicate that bidi smokers are at increased risk of oral cancer. It is important that this information be incorporated into smoking prevention and cessation efforts, particularly among the urban poor and rural mass in South Asian countries where bidi smoking is widely prevalent.     

Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers

Polymorphism in glutathione S-transferase (GST) genes, causing variations in enzyme activities, may influence susceptibility to oral cancer and leukoplakia in smokers and/or smokeless tobacco users. In this case-control study consisting of 109 leukoplakia and 256 oral cancer patients and 259 controls, genotype frequencies at GSTM1, GSTT1, GSTM3 and GSTP1 loci were determined by polymerase chain reaction-restriction fragment length polymorphism methods and analyzed by multiple logistic regression to determine the risks of the diseases. There were no significant differences in the distributions of GSTM1, GSTM3 and GSTT1 genotypes in patients and controls when all individuals were compared. In contrast, frequencies of ile/ile genotype at codon 105 and variant val-ala haplotype of GSTP1 was significantly higher (OR = 1.5; 95% CI = 1.0-2.0) and lower (OR = 1.4; 95% CI = 1.0-1.9) in oral cancer patients compare to controls, respectively. The impacts of all genotypes on risks of oral cancer and leukoplakia were also analyzed in patients with different tobacco habits and doses. Increased risks of cancer and leukoplakia were observed in tobacco smokers with GSTM3 (A/A) genotype (OR = 2.0, 95% CI = 1.0-4.0; OR = 2.0, 95% CI = 1.0-4.4, respectively). So, GSTM3 (A/A) genotype could become one of the markers to know which of the leukoplakia would be transformed into cancer. Heavy tobacco chewing (> 124 chewing-year) increased the risk of cancer in individuals with GSTT1 homozygous null genotype (OR = 3.0; 95% CI = 1.0-9.8). Furthermore, increased lifetime exposure to tobacco smoking (> 11.5 pack-year) increased the risk of leukoplakia in individuals with GSTM1 homozygous null genotype (OR = 2.4; 95% CI = 1.0-5.7). It may be suggested that polymorphisms in GSTP1, GSTM1, GSTM3 and GSTT1 genes regulate risk of cancer and leukoplakia differentially among different tobacco habituals.     

Risk of hepatocellular carcinoma and habits of alcohol drinking,betel quid chewing and cigarette smoking: a cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan

Objectives: Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC) in the world. The specific aim of this study is to assess the associations between the risk of HCC and habits of alcohol drinking, betel quid chewing and cigarette smoking among subjects with and without chronic HBV infection. Methods: A total of 11,837 male residents in Taiwan were recruited in this community-based cohort study. Hepatitis B surface antigen (HBsAg) and antibody against hepatitis C virus (anti-HCV) in serum were determined by enzyme immunoassay, and the habits of alcohol drinking, betel quid chewing and cigarette smoking were collected through standardized personal interview according to a structured questionnaire. During the follow-up period of 91,885 person-years, 115 incident HCC cases were identified through data linkage with national cancer registry profile. The relative risk (RR) of developing HCC for habits of various substance use and chronic HBV infection were estimated by Cox's proportional hazards regression analyses. Results: Significantly increased HCC risk was observed for seropositives of HBsAg or anti-HCV, alcohol drinkers, betel quid chewers and cigarette smokers. There was a significant dose–response relationship between the risk of HCC and the number of habits of substance use. The highest multivariate-adjusted HCC risk was observed among HBsAg-seropositive substance users (RRs: 17.9–26.9), followed by HBsAg-seropositive non-users (RRs: 13.1–19.2), HBsAg-seronegative substance users (RRs: 1.6–2.7) and HBsAg-seronegative non-users (referent with RR = 1). The multivariate-adjusted relative HCC risks for habits of use of various substances were more profound among HBsAg-seronegatives than HBsAg-seropositive ones. Conclusion: Habitual alcohol drinking, betel quid chewing and cigarette smoking are associated with an increased risk of HCC. Abstinence from substance use is important for the prevention of HCC in areas where chronic HBV infection is endemic.     

Dentition,oral hygiene,and risk of oral cancer: a case-control study in Beijing,People's Republic of China

A case-control study of oral cancer was conducted in Beijing, People's Republic of China. The study was hospitalbased and controls were hospital in-patients matched to the cases by age and gender. A total of 404 case/control pairs were interviewed. This paper provides data regarding oral conditions as risk factors for oral cancer, with every patient having an intact mouth examined (pre-operation among cases) using a standard examination completed by trained oral physicians. After adjustment for tobacco smoking and alcohol consumption, poor dentition—as reflected by missing teeth—emerged as a strong risk factor for oral cancer: the odds ratio (OR) for those who had lost 15 – 32 teeth compared to those who had lost none was 5.3 for men and 7.3 for women and the trend was significant (P <0.01) in both genders. Those who reported that they did not brush their teeth also had an elevated risk (OR =6.9 for men, 2.5 for women). Compared to those who had no oral mucosal lesions on examination (OR=1.0), persons with leukoplakia and lichen planus also showed an elevated risk of oral cancer among men and women. Denture wearing per se did not increase oral cancer risk (OR=1.0 for men, 1.3 for women) although wearing metal dentures augmented risk (OR=5.5 for men). These findings indicate that oral hygiene and several oral conditions are risk factors for oral cancer, independently of the known risks associated with smoking and drinking.From the Department of Epidemiology, National Institute of Environmental Health and Engineering, Chinese Academy of Preventive Medicine, Beijing, China (ZT; HH; NS); Unit of Analytical Epidemiology, International Agency for Research on Cancer, Lyon, France (PB; ZT); Beijing Union Hospital (DJ); Cancer Institute, Chinese Academy of Medical Science (JP); Beijing Medical University Stomatological Hospital (MD); Beijing Municipal Stomatological Hospital (SL); University Department of Oral Medicine and Oral Surgery, Bristol Dental Hospital and School, UK (CS); Department of Epidemiology, Harvard School of Public Health (BM; ZT). Address correspondence to Dr Zheng at the Cancer Prevention Research Unit, Yale University, School of Medicine, 26 High Street, New Haven, CT 06510, USA. Dr Zheng was partly supported by a grant from the DuPont Company.     

Smokeless tobacco and increased risk of hypopharyngeal and laryngeal cancers: a multicentric case-control study from India

Hypopharyngeal and laryngeal cancers are among the most common cancers in India. In addition to smoking, tobacco chewing may be a major risk factor for some of these cancers in India. Using data from a multicentric case-control study conducted in India that included 513 hypopharyngeal cancer cases, 511 laryngeal cancer cases and 718 controls, we investigated smoking and chewing tobacco products as risk factors for these cancers. Bidi smoking was a stronger risk factor compared to cigarette smoking for cancer of the hypopharynx (OR(bidi) 6.80 vs. OR(cig) 3.82) and supraglottis (OR(bidi) 7.53 vs. OR(cig) 2.14), while the effect of the 2 products was similar for cancer of the glottis (OR(bidi) 5.32 vs. OR(cig) 5.74). Among never-smokers, tobacco chewing was a risk factor for hypopharyngeal cancer, but not for laryngeal cancer. In particular, the risk of hypopharyngeal cancer increased with the use of Khaini (OR 2.02, CI 0.81-5.05), Mawa (OR 3.17, CI 1.06-9.53), Pan (OR 3.34, CI 1.68-6.61), Zarda (OR 3.58, CI 1.20-10.68) and Gutkha (OR 4.59, CI 1.21-17.49). A strong dose-response relationship was observed between chewing frequency and the risk of hypopharyngeal cancer (p(trend) < 0.001). An effect of alcohol on cancer of the hypopharynx and supraglottis was observed only among daily drinkers (OR 2.22, CI 1.11-4.45 and OR 3.76, CI 1.25-11.30, respectively). In summary, this study shows that chewing tobacco products commercially available in India are risk factors for hypopharyngeal cancer, and that the potency of Bidi smoking may be higher than that of cigarette smoking for hypopharyngeal and laryngeal cancers.     

Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia

Molecular markers for predicting oral cancer development in premalignant oral leukoplakia (OL) are urgently needed. The objective of this study was to examine the expression patterns of cancer stem cell markers ALDH1 and CD133 in samples from patients with OL, and determine their prognostic values for subsequent development of oral cancer. Immunohistochemistry for ALDH1 and CD133 was performed in samples from a cohort of 141 patients with biopsy‐proven OL who received a mean follow‐up of 5.5 years. Patient clinicopathologic and follow‐up data were analyzed. Expression of ALDH1 and CD133 was observed in 54 (38.3%) and 32 (22.7%) of 141 patients with OL, respectively. Kaplan–Meier analysis showed that 48.1% patients with ALDH1‐positivity developed oral cancer compared with 12.6% those with ALDH1‐negativity (p < 0.001). Meanwhile, 59.4% patients with CD133‐positivity developed oral cancer compared with 16.5% those with CD133‐negativity (p < 0.001). Multivariate analysis revealed that ALDH1 and CD133 expression was associated with 4.17‐fold [95% confidence interval (CI), 1.96–8.90; p < 0.001] and 2.86‐fold (95% CI, 1.48‐5.55; p = 0.002) increased risk of OL transformation, respectively. Collectively, these data demonstrated for the first time that the expression of ALDH1 and CD133 correlated with malignant transformation in a large series of patients with OL who received a long‐term follow‐up, which suggests that they may serve as predictors to identify OL with a high risk of oral cancer development.     

Campaign awareness and oral cancer knowledge in UK resident adult Bangladeshi: a cross-sectional study

Background:

This study reports awareness of the ‘Open up to Mouth Cancer'' campaign materials and oral cancer knowledge among two UK adult Bangladeshi communities, both at high risk for oral cancer.

Methods:

Differences in the outcomes of campaign awareness and knowledge of oral cancer risk factors and early signs were compared between campaign and comparison areas. Home-based interviews were conducted with representative samples from both areas by bilingual interviewers. Data collected included a modified 36-item Humphris Oral Cancer Knowledge Scale and socio-demographic information. The data were collected 4 weeks after the campaign completion and analysed using χ²-tests and binary logistic regressions.

Results:

The response rate was 77%. Both awareness of the campaign materials (29.99% (95% confidence interval (CI) 15.82, 46.99) vs 8.12% (95% CI 6.16, 10.62)) and the mean Humphris Oral Cancer Knowledge Scale scores (13.32 (95% CI 11.06, 15.57) vs 8.27 (95% CI 6.59, 9.94)) were higher in the campaign area. The campaign area sample was significantly more likely to be aware of the materials (odds ratio (OR)=6.03, 95% CI 3.00, 12.1).

Conclusion:

Superior awareness and oral cancer knowledge was identified in the community with access to the campaign materials. Further evaluation to identify long-term campaign impact is required.     

Randomized trial of fenretinide (4-HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results

We assessed the efficacy of fenretinide at preventing relapses, new lesions and carcinomas after surgical excision of oral leukoplakia. In a controlled multicenter study, 170 patients operated on for oral leukoplakias with benign postoperative histology were randomized to 200 mg fenretinide daily for 1 year vs. no intervention. Preliminary analysis indicated that fenretinide had good tolerability and was effective at preventing relapses and new lesions during treatment. Analysis after 5-year follow-up suggested that fenretinide protected against relapses and new lesions up to 19 months after randomization, with both limits of the 95% hazard ratio CI for fenretinide vs. control below 1 for 7 months after randomization. There was also a protective effect against all first events, including cancer, for 25 months, with both limits of the 95% CI below 1 up to 11 months after randomization. Subsequently, risk ratio estimates were unstable. Fenretinide was well tolerated and effective at preventing relapses and new leukoplakias during treatment and after. The trial had to be stopped prematurely for very low recruitment and had insufficient power to reveal any protective effect against oral carcinoma; nevertheless, continuing studies on this promising chemopreventive are justified.