Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients

There has been concern that long-term supplementation with high-dose antioxidant vitamins, especially vitamin E (alpha-tocopherol), may increase all-cause mortality. We conducted a randomized controlled trial with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) supplements among 540 head and neck cancer patients treated by radiation therapy. Supplementation with beta-carotene was discontinued during the trial. The supplements were given during radiation therapy and for 3 additional years. During the follow-up (median 6.5 years), 179 deaths were recorded. All death certificates were obtained. All-cause and cause-specific mortality rates were compared between the 2 arms of the trial by Cox regression. All-cause mortality was significantly increased in the supplement arm: hazard ratio: 1.38, 95% confidence interval 1.03-1.85. Cause-specific mortality rates tended to be higher in the supplement arm than in the placebo arm. Our results concur with previous reports to suggest that high-dose vitamin E could be harmful.     

The association between change in body mass index and upper aerodigestive tract cancers in the ARCAGE project: Multicenter case–control study

Previous studies reported an inverse relationship between body mass index (BMI) and upper aerodigestive tract (UADT) cancers. Examining change in BMI over time may clarify these previous observations. We used data from 2,048 cases and 2,173 hospital‐ and population‐based controls from ten European countries (alcohol‐related cancers and genetic susceptibility in Europe study) to investigate the relationship with BMI and adult change in BMI on UADT cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between BMI at three time intervals and BMI change on UADT cancer development, adjusting for center, age, sex, education, fruit and vegetable intake, smoking and alcohol consumption. We found an inverse relationship between UADT cancers and BMI at time of interview and 2 years before interview. No association was found with BMI at 30 years of age. Regarding BMI change between age 30 and 2 years before interview, BMI decrease (BMI change vs. BMI stability (?5% ≤ BMI change <5%) showed no overall association with UADT cancers (OR = 1.15; 95% CI = 0.89, 1.49). An increase in BMI (BMI change ≥+5%) was inversely associated with UADT cancers (OR = 0.74; 95% CI = 0.62, 0.89). BMI gain remained inversely associated across all subsites except for esophageal cancer. When stratified by smoking or by drinking, association with BMI gain was detected only in drinkers and smokers. In conclusion, BMI gain is inversely associated with UADT cancers. These findings may be influenced by smoking and/or drinking behaviors and/or the development of preclinical UADT cancers and should be corroborated in studies of a prospective nature.     

DNA repair gene XRCC2 and XRCC3 polymorphisms and susceptibility to cancers of the upper aerodigestive tract

Cigarette smoke can generate reactive oxygen species, which are capable of inducing double-strand breaks (DSBs) in DNA. Polymorphisms in XRCC2 and XRCC3 genes, involved in DSBs repair pathways, may alter an individual's susceptibility to smoking-related cancers. We investigated the effect of XRCC2 Arg(188)His and XRCC3 Thr(241)Met polymorphisms in cancer proneness in 121 oral/pharynx cancer cases, 129 larynx cancer cases and 172 noncancer controls, all Caucasian smokers. The XRCC2 His-allele was associated with a significantly increased risk of pharyngeal cancer (OR=2.9, 95% CI: 1.3-6.2). No significant associations were observed between the XRCC3 Thr(241)Met polymorphism and overall risk of developing UADT cancers. However, quite opposite to the expectations, a reduced risk of supraglottic cancer was found for carriers of the XRCC3 Met variant allele (OR=0.3, 95% CI: 0.2-0.7). These findings provide evidence for the view that polymorphisms in DNA repair genes may modify individual susceptibility to smoking-related cancers.     

Aspirin use and cancers of the upper aerodigestive tract

The role of aspirin on the risk of cancers of the upper aerodigestive tract was investigated in the combined data of three Italian case-control studies, including 965 cases and 1779 hospital controls. The odds ratio was 0.33 for users of > or = 5 years, and 0.51 for > or = 5 years since first use.     

Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: inefficacy of genetic or pharmacological disruption of COX-2

Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced forestomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive biomarkers COX-2, nuclear factor (NF)-kappa B p65 and leukotriene A(4) hydrolase (LTA(4)H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-2-/- forestomachs displayed strong LTA(4)H immunostaining, indicating activation of an alternative pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer.     

Body mass index change in adulthood and lung and upper aerodigestive tract cancers

Body mass index (BMI) has been inversely associated with lung and upper aerodigestive tract (UADT) cancers. However, only a few studies have assessed BMI change in adulthood in relation to cancer. To understand the relationship between BMI change and these cancers in both men and women, we analyzed data from a population-based case-control study conducted in Los Angeles County. Adulthood BMI change was measured as the proportional change in BMI between age 21 and 1 year before interview or diagnosis. Five categories of BMI change were included, and individuals with no more than a 5% loss or gain were defined as having a stable BMI (reference group). Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated using logistic regression models. Potential confounders included age, gender, ethnicity, education, tobacco smoking and energy intake. For UADT cancers, we also adjusted for alcohol drinking status and frequency. A BMI gain of 25% or higher in adulthood was inversely associated with lung cancer (OR 0.53, 95% CI 0.33-0.84) and UADT cancers (OR 0.44, 95% CI 0.27-0.71). In subgroup analyses, a BMI gain of ≥25% was inversely associated with lung and UADT cancers among current and former smokers, as well as among current and former alcohol drinkers. The inverse association persisted among moderate and heavy smokers (≥20 pack-years). The observed inverse associations between adulthood BMI gain and lung and UADT cancers indicate a potential role for body weight-related biological pathways in the development of lung and UADT cancers.     

Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract

Objectives The purpose of this study was to investigate the role of polymorphisms of genes involved in inflammation in the risk of cancers of the upper aerodigestive tract (UADT). Methods We have evaluated the role of polymorphisms in key genes related to inflammation, namely IL1B (rs1143627), COX2/PTGS2 (rs5275), and IL8 (rs4073) in a large case–control study comprising 811 UADT cancer cases and 1,083 controls. Results An association was observed for squamous cell carcinoma of the pharynx for a polymorphism in the promoter of the IL1B gene, with an OR of 2.39 (95% CI = 1.19–4.81) for the homozygotes for the minor allele A promoter polymorphism of IL8 was associated with decreased risk of laryngeal cancer, with an OR of 0.70 (95% CI = 0.50–0.98) for carriers of the minor allele. Conclusions To our knowledge, this is the first report on the role of these polymorphisms with respect to UADT carcinogenesis. Our results suggest that inflammation-related polymorphisms play a role, albeit minor, in the risk of developing cancers of the upper aerodigestive tract.     

Association between ambient exposure to PM2.5 and upper aerodigestive tract cancer in Los Angeles

Fine particulate matter (PM_2.5) contains carcinogens similar to those generated by tobacco smoking, which may increase the risks of developing smoking-related cancers, such as upper aerodigestive track (UADT) cancers, for both smokers and never-smokers. Therefore, it is imperative to understand the relation between ambient PM_2.5 exposure and risk of UADT cancers. A population-based case–control study involving 565 incident UADT cancer cases and 983 controls was conducted in Los Angeles County from 1999 to 2004. The average residential PM_2.5 concentration 1 year before the diagnosis date for cases and the reference date for controls was assessed using a chemical transport model. The association between ambient PM_2.5 and the UADT cancers was estimated by unconditional logistic regression, adjusting for confounders at the individual and block-group level. Stratified analyses were conducted by sex, tobacco smoking status and UADT subsites. We also assessed the interaction between PM_2.5 and tobacco smoking on UADT cancers. PM_2.5 concentrations were associated with an elevated odds of UADT cancers (adjusted odds ratio = 1.21 per interquartile range [4.5 μg/m³] increase; 95% confidence interval: 1.02, 1.44). The association between PM_2.5 and UADT cancers was similar across UADT subsites, sex and tobacco smoking status. The interaction between PM_2.5 and tobacco smoking on UADT cancers was approximately additive on the odds scale. The effect estimate for PM_2.5 and UADT cancers was similar among never smokers. Our findings support the hypothesis that exposure to PM_2.5 increases the risk of UADT cancers. Improvements in air quality may reduce the risk of UADT cancers.     

Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland)

Objectives: Epidemiological studies have suggested a protective effect of vegetables and fruits on urinary tract cancer but the possible protective nutrients are unknown. We studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation on urinary tract cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: A total of 29,133 male smokers aged 50–69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5–8 years (median 6.1 years). Incident urothelial cancers (bladder, ureter, and renal pelvis; n = 169) and renal cell cancers (n = 102) were identified through the nationwide cancer registry. The diagnoses were centrally confirmed by review of medical records and pathology specimens. The supplementation effects were estimated using a proportional hazards model. Results: Neither alpha-tocopherol nor beta-carotene affected the incidence of urothelial cancer, relative risk 1.1 (95% confidence interval (CI) 0.8–1.5) and 1.0 (95% CI 0.7–1.3), respectively, or the incidence of renal cell cancer, relative risk 1.1 (95% CI 0.7–1.6) and 0.8 (95% CI 0.6–1.3), respectively. Conclusion: Long-term supplementation with alpha-tocopherol and beta-carotene has no preventive effect on urinary tract cancers in middle-aged male smokers.     

Air pollution and incidence of cancers of the stomach and the upper aerodigestive tract in the European Study of Cohorts for Air Pollution Effects (ESCAPE)

Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long‐term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land‐use regression models for particulate matter (PM) below 10 µm (PM₁₀), below 2.5 µm (PM_2.5), between 2.5 and 10 µm (PM_coarse), PM_2.5 absorbance and nitrogen oxides (NO₂ and NO_X) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort‐specific analyses. Combined estimates were determined with random effects meta‐analyses. During average follow‐up of 14.1 years of 305,551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 µg/m³ of PM_2.5 was 1.38 (95% CI 0.99; 1.92) for gastric and 1.05 (95% CI 0.62; 1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM_2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM_2.5 was found in men (HR 1.98 [1.30; 3.01]) as compared to women (HR 0.85 [0.5; 1.45]). This large multicentre cohort study shows an association between long‐term exposure to PM_2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk.     

Soft palatal melanosis,a simple predictor for neoplasia in the upper aerodigestive tract in Japanese alcoholic men

Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. The aim of this study was to evaluate the association between squamous cell neoplasia in the upper aerodigestive tract (UAT) and soft palatal melanosis. We reviewed digitized records of high‐quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening. Soft palatal melanosis was observed in 381 (21.3%) of the subjects (distinct, 6.3%). Older age, an inactive heterozygous aldehyde dehydrogenase‐2 genotype, smoking, and a high mean corpuscular volume were positively associated with the presence of soft palatal melanosis. The age‐adjusted odds ratio (95% confidence interval) for UAT neoplasia was 1.92 (1.40–2.64) in the group with melanosis and 2.51 (1.55–4.06) in the group with distinct melanosis, compared with the melanosis‐free group. A multivariate analysis showed that the presence of soft palatal melanosis was independently associated with a high risk of UAT neoplasia. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, mean corpuscular volume ≥106 fL, and distinct soft palatal melanosis. Compared with the risk‐factor‐free condition, the odds ratio (95% confidence interval) values of UAT neoplasia for one, two, three, and four risk factors were 1.49 (0.97–2.30), 3.14 (2.02–4.88), 4.80 (2.71–8.51), and 7.80 (2.17–28.1), respectively. The presence of soft palatal melanosis provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.     

Effects of alpha-tocopherol and beta-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study,Finland)

Objectives: This study investigated the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of gastric cancer. Methods: A total of 29,133 male smokers, aged 50–69 years, participated in a placebo-controlled prevention trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in southwestern Finland between 1985 and 1993. The men were randomly assigned to receive alpha-tocopherol (50 mg/day) or beta-carotene (20 mg/day) supplementation in a 2 × 2 factorial design. We identified 126 gastric cancer cases during the median follow-up of six years. Of these, 122 were adenocarcinomas: 75 of intestinal type, 30 of diffuse type, and 17 of mixed type. Results: There was no significant effect for either supplementation on the overall incidence of gastric cancer: relative risk (RR) 1.21, 95% confidence interval (CI) 0.85–1.74 for alpha-tocopherol, and RR 1.26, 95% CI 0.88–1.80 for beta-carotene. Subgroup analyses by histologic type suggested an increased risk for beta-carotene on intestinal type cancers, RR 1.59, 95% CI 0.99–2.56. There were no differences across anatomic locations (cardia/noncardia) in the effects of alpha-tocopherol or beta-carotene supplementation. Conclusions: Our study found no overall preventive effect of long-term supplementation with alpha-tocopherol or beta-carotene on gastric cancer in middle-aged male smokers.     

A case-control study of the association of the polymorphisms and haplotypes of DNA ligase I with lung and upper-aerodigestive-tract cancers

Tobacco smoking is a major risk factor for lung and upper-aerodigestive-tract (UADT) cancers. One possible mechanism for the associations may be through DNA damage pathways. DNA Ligase I (LIG1) is a DNA repair gene involved in both the nucleotide excision repair (NER) and the base excision repair (BER) pathways. We examined the association of 4 LIG1 polymorphisms with lung and UADT cancers, and their potential interactions with smoking in a population-based case-control study in Los Angeles County. We performed genotyping using the SNPlex method from Applied Biosystems. Logistic regression analyses of 551 lung cancer cases, 489 UADT cancer cases and 948 controls showed the expected associations of tobacco smoking with lung and UADT cancers and new associations between the LIG1 haplotypes and these cancers. For lung cancer, when compared to the most common haplotype (rs20581-rs20580-rs20579-rs439132 = T-C-C-A), the adjusted odds ratio (OR) is 1.2 (95% confidence limits (CL) = 0.95, 1.5) for the CACA haplotype, 1.4 (1.0, 1.9) for the CATA haplotype and 1.8 (1.1, 2.8) for the CCCG haplotype, after controlling for age, gender, race/ethnicity, education and tobacco smoking. We observed weaker associations between the LIG1 haplotypes and UADT cancers. Our findings suggest the LIG1 haplotypes may affect the risk of lung and UADT cancers.     

Low doses of beta-carotene and lutein inhibit AOM-induced rat colonic ACF formation but high doses augment ACF incidence

Epidemiological studies suggest that carotenoids such as beta-carotene and lutein play an important role in reducing the risk for several cancers. However, in colon cancer there is ambiguity with regard to the role of these compounds in that both preventive effects and tumor promotion have been observed. In the present study we observed that male F344 rats were able to tolerate up to 2,500 ppm of beta-carotene as well as of lutein. We have then assessed the chemopreventive efficacy of beta-carotene and lutein at dose levels of approximately 4 and 8% of the 2,500 ppm tolerated dose (TD) and also approximately 40 and 80% of the TD on azoxymethane (AOM)-induced colon carcinogenesis, using aberrant crypt foci (ACF) as a surrogate biomarker for colon cancer. Throughout the experiments, 5-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 100 or 200 ppm (approximately 4 or 8% of the 2,500 ppm TD), or 1,000 or 2,000 ppm ( approximately 40 or 80% of the 2,500 ppm TD) of beta-carotene and lutein (n=10 rats/group). After 2 weeks on the experimental or control diets, all animals were injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 14 weeks of age, all rats were killed, and their colons were evaluated for ACF. Administration of 100 or 200 ppm of beta-carotene inhibited AOM-induced total colonic ACF formation by 24% (p<0.01) and 36% (p<0.001), respectively, whereas lutein at 200 ppm produced a 27% inhibition (p<0.01) yet had no significant effect at the 100 ppm dose level. Surprisingly, administration of 1,000 or 2,000 ppm of beta-carotene and lutein increased colonic ACF formation in a dose-dependent manner, i.e., to 124% and 144% for the former and 110% and 159% for the latter. These results clearly suggest that further studies are warranted to determine whether the increase in ACF incidence by high doses of beta-carotene and lutein will also lead to an increase in tumor outcome. Taken together these data indicate that the chemopreventive activity of beta-carotene and lutein against colon carcinogenesis depends on the dose level.     

Effects of α‐tocopherol and β‐carotene supplementation on cancer incidence and mortality: 18‐Year postintervention follow‐up of the Alpha‐Tocopherol,Beta‐Carotene Cancer Prevention Study

In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50–69 years, daily α‐tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β‐carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α‐tocopherol and β‐carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post‐trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β‐carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89–1.05) among α‐tocopherol recipients compared with nonrecipients with the preventive effect of α‐tocopherol continuing ～8 years postintervention. Body mass index significantly modified the effect of α‐tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88–1.14) in normal‐weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post‐trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α‐tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β‐carotene recipients compared with nonrecipients. α‐Tocopherol decreased post‐trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β‐carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α‐tocopherol and β‐carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate‐dose α‐tocopherol on prostate cancer continued several years post‐trial and resulted in lower prostate cancer mortality.     

Family history of prostate cancer and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

Prostate cancer family history has been associated with increased risk of the malignancy. Most prior studies have been retrospective and subject to recall bias, however, and data evaluating interactions with other important risk factors are limited. We examined the relationship between a family history of prostate cancer and prostate cancer risk in relation to body size, micronutrients and other exposures in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of Finnish male smokers. Family history of cancer information was self-reported once during the study in 1991, and anthropometry was measured by trained personnel. Among 19,652 men with complete data, 1,111 incident cases were identified during up to 12.3 years of follow-up. A first-degree family history of prostate cancer was associated with an overall relative risk (RR) of 1.91 (95% CI = 1.49-2.47) and a RR of 4.16 (95% CI = 2.67-6.49) for advanced disease (stage >or= 3), adjusted for age and trial intervention. Our data also suggest that to some degree, height, body mass index, and serum alpha-tocopherol and beta-carotene modify the family history and prostate cancer association, although the interactions were not statistically significant. Supplementation with vitamin E or beta-carotene did not modify the family history-prostate cancer association. This study provides additional evidence that family history is a significant risk factor for prostate cancer.     

Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial

Randomized trials have shown, unexpectedly, that supplementation with selenium or vitamin E is associated with a reduction of prostate cancer risk. We assess whether a supplementation with low doses of antioxidant vitamins and minerals could reduce the occurrence of prostate cancer and influence biochemical markers. The SU.VI.MAX trial comprised 5,141 men randomized to take either a placebo or a supplementation with nutritional doses of vitamin C, vitamin E, beta-carotene, selenium and zinc daily for 8 years. Biochemical markers of prostate cancer risk such as prostate-specific antigen (PSA) and insulin-like growth factors (IGFs) were measured on plasma samples collected at enrollment and at the end of follow-up from 3,616 men. Cox regression models were used to estimate the hazard ratio and related 95% confidence interval of prostate cancer associated with the supplementation and to examine whether the effect differed among predetermined susceptible subgroups. During the follow-up, 103 cases of prostate cancer were diagnosed. Overall, there was a moderate nonsignificant reduction in prostate cancer rate associated with the supplementation (hazard ratio = 0.88; 95% CI = 0.60-1.29). However, the effect differed significantly between men with normal baseline PSA (< 3 microg/L) and those with elevated PSA (p = 0.009). Among men with normal PSA, there was a marked statistically significant reduction in the rate of prostate cancer for men receiving the supplements (hazard ratio = 0.52; 95% CI = 0.29-0.92). In men with elevated PSA at baseline, the supplementation was associated with an increased incidence of prostate cancer of borderline statistical significance (hazard ratio = 1.54; 95% CI = 0.87-2.72). The supplementation had no effect on PSA or IGF levels. Our findings support the hypothesis that chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals.     

Treatment of oral leukoplakia with a low‐dose of beta‐carotene and vitamin C supplements: A randomized controlled trial

Management of oral leukoplakia—a potentially malignant disorder—is currently not evidence‐based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi‐centre, randomized, double‐blind controlled trial (RCT) was undertaken to evaluate the use of low‐dose beta‐carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day^?1 of beta‐carotene and 500 mg day^?1 of vitamin C) or placebo arm (50 mg day^?1 of vitamin C). Current or ex‐smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1‐year and the likelihood of malignant transformation during a 5‐year follow‐up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p = 0.346). During the median 60‐month follow‐up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention‐to‐treat principle, relative risk by supplementing with beta‐carotene and vitamin C was 0.77 (95%CI: 0.28–1.89) (p = 0.580) by the Cox proportional hazards model. No unfavorable side‐effects were noted. Beta‐carotene (10 mg day^?1) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia.