beta-carotene and Head-and-Neck-Neoplasms

Topics: alpha-Tocopherol; Anticarcinogenic Agents; Antioxidants; beta Carotene; Biomarkers, Tumor; Double-Blind Method; Head and Neck Neoplasms; Humans; Multicenter Studies as Topic; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Radiotherapy; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Failure; Treatment Outcome

Chemoprevention of cancer is reviewed from the viewpoints of action mechanisms and methodology of clinical trials in order to introduce promising agents discovered by in vitro and/or in vivo studies to applications in humans. The clinical trial procedure essentially follows the phase study which has been employed for chemotherapeutic drugs. Chemoprevention of bladder cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, breast cancer, head and neck cancer, colorectal cancer and lung cancer is reviewed, mainly focusing on clinical trials. Previous clinical trials have shown the effectiveness of the following: polyprenoic acid (acyclic retinoid) for hepatocellular carcinoma; tamoxifen for breast cancer; retinoic acids for head and neck tumor; and aspirin, a COX-2 inhibitor, for colorectal cancer. Despite the advantageous effects of some of these agents, their toxic effects must also be of concern at the same time. For example, in a chemoprevention trial of lung cancer, beta-carotene was unexpectedly found to increase the risk of lung cancer among high-risk groups. It is also noted that large-scale clinical trials demand large research grants, which may not be affordable in Japan. Chemoprevention is still an emerging field of oncology where researchers in both basic and clinical sciences face great challenges.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; beta Carotene; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasms; Prostatic Neoplasms; Tamoxifen; Tretinoin; Urinary Bladder Neoplasms

Topics: Anticarcinogenic Agents; Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Chemoprevention; Head and Neck Neoplasms; Humans; Leukoplakia, Oral; Retinoids; Tea

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.

Topics: beta Carotene; Biomarkers, Tumor; Clinical Trials as Topic; Head and Neck Neoplasms; Humans; Leukoplakia; Lung Neoplasms; Precancerous Conditions; Retinoids; Vitamin A

This manuscript will review the probable role of reactive oxygen metabolites (ROM) in the etiopathogenesis of head and neck cancer (HNC). Cancer is a heterogeneous disorder with multiple etiologies including somatic and germ-line mutations, cellular homeostatic disturbances, and environmental triggers. Certain etiologies are characteristic of HNC and include infectious agents such as the Epstein-Barr virus, the use of tobacco, and consumption of alcohol. A large body of evidence implicates ROM in tumor formation and promotion. ROM species are formed in the process of cellular respiration, specifically during oxidative phosphorylation. These ubiquitous molecules are highly toxic in the cellular environment. Of the many effects of ROM, especially important are their effect on DNA. Specifically, ROM cause a variety of DNA damage, including insertions, point mutations, and deletions. Thus, it is hypothesized that ROM may be critically involved in the etiology of malignant disease through their possible impact on protooncogenes and tumor suppressor genes. Additionally, empirical evidence suggests that ROM may also affect the balance between apoptosis and cellular proliferation. If apoptotic mechanisms are overwhelmed, uncontrolled cellular proliferation may follow, potentially leading to tumor formation. Thus, this manuscript will critically review the evidence that supports the role of ROM in tumorigenesis. ROM scavengers and blockers have shown both in vivo and in vitro effects of attenuating the toxicity of ROM. Such compounds include the antioxidant vitamins (A, C, and E), nutrient trace elements (selenium), enzymes (superoxide dismutase, glutathione peroxidase, and catalase), hormones (melatonin), and a host of natural and synthetic compounds (lazaroids, allopurinol, gingko extract). Thus, this paper will also review the possible benefit derived from the use of such scavengers/blockers in the prevention of HNC.

Topics: Animals; Antioxidants; Apoptosis; beta Carotene; Chemoprevention; Diet; Head and Neck Neoplasms; Humans; Reactive Oxygen Species; Vitamin E

Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions.

Topics: beta Carotene; Biomarkers, Tumor; Diet; Genetic Predisposition to Disease; Genotype; Head and Neck Neoplasms; Humans; Incidence; Neoplasms, Second Primary; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retinoids; Risk; Smoking; Vitamin A

Second primary cancers often occur in head and neck cancer patients successfully treated by radiation therapy. Experimental and epidemiological data suggest that these second primaries might be prevented by antioxidant vitamins, in particular beta-carotene and alpha-tocopherol. A randomized double-blind clinical trial is being conducted in Canada to determine whether vitamin supplementation with beta-carotene (30 mg/d) and alpha-tocopherol (400 IU/d) reduces the incidence of second primaries in head and neck cancer patients treated by radiation therapy.

Topics: Acetylcysteine; Antineoplastic Agents; Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Follow-Up Studies; Head and Neck Neoplasms; Humans; Neoplasm Staging; Neoplasms, Second Primary; Risk Factors; Vegetables; Vitamin A; Vitamin E; Vitamins

Topics: Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Head and Neck Neoplasms; Humans; Isotretinoin

A brief review is presented of various ongoing chemoprevention studies on head and neck cancer. Although beta carotene and several retinoids seem to be effective, scientific proof is at yet insufficient. The need of biomarkers as intermediate end-points is stressed.

Topics: Anticarcinogenic Agents; Antioxidants; beta Carotene; Biomarkers; Head and Neck Neoplasms; Humans; Precancerous Conditions; Retinoids

Chemoprevention entails using specific agents to suppress carcinogenesis and thereby prevent the development of primary or second primary cancers. Because the concept of chemoprevention in patients with or at risk of lung cancer is new, ongoing clinical trials are based on data from epidemiologic and preclinical research, as well as on results of chemoprevention studies in head and neck cancer. The latter studies have provided a model for such studies in lung cancer, considering the two diseases have a similar etiology and biology of field carcinogenesis. Beta-carotene, natural vitamin A, and the retinoids may be effective chemopreventive agents. However, chronic administration of such agents may be required to prevent the development of cancer. Results of chemoprevention trials in head and neck cancer have demonstrated effective inhibition of the development of second primary tumors with the synthetic retinoid 13-cis-retinoic acid; investigators are hopeful this will be repeated in patients with lung cancer. Results of ongoing phase III trials and continued advances in the epidemiologic and biologic study of lung carcinogenesis should contribute to future research in this area.

Topics: beta Carotene; Carotenoids; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia, Oral; Lung Neoplasms; Neoplasms, Second Primary; Risk Factors; Vitamin A

Topics: Animals; Anticarcinogenic Agents; beta Carotene; Carotenoids; Diet; Global Health; Head and Neck Neoplasms; Humans; Neoplasms, Experimental; Prospective Studies; Respiratory Tract Neoplasms; Retrospective Studies; Risk; Rodentia; Smoking; United States; Vitamin A

Topics: Alcohol Drinking; Animals; Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Differentiation; Clinical Trials as Topic; Cricetinae; Diet; Drug Screening Assays, Antitumor; Head and Neck Neoplasms; Humans; Leukoplakia, Oral; Mesocricetus; Respiratory Tract Neoplasms; Smoking; United States; Vitamin A

The purpose of the study was to identify factors associated with weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer.. This study was conducted as part of a phase III chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Patients' characteristics, dietary intake, health-related quality of life (HRQOL), tumor characteristic, treatment characteristics, and acute adverse effects of RT were evaluated at baseline and during RT. Factors independently associated with weight loss during RT were identified using the multiple linear regression (P ≤ 0.05).. The mean weight loss during RT was 2.2 kg (standard deviation, 3.4). In bivariate analyses, the occurrence of adverse effects of RT and most of the HRQOL dimensions evaluated during RT were correlated with weight loss. In the multivariate analysis, eight factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P < 0.001), TNM stage II disease (P = 0.01), higher pre-RT body weight (P < 0.001), dysphagia before RT (P < 0.005), higher mucosa adverse effect of RT (P = 0.03), lower dietary energy intake during RT (P < 0.001), lower score of the digestive dimension on the Head and Neck Radiotherapy Questionnaire (P < 0.001) and a higher score of the constipation symptom on the EORTC QLQ-C30 during RT (P = 0.02).. The results underline the importance of maintaining energy intake in early stage HN cancer patients during RT and the importance of preventing and treating adverse effects.

Topics: alpha-Tocopherol; beta Carotene; Body Weight; Carcinoma, Squamous Cell; Causality; Chemoprevention; Chemoradiotherapy; Comorbidity; Double-Blind Method; Eating; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mucositis; Neoplasm Staging; Neoplasms, Second Primary; Population Surveillance; Quality of Life; Radiotherapy; Risk Factors; Surveys and Questionnaires; Weight Loss

Radiation therapy (RT) causes acute and late toxicities that affect various organs and functions. In a large cohort of patients treated with RT for localized head and neck cancer (HNC), we prospectively assessed the occurrence of RT-induced acute and late toxicities and identified characteristics that predicted these toxicities.. We conducted a randomized trial among 540 patients treated with RT for localized HNC to assess whether vitamin E supplementation could improve disease outcomes. Adverse effects of RT were assessed using the Radiation Therapy Oncology Group Acute Radiation Morbidity Criteria during RT and one month after RT, and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme at six and 12 months after RT. The most severe adverse effect among the organs/tissues was selected as an overall measure of either acute or late toxicity. Grade 3 and 4 toxicities were considered as severe. Stepwise multivariate logistic regression models were used to identify all independent predictors (p < 0.05) of acute or late toxicity and to estimate odds ratios (OR) for severe toxicity with their 95% confidence intervals (CI).. Grade 3 or 4 toxicity was observed in 23% and 4% of patients, respectively, for acute and late toxicity. Four independent predictors of severe acute toxicity were identified: sex (female vs. male: OR = 1.72, 95% confidence interval [CI]: 1.06-2.80), Karnofsky Performance Status (OR = 0.67 for a 10-point increment, 95% CI: 0.52-0.88), body mass index (above 25 vs. below: OR = 1.88, 95% CI: 1.22-2.90), TNM stage (Stage II vs. I: OR = 1.91, 95% CI: 1.25-2.92). Two independent predictors were found for severe late toxicity: female sex (OR = 3.96, 95% CI: 1.41-11.08) and weight loss during RT (OR = 1.26 for a 1 kg increment, 95% CI: 1.12-1.41).. Knowledge of these predictors easily collected in a clinical setting could help tailoring therapies to reduce toxicities among patients treated with RT for HNC.

Topics: Acute Disease; beta Carotene; Body Mass Index; Confidence Intervals; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Karnofsky Performance Status; Logistic Models; Male; Middle Aged; Neoplasm Staging; Odds Ratio; Prospective Studies; Quebec; Radiation Injuries; Sex Factors; Vitamin E; Vitamins; Weight Loss

Although smoking and alcohol consumption are the major risk factors for upper aerodigestive tract cancers, observational studies indicate a protective role for fruits, vegetables, and antioxidant nutrients.. The authors examined whether daily supplementation with 50 mg dl alpha-tocopheryl acetate and/or 20 mg beta-carotene reduced the incidence of or mortality from oral/pharyngeal, esophageal, and laryngeal cancers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a double-blind, placebo-controlled primary prevention trial conducted in southwestern Finland. A total of 29,133 male smokers, aged 50-69 years and free of cancer at baseline, were randomized in a 2 x 2 factorial design to the supplementation regimen for 5-8 years (median, 6.1 years). Incident cancers of the oral cavity and pharynx (n = 65), esophagus (n = 24), and larynx (n = 56) were identified through the Finnish Cancer Registry. Intervention effects were assessed using survival analysis and proportional hazards models.. There was no effect of either agent on the overall incidence of any upper aerodigestive tract cancer. For larynx, however, exploratory subgroup analyses were suggestive of a protective effect of beta-carotene supplementation on the incidence of early stage malignancies (stage I, relative risk [RR], 0.28, 95% confidence interval [CI]: 0.10-0.75). Neither agent affected mortality from these neoplasms.. The results do not provide support for a protective effect of vitamin E or beta-carotene supplementation on upper aerodigestive tract cancers, although beta-carotene supplementation may impact the incidence of some subtypes of laryngeal tumors.

Topics: Aged; alpha-Tocopherol; beta Carotene; Dietary Supplements; Double-Blind Method; Head and Neck Neoplasms; Humans; Incidence; Male; Middle Aged; Primary Prevention; Smoking; Vitamins

There is a debate concerning the effects of antioxidant vitamins during radiation therapy: Can they reduce the adverse effects of therapy without reducing treatment efficacy? We examined whether dietary and plasma beta carotene and alpha tocopherol were related to severe acute adverse effects of radiation therapy and to cancer local recurrence. We conducted a prospective study of 540 head and neck cancer patients treated by radiation therapy. Dietary intakes of beta carotene and alpha tocopherol were measured by a validated food frequency questionnaire and plasma levels were determined. Acute adverse effects of radiation therapy and local recurrence were documented. A higher beta carotene dietary intake was associated with fewer severe acute adverse effects: odds ratio (OR) = 0.61 [95% confidence interval (CI) = 0.40-0.93]. There was a tendency for a similar effect for plasma beta carotene: OR = 0.73 (95% CI = 0.48-1.11). Participants with higher plasma beta carotene had a significantly lower rate of local recurrence (hazard ratio = 0.67; 95% CI = 0.45-0.99). Alpha tocopherol was not related to severe adverse effects or to cancer recurrence. This study suggests that a higher usual dietary beta carotene intake can reduce the occurrence of severe adverse effects of radiation therapy and decrease local cancer recurrence.

Topics: alpha-Tocopherol; Antioxidants; beta Carotene; Confidence Intervals; Diet; Dietary Supplements; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Odds Ratio; Prospective Studies; Radiation Injuries; Surveys and Questionnaires

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.

Topics: alpha-Tocopherol; Antioxidants; beta Carotene; Dietary Supplements; Head and Neck Neoplasms; Humans; Placebos; Survival Analysis; Vitamins

Although low dietary intakes of antioxidant vitamins and minerals have been associated with higher risks of cancer, results of trials testing antioxidant supplementation for cancer chemoprevention have been equivocal. We assessed whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer.. We conducted a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between October 1, 1994, and June 6, 2000. Supplementation with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. In the course of the trial, beta-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received alpha-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.. After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with alpha-tocopherol. The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms.. alpha-Tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.

Topics: Adult; Aged; alpha-Tocopherol; Anticarcinogenic Agents; Antioxidants; beta Carotene; Confounding Factors, Epidemiologic; Double-Blind Method; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Incidence; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Odds Ratio; Proportional Hazards Models; Radiotherapy; Survival Analysis; Treatment Failure

Many cancer patients take antioxidant vitamin supplements with the hope of improving the outcome of conventional therapies and of reducing the adverse effects of these treatments. A randomized trial was conducted to determine whether supplementation with antioxidant vitamins could reduce the occurrence and severity of acute adverse effects of radiation therapy and improve quality of life without compromising treatment efficacy.. We conducted a randomized, double-blind, placebo-controlled trial among 540 head and neck cancer patients treated with radiation therapy. Patients were randomly assigned into two arms. The supplementation with alpha-tocopherol (400 IU/d) and beta-carotene (30 mg/d) or placebos was administered during radiation therapy and for 3 years thereafter. During the course of the trial, supplementation with beta-carotene was discontinued because of ethical concerns.. Patients randomly assigned in the supplement arm tended to have less severe acute adverse effects during radiation therapy (odds ratio [OR], 0.72; 95% CI, 0.52 to 1.02). The reduction was statistically significant when the supplementation combined alpha-tocopherol and beta-carotene for adverse effects to the larynx (OR, 0.38; 95% CI, 0.21 to 0.71) and overall at any site (OR, 0.38; 95% CI, 0.20 to 0.74). Quality of life was not improved by the supplementation. The rate of local recurrence of the head and neck tumor tended to be higher in the supplement arm of the trial (hazard ratio, 1.37; 95% CI, 0.93 to 2.02).. Supplementation with high doses of alpha-tocopherol and beta-carotene during radiation therapy could reduce the severity of treatment adverse effects. However, this trial suggests that use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment efficacy.

Topics: Acute Disease; alpha-Tocopherol; Analysis of Variance; Antioxidants; beta Carotene; Chi-Square Distribution; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Proportional Hazards Models; Quality of Life; Radiation Injuries; Survival Analysis

Supplemental beta-carotene has been shown to increase lung cancer risk in recent chemoprevention trials, especially in current smokers. Several possible mechanisms for this effect have been suggested based upon in vitro and animal studies, but mechanistic data from human studies to explain the excess risk are lacking. beta-Carotene has both antioxidant and prooxidant effects in vitro; therefore, we evaluated whether or not high-dose supplemental beta-carotene might have prooxidant effects in vivo, especially in current smokers taking high-dose supplemental beta-carotene for several years (median 4.0 yr). Urine samples (n = 55 total) were collected from both smokers and nonsmokers participating in a multiyear randomized chemoprevention trial of supplemental beta-carotene (50 mg/day) versus placebo. Samples were analyzed by GC/MS for total isoprostanes and for 8-iso-prostaglandin F2 (8-iso-PGF2), stable end products of lipid peroxidation in vivo. Smokers had higher levels of both total isoprostanes and 8-iso-PGF2. Smokers and nonsmokers randomized to beta-carotene had nonsignificantly lower concentrations of total isoprostanes and of 8-iso-PGF2 [mean +- SD 8-iso-PGF2/ml = 2.00 +- 1.72 (placebo smoker); 1.72 +- 1.66 (beta-carotene smoker); 1.22 +- 0.68 (placebo nonsmoker); 0.97 +- 0.62 (beta-carotene nonsmoker)]. These results indicate that supplemental beta-carotene, even when given at high doses for many years, does not have prooxidant effects in either smokers or nonsmokers, as measured by urinary excretion of F2-isoprostanes.

Topics: Adult; Aged; Anticarcinogenic Agents; Antioxidants; beta Carotene; Dietary Supplements; Double-Blind Method; F2-Isoprostanes; Gas Chromatography-Mass Spectrometry; Head and Neck Neoplasms; Humans; Lipid Peroxidation; Longitudinal Studies; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Placebos; Smoking

Beta-carotene has established efficacy in animal models of oral carcinogenesis and has been shown to regress oral precancerous lesions in humans. The purpose of this study was to see whether these effects extended to the prevention of oral/pharyngeal/laryngeal (head and neck) cancer in humans. The subject population for this randomized, placebo-controlled, double-blinded clinical trial included 264 patients who had been curatively treated for a recent early-stage squamous cell carcinoma of the oral cavity, pharynx, or larynx. Patients were assigned randomly to receive 50 mg of beta-carotene per day or placebo and were followed for up to 90 months for the development of second primary tumors and local recurrences. After a median follow-up of 51 months, there was no difference between the two groups in the time to failure [second primary tumors plus local recurrences: relative risk (RR), 0.90; 95% confidence interval (CI), 0.56-1.45]. In site-specific analyses, supplemental beta-carotene had no significant effect on second head and neck cancer (RR, 0.69; 95% CI, 0.39-1.25) or lung cancer (RR, 1.44; 95% CI, 0.62-3.39). Total mortality was not significantly affected by this intervention (RR, 0.86; 95% CI, 0.52-1.42). Whereas none of the effects were statistically significant, the point estimates suggested a possible decrease in second head and neck cancer risk but a possible increase in lung cancer risk. These effects are consistent with the effects observed in trials using intermediate end point biological markers in humans, in which beta-carotene has established efficacy in oral precancerous lesions but has no effect or slightly worsens sputum cytology, and in animal carcinogenicity studies, in which beta-carotene has established efficacy in buccal pouch carcinogenesis in hamsters but not in animal models of respiratory tract/lung carcinogenesis, with some suggestions of tumor-promoting effects in respiratory tract/lung. If our results are replicated by other ongoing/completed trials, this suggests a critical need for mechanistic studies addressing differential responses in one epithelial site (head and neck) versus another (lung).

Topics: Adult; Aged; Anticarcinogenic Agents; Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Dietary Supplements; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasms, Second Primary; Placebos

High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity.. In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months.. In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy.. When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Female; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Remission Induction

Topics: Administration, Oral; Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Connecticut; Diet Surveys; Double-Blind Method; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Incidence; Male; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Patient Compliance; Risk Factors; Treatment Failure

Experimental studies suggest that carotenoids and retinol may play a role in carcinogenesis, but epidemiological evidence is lacking. We investigated the prospective associations between plasma concentrations of major carotenoids and retinol, and overall and breast cancer risk. A nested case-control study included all first incident cancer cases diagnosed in the SU.VI.MAX cohort between 1994 and 2002 (n = 159 cases, 1 matched control/case). Baseline plasma concentrations of carotenoids and retinol were measured by high-performance liquid chromatography. Conditional logistic regression was used to assess odds ratios for an increase of 0.1 μmol/L [odds ratio (OR)] and 95% confidence intervals (CI). Plasma β-carotene (OR = 0.95, 95% CI = 0.90-0.99, Ptrend = 0.04) and β-cryptoxanthin concentrations (OR = 0.89, 95% CI = 0.81-0.99, Ptrend = 0.03) were inversely associated with overall cancer risk. Plasma β-cryptoxanthin concentration was inversely associated with breast cancer risk (OR = 0.83, 95% CI = 0.71-0.96, Ptrend = 0.02). The OR between plasma lycopene concentration and overall cancer risk was 1.07 (0.99-1.15), Ptrend = 0.06. This association turned significant (Ptrend = 0.01) when excluding cancer cases diagnosed during the first year of follow-up. This prospective study suggests an inverse association between plasma concentrations of β-cryptoxanthin and both overall and breast cancer risk, and an inverse association between β-carotene and overall cancer risk. The direct association between lycopene concentration and cancer risk deserves further investigation.

Topics: Adult; beta Carotene; Body Mass Index; Breast Neoplasms; Carotenoids; Case-Control Studies; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Cryptoxanthins; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Logistic Models; Lung Neoplasms; Lycopene; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Vitamin A

The aim of our study was to compare plasma carotenoids (i.e., biomarkers of fruits and vegetables intake) and tocopherols in 29 head and neck squamous cell carcinoma (HNSCC) patients with 51 healthy controls and to explore the possibility whether these plasma antioxidants could be related to outcome among patients. The patients' blood samples were taken at the end of radiotherapy. We observed that plasma lutein, zeaxanthin, alpha-carotene, beta-carotene, lycopene, and total carotenoids were significantly lower in HNSCC patients than controls. Among the patients, 18 died and 11 were still alive during median follow-up of 55 mo for survivors. We found a significant positive association between postradiotherapy plasma carotenoids (lutein, alpha-carotene, and beta-carotene) and progression-free survival in these patients. This study indicates that increasing postradiotherapy plasma carotenoid concentration may reduce risk of premature death or recurrence of tumor in HNSCC patients. Increasing plasma carotenoid concentration should be done by increasing intake of carotenoid-rich fruits and vegetables, as other studies have shown either no or negative effects due to use of carotenoid supplements.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Disease-Free Survival; Female; Head and Neck Neoplasms; Humans; Lutein; Male; Middle Aged; Tocopherols

Smoking negatively affects serum carotenoid levels, and it is a negative prognostic factor for head and neck cancer. In this study, micronutrient levels were examined in 60 smoking and non-smoking head and neck cancer patients. The goal was to determine if oxidation of the carotenoid lycopene would occur to a greater extent in smokers. Subjects were drawn from a prospective cohort study and matched on seven demographic factors. Serum levels of alpha-carotene, zeaxanthin, and 2,6-cyclolycopene-1,5-diol A, an oxidation product of lycopene, were all lower in smokers versus non-smokers (18%, 22%, and 8%, respectively) while beta-carotene, beta-cryptoxanthin, and lutein were about the same in the two groups. Levels of lycopene, gamma-tocopherol, and alpha-tocopherol were higher in smokers, and notably serum alpha-tocopherol was 48% higher in smokers. The majority of vitamin E intake was from supplements. The higher levels of alpha-tocopherol in smokers were interesting in that higher alpha-tocopherol levels have been associated with higher mortality in head and neck cancer. Although this was a pilot investigation, there was no evidence that 2,6-cyclolycopene-1,5-diol A formation was appreciably affected by smoking status, but alpha-tocopherol levels were higher in smokers.

Topics: Adult; Aged; alpha-Tocopherol; beta Carotene; Carotenoids; Case-Control Studies; Cohort Studies; Cryptoxanthins; Diet Records; Female; gamma-Tocopherol; Head and Neck Neoplasms; Humans; Lutein; Lycopene; Male; Micronutrients; Middle Aged; Neoplasms, Squamous Cell; Oxidative Stress; Pilot Projects; Prospective Studies; Smoking; Xanthophylls; Zeaxanthins

Topics: alpha-Tocopherol; Antioxidants; beta Carotene; Head and Neck Neoplasms; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic; Smoking; Vitamin A

Joint modelling of longitudinal and survival data has received much attention in recent years. Most have concentrated on a single longitudinal variable. This paper considers joint modelling in the presence of multiple longitudinal variables. We explore direct association of time-to-event and multiple longitudinal processes through a frailty model and use a mixed effects model for each of the longitudinal variables. Correlations among the longitudinal variables are induced through correlated random effects. We allow effects of categorical and continuous covariates on both longitudinal and time-to-event responses and explore interactions between the longitudinal variables and other covariates on time-to-event. Estimates of the parameters are obtained by maximizing the joint likelihood for the longitudinal variable processes and the event process. We use a one-step-late EM algorithm to handle the direct dependence of the event process on the modelled longitudinal variables along with the presence of other fixed covariates in both processes. We argue that such a joint analysis with multiple longitudinal variables is advantageous to one with only a single longitudinal variable in revealing interplay among multiple longitudinal variables and the time-to-event.

Topics: beta Carotene; Head and Neck Neoplasms; Humans; Likelihood Functions; Longitudinal Studies; Monte Carlo Method; Multivariate Analysis; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Survival Analysis

Retinoid is one of the most promising substances for chemoprevention and anti-cancer effect. Retinoid has the following reported actions: induction of cell differentiation, control of cancer growth, repair of the precancerous lesion, prevention of the secondary carcinogenesis, control of angiogenesis and prevention of metastasis, and immunostimulation. In the present study, retinoid modified the cell cycle, reinforced the G1 check mechanism which is lost in cancer cells and induced apoptosis. Retinoid augmented the membrane permeability of anti-cancer drugs such as 5-FU, and reduced the exocytosis of anti-cancer drugs by suppressing the expression of the transport protein cMOAT. Retinoid also suppressed the invasive growth of the cancer cells. With the FAR therapy regimen (5-FU and retinil palmitate with radiation) and subsequent surgery, the disease-specific five-year survival rate was close to 50% in various head and neck cancers. Thus, the chemoprevention and anti-cancer effects of retinoid may play an important role in the preservation of organs and QOL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; beta Carotene; Cell Division; Combined Modality Therapy; Female; Fluorouracil; Genes, MDR; Head and Neck Neoplasms; Humans; Male; Retinoids

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Mouth Neoplasms; Time Factors; Treatment Outcome

Topics: beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms

Second primary tumors constitute one of the most challenging problems in head and neck cancer. Their etiology is not yet fully understood. For this reason, we studied the relationships of vitamins A and E and beta-carotene serum levels in patients with head and neck cancer with and without second primary tumors. The results indicate lowered levels of beta-carotene in both groups of patients, while the levels of vitamin A and vitamin E were statistically significantly lower in patients with second tumors than in the group with a single head and neck cancer. This suggests that low vitamin A and vitamin E levels may play a role in the etiology of second tumors in head and neck cancer patients.

Topics: beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Head and Neck Neoplasms; Humans; Neoplasms, Multiple Primary; Vitamin A; Vitamin E