RESUMEN
IMPORTANCE: Not all women initiate clinically indicated breast cancer adjuvant treatment. It is important for clinicians to identify women at risk for noninitiation. OBJECTIVE: To determine whether complementary and alternative medicine (CAM) use is associated with decreased breast cancer chemotherapy initiation. DESIGN, SETTING, AND PARTICIPANTS: In this multisite prospective cohort study (the Breast Cancer Quality of Care [BQUAL] study) designed to examine predictors of breast cancer treatment initiation and adherence, 685 women younger than 70 years with nonmetastatic invasive breast cancer were recruited from Columbia University Medical Center, Kaiser Permanente Northern California, and Henry Ford Health System and enrolled between May 2006 and July 31, 2010. Overall, 306 patients (45%) were clinically indicated to receive chemotherapy per National Comprehensive Cancer Network guidelines. Participants were followed for up to 12 months. EXPOSURES: Baseline interviews assessed current use of 5 CAM modalities (vitamins and/or minerals, herbs and/or botanicals, other natural products, mind-body self-practice, mind-body practitioner-based practice). CAM use definitions included any use, dietary supplement use, mind-body use, and a CAM index summing the 5 modalities. MAIN OUTCOMES AND MEASURES: Chemotherapy initiation was assessed via self-report up to 12 months after baseline. Multivariable logistic regression models examined a priori hypotheses testing whether CAM use was associated with chemotherapy initiation, adjusting for demographic and clinical covariates, and delineating groups by age and chemotherapy indication. RESULTS: A cohort of 685 women younger than 70 years (mean age, 59 years; median age, 59 years) with nonmetastatic invasive breast cancer were recruited and followed for up to 12 months to examine predictors of breast cancer treatment initiation. Baseline CAM use was reported by 598 women (87%). Chemotherapy was initiated by 272 women (89%) for whom chemotherapy was indicated, compared with 135 women (36%) for whom chemotherapy was discretionary. Among women for whom chemotherapy was indicated, dietary supplement users and women with high CAM index scores were less likely than nonusers to initiate chemotherapy (odds ratio [OR], 0.16; 95% CI, 0.03-0.51; and OR per unit, 0.64; 95% CI, 0.46-0.87, respectively). Use of mind-body practices was not related to chemotherapy initiation (OR, 1.45; 95% CI, 0.57-3.59). There was no association between CAM use and chemotherapy initiation among women for whom chemotherapy was discretionary. CONCLUSIONS AND RELEVANCE: CAM use was high among patients with early-stage breast cancer enrolled in a multisite prospective cohort study. Current dietary supplement use and higher number of CAM modalities used but not mind-body practices were associated with decreased initiation of clinically indicated chemotherapy. Oncologists should consider discussing CAM with their patients during the chemotherapy decision-making process.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante/estadística & datos numéricos , Terapias Complementarias/estadística & datos numéricos , Terapia por Acupuntura/estadística & datos numéricos , Adulto , Anciano , Antioxidantes/uso terapéutico , Estudios de Cohortes , Suplementos Dietéticos/estadística & datos numéricos , Femenino , Aceites de Pescado/uso terapéutico , Glucosamina/uso terapéutico , Conductas Relacionadas con la Salud , Humanos , Modelos Logísticos , Masaje/estadística & datos numéricos , Meditación , Melatonina/uso terapéutico , Persona de Mediana Edad , Terapias Mente-Cuerpo/estadística & datos numéricos , Análisis Multivariante , Preparaciones de Plantas/uso terapéutico , Estudios Prospectivos , Autoinforme , Tacto Terapéutico/estadística & datos numéricos , Vitaminas/uso terapéutico , YogaRESUMEN
PURPOSE: The effectiveness of survivorship care plans has not been widely tested. We evaluated whether a one-time brief lifestyle consultation as part of a broader survivorship care plan was effective at changing diet and lifestyle patterns. METHODS: A diverse sample of women with stage 0-III breast cancer were randomized to control or intervention groups within 6 weeks of completing adjuvant treatment. Both groups received the National Cancer Institute publication, "Facing Forward: Life after Cancer Treatment." The intervention group also met with a nurse (1 h) and a nutritionist (1 h) to receive personalized lifestyle recommendations based upon national guidelines. Diet, lifestyle, and perceived health were assessed at baseline, 3 and 6 months. Linear regression analyses evaluated the effects of the intervention adjusted for covariates. RESULTS: A total of 126 women completed the study (60 control/66 intervention, 61 Hispanic/65 non-Hispanic). At 3 months, the intervention group reported greater knowledge of a healthy diet (P = 0.047), importance of physical activity (P = 0.03), and appropriate use of dietary supplements (P = 0.006) and reported lower frequency of alcohol drinking (P = 0.03) than controls. At 6 months, only greater knowledge of a healthy diet (P = 0.01) persisted. The intervention was more effective among non-Hispanics than Hispanics on improving attitude towards healthy eating (P = 0.03) and frequency of physical activity (P = 0.006). CONCLUSIONS: The intervention changed lifestyle behaviors and knowledge in the short-term, but the benefits did not persist. IMPLICATIONS FOR CANCER SURVIVORS: Culturally competent long-term behavioral interventions should be tested beyond the survivorship care plan to facilitate long-term behavior change among breast cancer survivors.
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Neoplasias de la Mama/mortalidad , Estilo de Vida , Planificación de Atención al Paciente , Sobrevivientes/psicología , Neoplasias de la Mama/epidemiología , Ejercicio Físico , Femenino , Humanos , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Non-adherence to adjuvant endocrine therapy (ET) for breast cancer (BC) is common. Our goal was to determine the associations between psychosocial factors and ET non-persistence. We recruited women with BC receiving care in an integrated healthcare system between 2006 and 2010. Using a subset of patients treated with ET, we investigated factors related to ET non-persistence (discontinuation) based on pharmacy records (≥90 days gap). Serial interviews were conducted at baseline and every 6 months. The Functional Assessment of Cancer Therapy (FACT), Medical Outcomes Survey, Treatment Satisfaction Questionnaire (TSQM), Impact of Events Scale (IES), Interpersonal Processes of Care measure, and Decision-making beliefs and concerns were measured. Multivariate models assessed factors associated with non-persistence. Of the 523 women in our final cohort who initiated ET and had a subsequent evaluation, 94 (18 %) were non-persistent over a 2-year follow-up. The cohort was primarily white (74.4 %), stage 1 (60.6 %), and on an aromatase inhibitor (68.1 %). Women in the highest income category had a lower odds of being non-persistent (OR 0.43, 95 % CI 0.23-0.81). Quality of life and attitudes toward ET at baseline were associated with non-persistence. At follow-up, the FACT, TSQM, and IES were associated with non-persistence (p < 0.001). Most women continued ET. Women who reported a better attitude toward ET, better quality of life, and more treatment satisfaction, were less likely to be non-persistent and those who reported intrusive/avoidant thoughts were more likely to be non-persistent. Interventions to enhance the psychosocial well-being of patients should be evaluated to increase adherence.
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Neoplasias de la Mama/tratamiento farmacológico , Cumplimiento de la Medicación/psicología , Calidad de Vida/psicología , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/psicología , Quimioterapia Adyuvante , Femenino , Humanos , Cumplimiento de la Medicación/etnología , Factores de RiesgoRESUMEN
PURPOSE: US cancer survivors commonly use vitamins/minerals and complementary and alternative medicine (CAM). We compare use of vitamins/minerals and CAM between adult cancer survivors and cancer-free adults and estimate annual out-of-pocket expenses. METHODS: Data on self-reported vitamin/mineral and CAM use in the past 12 months from the cross-sectional 2012 US National Health Interview Survey were used to estimate prevalence of use and out-of-pocket expenditures. The cohort included adults with (n = 2977) and without (n = 30,551) a self-reported cancer diagnosis. RESULTS: Approximately 79 % of cancer survivors and 68 % of cancer-free adults reported using ≥1 vitamins/minerals and/or CAM modality in the past year. Compared to cancer-free adults, cancer survivors were more likely to report use of vitamin/minerals (75 vs. 61 %, P < 0.001), non-vitamin/mineral natural products (24 vs. 19 %, P < 0.001), manipulative and body-based therapies (19 vs. 17 %, P = 0.03), and alternative medical systems (5 vs. 4 %, P = 0.04). Adult cancer survivors and cancer-free adults spent an annual estimated $6.7 billion and $52 billion out-of-pocket, respectively, on vitamins/minerals and CAM. Survivors spent 60 % of the total on vitamins/minerals ($4 billion), 18 % ($1.2 billion) on non-vitamin/mineral natural products, and 7 % ($0.5 billion) on massage. CONCLUSIONS: Compared with cancer-free adults, a higher proportion of cancer survivors report vitamin/mineral and CAM use. Cancer survivors, who accounted for 6.9 % of the total population, accrued more than 11.4 % of the annual out-of-pocket costs on vitamins/minerals and CAM spent by US adults. IMPLICATIONS FOR CANCER SURVIVORS: Given the high use of vitamins/minerals and CAM in cancer survivors, studies are needed to analyze health outcomes and the cost/benefit ratio of such use.
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Terapias Complementarias/economía , Terapias Complementarias/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Neoplasias/terapia , Sobrevivientes/psicología , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/economía , Neoplasias/epidemiología , Neoplasias/psicología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Pocock et al. (2012, European Heart Journal 33, 176-182) proposed a win ratio approach to analyzing composite endpoints comprised of outcomes with different clinical priorities. In this article, we establish a statistical framework for this approach. We derive the null hypothesis and propose a closed-form variance estimator for the win ratio statistic in all pairwise matching situation. Our simulation study shows that the proposed variance estimator performs well regardless of the magnitude of treatment effect size and the type of the joint distribution of the outcomes.
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Algoritmos , Interpretación Estadística de Datos , Evaluación de Resultado en la Atención de Salud/métodos , Rivaroxabán/uso terapéutico , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Intervalos de Confianza , Inhibidores del Factor Xa/uso terapéutico , Humanos , Oportunidad Relativa , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Sensibilidad y Especificidad , Distribuciones Estadísticas , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. RESULTS: Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. CONCLUSION: Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.
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Antioxidantes/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Fosfatidilcolinas/administración & dosificación , Silybum marianum , Silimarina/administración & dosificación , Antioxidantes/efectos adversos , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Silybum marianum/efectos adversos , Fosfatidilcolinas/efectos adversos , Silibina , Silimarina/efectos adversos , Silimarina/sangreRESUMEN
PURPOSE: For some women, adjuvant chemotherapy for nonmetastatic breast cancer decreases recurrences and increases survival; however, patient-physician decisions regarding chemotherapy receipt can be influenced by medical and nonmedical factors. PATIENTS AND METHODS: We used a prospective cohort design and multivariate modeling to investigate factors related to noninitiation of chemotherapy among women with newly diagnosed breast cancer recruited from three US sites. We interviewed patients at baseline and during treatment on sociodemographic, tumor, and treatment decision-making factors. Patients were categorized according to National Comprehensive Cancer Network guidelines as those for whom chemotherapy was definitely indicated, clinically discretionary, or discretionary based on age greater than 70 years. RESULTS: Of 1,145 patients recruited, chemotherapy was clinically indicated for 392 patients, clinically discretionary for 459 patients, discretionary because of age for 169 patients, and not indicated for 93 patients; data were insufficient for 32 patients. Chemotherapy rates were 90% for those in whom chemotherapy was clinically indicated, 36% for those in whom it was discretionary because of clinical factors, and 19% for those in whom it was discretionary based on age greater than 70 years. Nonreceipt of chemotherapy was associated with older age, more negative beliefs about treatment efficacy, less positive beliefs about chemotherapy, and more concern about adverse effects. In the two discretionary groups, clinical predictors of worse outcome (greater tumor size, positive nodes, worse grade, and estrogen receptor- and progesterone receptor-negative status) were associated with increased chemotherapy initiation. CONCLUSION: Utilization of adjuvant chemotherapy was most common among patients who, based on clinical criteria, would most likely benefit from it, patients with more positive than negative beliefs regarding treatment efficacy, and patients with few concerns about adverse effects.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Quimioterapia Adyuvante/psicología , Negativa del Paciente al Tratamiento/psicología , Adulto , Anciano , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/normas , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Calidad de la Atención de Salud , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study. METHODS All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively. Results At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P < .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P < .01). CONCLUSION Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.
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Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapias Complementarias , Desoxicitidina/análogos & derivados , Suplementos Dietéticos , Neoplasias Pancreáticas/terapia , Péptido Hidrolasas/uso terapéutico , Adenocarcinoma/dietoterapia , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapias Complementarias/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/dietoterapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Péptido Hidrolasas/efectos adversos , Modelos de Riesgos Proporcionales , Calidad de Vida , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: Adjuvant radiotherapy following breast conservation surgery (BCS) is considered to be an indicator of quality of care for the majority of women with breast cancer, but many women do not receive adjuvant radiotherapy. We investigated the association of surgeon-related factors with receipt of adjuvant radiotherapy after BCS. METHODS: We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database to identify women aged 65 years or older with stage I/II breast cancer who were diagnosed between 1991 and 2002 and underwent BCS. We collected demographic and clinical data from SEER and treatment information from Medicare claims data. The American Medical Association Masterfile was used to obtain information on surgeons' characteristics, including sex, medical school location (United States or elsewhere), and type of degree (MD or Doctorate in Osteopathic Medicine [DO]). The associations of patient (age, race, rural vs urban residence, comorbidities, marital status), tumor (hormone receptor status, grade, stage), and surgeon-related factors with receipt of adjuvant radiotherapy were analyzed using Generalized Estimating Equations to control for clustering. All statistical tests were two-sided. RESULTS: Of 29,760 women in our sample, 22,207 (75%) received radiotherapy. Patients who received adjuvant radiotherapy were younger, had fewer comorbidities, and were more likely to be white, married, from an urban area, and diagnosed in a later year compared with those who did not. They were also more likely to have a surgeon who was female (79% vs 73%), had an MD degree (75% vs 68%), or was US trained (75% vs 70%). The multivariable analysis confirmed the association of radiotherapy with having a surgeon who was female (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.06 to 1.27), had an MD degree (OR = 1.55; 95% CI = 1.24 to 1.91), was US trained (OR = 1.12; 95% CI = 1.01 to 1.25), or had more than 15 patients (OR = 1.18; 95% CI = 1.10 to 1.28). CONCLUSIONS: Surgeon characteristics were associated with patients' receipt of adjuvant radiotherapy after BCS after controlling for patient and tumor characteristics, although the individual effect sizes were small for surgeon sex, location of training, and type of medical degree. More research is warranted to confirm the associations to determine whether they reflect surgeon behavior, patient response, or physician-patient interactions.
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Neoplasias de la Mama/radioterapia , Mastectomía Segmentaria , Médicos/estadística & datos numéricos , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Análisis por Conglomerados , Comorbilidad , Factores de Confusión Epidemiológicos , Educación Médica/estadística & datos numéricos , Femenino , Humanos , Estado Civil , Medicare , Análisis Multivariante , Estadificación de Neoplasias , Oportunidad Relativa , Radioterapia Adyuvante/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Programa de VERF , Factores Sexuales , Estados Unidos/epidemiología , Población Urbana/estadística & datos numéricosRESUMEN
PURPOSE: In randomized trials, patients with stage III colon cancer who received 6 months of fluorouracil (FU)-based adjuvant chemotherapy had better survival than patients who did not. However, little is known about the predictors of, or the survival associated with, duration of chemotherapy in the community. PATIENTS AND METHODS: The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify individuals > or = 65 years of age diagnosed with stage III colon cancer between 1995 and 1999. We used logistic and Cox proportional hazards regression models to analyze factors associated with early discontinuation of FU-based chemotherapy among these elderly colon cancer patients. RESULTS: Among 1,722 patients who received 1 to 7 months of FU-based chemotherapy, older age, being unmarried, and having comorbid conditions were associated with receiving less than 5 months of treatment. Among the 1,579 patients who survived > or = 8 months, the 1,091 (69.1%) who received 5 to 7 months of treatment had lower overall (hazard ratio [HR], 0.59; 95%, CI 0.49 to 0.71) and colon cancer-specific (HR, 0.53; 95% CI, 0.43 to 0.66) mortality than the 488 (30.9%) who received 1 to 4 months of treatment. CONCLUSION: More than 30% of elderly patients who initiated FU-based chemotherapy for stage III colon cancer and survived for at least 8 months discontinued treatment early. Mortality rates among such patients were nearly twice as high as among patients who completed 5 to 7 months of treatment. If the association we observed between duration of treatment and survival is confirmed, additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment are responsible.
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Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante , Neoplasias del Colon/mortalidad , Bases de Datos como Asunto , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Medicare , Programa de VERF , Análisis de Supervivencia , Factores de Tiempo , Estados UnidosRESUMEN
BACKGROUND: Elevated benzo(a)pyrene [B(a)P]-DNA adducts have been associated with 3-fold increased risk of lung cancer in current smokers. We assessed the chemopreventive effects of antioxidant supplementation using B(a)P-DNA adducts in leukocytes as an intermediate cancer risk marker. METHODS: Subjects were randomized to a double-blinded placebo-controlled clinical trial of antioxidant vitamin supplementation [500 mg vitamin C and 400 IU vitamin E (dl-alpha-tocopherol) daily] or placebo. Smokers with > or =10 cigarettes per day and serum cotinine > or =25 ng/mL were eligible for the study. B(a)P-DNA adduct level was the outcome. The randomization was stratified by gender and cigarettes per day (< or =20 or >20). Smoking habits and blood samples were collected every 3 months during the 15-month treatment period. Samples were analyzed for B(a)P-DNA adducts (high-performance liquid chromatography), plasma cotinine, vitamin levels, and GSTM1 genotype. The intent-to-treat model adjusted for B(a)P-DNA and cotinine at randomization. RESULTS: Overall and among men, there was no effect of treatment on B(a)P-DNA adduct levels. Among treated women, B(a)P-DNA adducts decreased by 31% compared with women on placebo (P = 0.03). Among treated women with the GSTM1 genotype, there was a 43% decrease in adducts (P = 0.04). CONCLUSION: Our primary hypothesis that the mean level of smoking-related B(a)P-DNA adducts would be lower in all subjects in the vitamin treatment group compared with all placebo-treated subjects was not substantiated. However, oursecondary gender-specific analysis found a significant reduction in B(a)P-DNA adducts in women with vitamin treatment, suggesting that antioxidant supplementation maymitigate some of the procarcinogenic effects of exposuretoB(a)P. The effect in GSTM1-null women suggeststhat certain subgroups may derive more benefit fromsupplementation. Although the results of this trial showthe potential chemopreventive role of antioxidants, thebest way for smokers to reduce their cancer risk remains smoking cessation.