Patricia A. Ganz

Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

CONTEXT Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00006392.

Karnofsky performance status revisited: reliability, validity, and guidelines.

Little research has been conducted documenting the reliability and validity of the Karnofsky Performance Status (KPS) scale, and guidelines based on empirical data do not exist to govern its use. Two hundred ninety-three cancer patients completed a questionnaire that assesses their physical and psychosocial difficulties. Physicians rated patients on the KPS and a subsample of 75 patients was used to evaluate interrater reliability. Analyses were conducted to evaluate the interrater reliability and construct validity of the KPS. The KPS was shown to have good reliability and validity. Detailed examination of the reliability data suggested areas in which physicians err in their judgments. Multiple regression techniques were used to empirically identify seven behaviorally based questions that would be helpful in predicting KPS scores. The seven variables included weight loss, weight gain, reduced energy, difficulty walking, driving, grooming, and working part time. An interview approach with behaviorally based guidelines is presented using these variables to obtain relevant data and make more accurate KPS ratings. With the approach suggested and the guidelines presented, oncologists may train themselves to use the KPS in a standard way, which should increase reliability and validity of the KPS and has implications for patients and research studies that use KPS as a stratifying variable.

Life after breast cancer: understanding women's health-related quality of life and sexual functioning.

PURPOSE To describe the health-related quality of life (HRQL), partner relationships, sexual functioning, and body image concerns of breast cancer survivors (BCS) in relation to age, menopausal status, and type of cancer treatment. PATIENTS AND METHODS A cross-sectional sample of BCS in two large metropolitan areas was invited to participate in a survey study that included the following standardized measures: the RAND 36-Item Health Survey; the Centers for Epidemiologic Studies-Depression Scale (CES-D); the Dyadic Adjustment Scale (DAS); the Breast Cancer Prevention Trial (BCPT) Symptom Checklist; the Watts Sexual Functioning Questionnaire (WSFQ); and subscales from the Cancer Rehabilitation Evaluation System (CARES). RESULTS Eight hundred sixty-four BCS completed the survey. RAND Health Survey scores were as good or better than those of healthy, age-matched women, and the frequency of depression was similar to general population samples. Marital/partner adjustment was similar to normal healthy samples, and sexual functioning mirrored that of healthy, age-matched postmenopausal women. However, these BCS reported higher rates of physical symptoms (eg, joint pains, headaches, and hot flashes) than healthy women. Sexual dysfunction occurred more frequently in women who had received chemotherapy (all ages), and in younger women who were no longer menstruating. In women > or = 50 years, tamoxifen therapy was unrelated to sexual functioning. CONCLUSION BCS report more frequent physical and menopausal symptoms than healthy women, yet report HRQL and sexual functioning comparable to that of healthy, age-matched women. Nevertheless, some survivors still experience poorer functioning, and clinicians should inquire about common symptoms to provide symptomatic management or counseling for these women.

Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life.

PURPOSE To describe the occurrence of fatigue in a large sample of breast cancer survivors relative to general population norms and to identify demographic, medical, and psychosocial characteristics of fatigued survivors. PATIENTS AND METHODS Breast cancer survivors in two large metropolitan areas completed standardized questionnaires as part of a survey study, including the RAND 36-item Health Survey, Center for Epidemiological Studies-Depression Scale, Breast Cancer Prevention Trial Symptom Checklist, Medical Outcomes Study Sleep Scale, and demographic and treatment-related measures. RESULTS On average, the level of fatigue reported by the breast cancer survivors surveyed (N = 1,957) was comparable to that of age-matched women in the general population, although the breast cancer survivors were somewhat more fatigued than a more demographically similar reference group. Approximately one third of the breast cancer survivors assessed reported more severe fatigue, which was associated with significantly higher levels of depression, pain, and sleep disturbance. In addition, fatigued women were more bothered by menopausal symptoms and were somewhat more likely to have received chemotherapy (with or without radiation therapy) than nonfatigued women. In multivariate analyses, depression and pain emerged as the strongest predictors of fatigue. CONCLUSION Although the majority of breast cancer survivors in this large and diverse sample did not experience heightened levels of fatigue relative to women in the general population, there was a subgroup of survivors who did report more severe and persistent fatigue. We identified characteristics of these women that may be helpful in elucidating the mechanisms underlying fatigue in this population, as well as directing intervention efforts.

Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality

CONTEXT Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE To estimate risk and mortality reduction stratified by mutation and prior cancer status. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. MAIN OUTCOMES MEASURES Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. RESULTS No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). CONCLUSIONS Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure.

OBJECTIVES The need for accurate measures of health-related quality of life (HRQOL) in men treated for prostate cancer is of paramount importance because patients may survive for many years after their diagnosis. Hence, interest has increased in choosing treatments that optimize both the quality and quantity of life in patients with this disease. This study sought to develop and evaluate a self-administered, multiitem, disease-specific instrument to capture the health concerns central to the quality of life of men treated for early stage prostate cancer. METHODS After focus group analysis and pilot testing, the instrument was tested with a large retrospective, cross-sectional survey. Exploratory factor analysis and multitrait scaling analysis were used to facilitate the formation of six scales containing 20 disease-targeted items that address impairment in the urinary, bowel, and sexual domains. The psychometric properties of the new scales were assessed by measuring test-retest reliability, internal consistency reliability, and construct validity. Performance on the new scales was compared with scores on other established cancer-related health-related quality of life instruments. Two hundred fifty-five long-term survivors of prostate cancer treatment and 273 age-matched and ZIP code-matched comparison subjects without prostate cancer from a large managed care population in California were studied. Mean age was 72.7 years. In addition to the new scales, the RAND 36-Item Health Survey (SF-36) was used as a generic core measure, and a cancer-related health-related quality of life instrument (the Cancer Rehabilitation System-Short Form) was used to provide construct validity. RESULTS For the new scales, test-retest reliability ranged from 0.66 to 0.93, and internal consistency ranged from 0.65 to 0.93. Disease-targeted measures of function and bother in the three domains correlated substantially with one another. Scale scores correlated well with related, established scales. Men undergoing prostatectomy or pelvic irradiation demonstrated the expected differences in performance on the disease-specific health-related quality of life scales when compared with each other or with comparison subjects. Age was inversely related to sexual and bowel function. CONCLUSIONS The UCLA Prostate Cancer Index performed well in this population of older men with and without prostate cancer. It demonstrated good psychometric properties and appeared to be well understood and easily completed. The high response among patients suggests that these men especially are interested in addressing both the general and disease-specific concerns that impact their daily quality of life.

Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups.

In recent years, research on menopausal symptomalogy has focused on identifying symptom groupings experienced by women as they progress from premenopausal to postmenopausal status. However, most of these studies have been conducted among Caucasian women from western cultures. This leaves open the question of whether the findings from these studies can be extended to women of other racial/ethnic groups or cultures. Furthermore, many of the previous studies have been conducted on relatively small samples. This paper addresses the diversity of the menopause experience by comparing symptom reporting in a large cross-sectional survey of women aged 40-55 years among racial/ethnic groups of women in the United States (Caucasian, African-American, Chinese, Japanese, and Hispanic). Evaluation of the extent to which symptoms group together and consistently relate to menopausal status across these five samples provides evidence for or against a universal menopausal syndrome. The specific research questions addressed in this paper are: (1) How does the factor structure of symptoms among mid-aged women compare across racial/ethnic groups? (2) Is symptom reporting related to race/ethnicity or menopausal status? and (3) Does the relation between menopausal status and symptoms vary across racial/ethnic groups? Analyses are based on 14,906 women who participated in the multi-ethnic, multi-race, multi-site study of mid-aged women called the Study of Womens Health Across the Nation (SWAN). Study participants completed a 15-min telephone or in-person interview that contained questions on a variety of health-related topics. Items of interest for these analyses include symptoms, menstrual history (to assess menopausal status), health status, and sociodemographics. Factor analysis results showed that across all five racial/ethnic groups, two consistent factors emerged; one consisting of clearly menopausal symptoms -- hot flashes and night sweats -- and the other consisting of psychological and psychosomatic symptoms. Results of regression analyses showed racial/ethnic differences in symptom reporting, as well as differences by menopausal status. Controlling for age, education, health, and economic strain, Caucasian women reported significantly more psychosomatic symptoms than other racial/ethnic groups. African-American women reported significantly more vasomotor symptoms. Perimenopausal women, hormone users, and women who had a surgical menopause reported significantly more vasomotor symptoms. All of these groups, plus postmenopausal women, reported significantly more vasomotor symptoms than premenopausal women. The pattern of results argues against a universal menopausal syndrome consisting of a variety of vasomotor and psychological symptoms.

Polychemotherapy in advanced non small cell lung cancer: a meta-analysis

We did a meta-analysis of all published polychemotherapy vs supportive care clinical trials in patients with non-resectable non small cell lung cancer. 7 studies with more than 700 patients were selected. We used the number of deaths at 3, 6, 9, 12, and 18 months as the endpoints because we were unable to obtain all the individual data. Our analysis showed a reduction in mortality during the first 6 months with polychemotherapy. Although small, this increase in survival, together with an improved quality of life, suggests that polychemotherapy should be recommended for patients with non-resectable non small cell lung cancer.

Update of the national surgical adjuvant breast and bowel project Study of Tamoxifen and Raloxifene (STAR) P-2 trial: Preventing breast cancer

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)–approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05–1.47) and for noninvasive disease, 1.22 (95% CI, 0.95–1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36–0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60–0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer. Cancer Prev Res; 3(6); 696–706. ©2010 AACR.

Fatigue and Proinflammatory Cytokine Activity in Breast Cancer Survivors

Objective Fatigue is a common problem among cancer patients and survivors, yet the mechanisms underlying the occurrence and persistence of this symptom are not known. Activation of the immune system may evoke feelings of fatigue, which are mediated by proinflammatory cytokines. We examined whether fatigued breast cancer survivors would show elevations in proinflammatory cytokines and markers of cytokine activity compared with nonfatigued survivors. Differences in lymphocyte subsets, cortisol, and behavioral symptoms associated with proinflammatory cytokines were also assessed. Methods Forty breast cancer survivors (20 fatigued, 20 nonfatigued) provided blood samples at visits scheduled to control for diurnal variability. Cytokines, soluble markers of cytokine activity, and cortisol were measured by immunoassay and lymphocyte subsets by flow cytometry. Participants also completed questionnaires measuring demographic, medical, and behavioral variables. Results Fatigued breast cancer survivors had significantly higher serum levels of several markers associated with proinflammatory cytokine activity than nonfatigued survivors, including interleukin-1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor type II (sTNF-RII), and neopterin. They were also more likely to report behavioral problems that co-occur with fatigue in the context of immune activation. Fatigued survivors had significantly lower serum levels of cortisol than the nonfatigued group as well as differences in two lymphocyte populations. Conclusions Fatigued breast cancer survivors showed elevations in serum markers associated with proinflammatory cytokine activity an average of 5 years after diagnosis. Results suggest mechanisms through which enduring immune activation may occur, including alterations in cortisol and in lymphocyte subsets.