Abstract
Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: A phase 2 randomized study. JAMA. 2009;302:774–780.
Context: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy.
Objective: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer.
Design, Setting, and Patients: A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (≥24 wk) or relapse (after ≥2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response.
Intervention: Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily.
Main Outcome Measures: Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). Secondary outcomes: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18.
Results: The adverse event rate (≥ grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; p = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (≥ 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation.
Conclusion: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials.
Trial Registration: clinicaltrials.gov Identifier: NCT00324259.
Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009;361:766–776.
Background: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone.
Methods: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women.
Results: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; p = 0.08). The rate of adverse events was as expected on the basis of previous reports of letrozole and tamoxifen therapy.
Conclusions: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.) 2009 Massachusetts Medical Society.
Lactation and incidence of premenopausal breast cancer: A longitudinal study. Arch Intern Med. 2009;169:1364–1371.
Background: Findings from observational studies suggest an inverse association between lactation and premenopausal breast cancer risk, but results are inconsistent, and data from large prospective cohort studies are lacking.
Methods: We used information from 60,075 parous women participating in the prospective cohort study of the Nurses' Health Study II from 1997 to 2005. Our primary outcome was incident premenopausal breast cancer.
Results: We ascertained 608 incident cases of premenopausal breast cancer during 357,556 person-years of follow-up. Women who had ever breastfed had a covariate-adjusted hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.56-1.00) for premenopausal breast cancer compared with women who had never breastfed. No linear trend was found with duration of total lactation (p = .95), exclusive lactation (p = .74), or lactation amenorrhea (p = .88). The association between lactation and premenopausal breast cancer was modified by family history of breast cancer (p value for interaction = .03). Among women with a first-degree relative with breast cancer, those who had ever breastfed had a covariate-adjusted HR of 0.41 (95% CI, 0.22-0.75) for premenopausal breast cancer compared with women who had never breastfed, whereas no association was observed among women without a family history of breast cancer.
Conclusion: In this large, prospective cohort study of parous premenopausal women, having ever breastfed was inversely associated with incidence of breast cancer among women with a family history of breast cancer.
Alcohol and risk of breast cancer by histologic type and hormone receptor status in postmenopausal women: The NIH-AARP Diet and Health Study. Am J Epidemiol. 2009;170:308–317. Epub 2009 Jun 18.
Little is known about the association between alcohol and breast cancer by different tumor characteristics. The study consisted of 184,418 postmenopausal women aged 50–71 years in the National Institutes of Health-AARP Diet and Health Study (1995–2003). Alcohol use, diet, and potential risk factors for cancer were assessed with a mailed questionnaire at baseline. The relative risks and 95% confidence intervals were estimated by using Cox proportional hazards regression. Breast cancer cases and estrogen receptor and progesterone receptor status were identified through linkage to state cancer registries. During an average of 7 years of follow-up, 5,461 breast cancer cases were identified. Alcohol was significantly positively associated with total breast cancer: Even a moderate amount of alcohol (>10 g/day) significantly increased breast cancer risk. In a comparison of >35 g versus 0 g/day, the multivariate relative risks were 1.35 (95% confidence interval (CI): 1.17, 1.56) for total breast cancer, 1.46 (95% CI: 1.22, 1.75) for ductal tumors, and 1.52 (95% CI: 0.95, 2.44) for lobular tumors. The multivariate relative risks for estrogen receptor-positive/progesterone receptor-positive, estrogen receptor-positive/progesterone receptor-negative, and estrogen receptor-negative/progesterone receptor-negative tumors were 1.46 (95% CI: 1.12, 1.91) for >35 g versus 0 g/day, 1.13 (95% CI: 0.73, 1.77) for >20 g versus 0 g/day, and 1.21 (95% CI: 0.79, 1.84) for >20 g versus 0 g/day, respectively. Moderate consumption of alcohol was associated with breast cancer, specifically hormone receptor-positive tumors.
Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med. 2009;361:664–673.
Background: Weight lifting has generally been proscribed for women with breast-cancer-related lymphedema, preventing them from obtaining the well-established health benefits of weight lifting, including increases in bone density.
Methods: We performed a randomized, controlled trial of twice-weekly progressive weight lifting involving 141 breast-cancer survivors with stable lymphedema of the arm. The primary outcome was the change in arm and hand swelling at 1 year, as measured through displaced water volume of the affected and unaffected limbs. Secondary outcomes included the incidence of exacerbations of lymphedema, number and severity of lymphedema symptoms, and muscle strength. Participants were required to wear a well-fitted compression garment while weight lifting.
Results: The proportion of women who had an increase of 5% or more in limb swelling was similar in the weight-lifting group (11%) and the control group (12%) (cumulative incidence ratio, 1.00; 95% confidence interval, 0.88 to 1.13). As compared with the control group, the weight-lifting group had greater improvements in self-reported severity of lymphedema symptoms (p = 0.03) and upper- and lower-body strength (p < 0.001 for both comparisons) and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% vs. 29%, p = 0.04). There were no serious adverse events related to the intervention.
Conclusions: In breast-cancer survivors with lymphedema, slowly progressive weight lifting had no significant effect on limb swelling and resulted in a decreased incidence of exacerbations of lymphedema, reduced symptoms, and increased strength. (ClinicalTrials.gov number, NCT00194363.) 2009 Massachusetts Medical Society
Associations between endogenous sex hormone levels and mammographic and bone densities in premenopausal women. Cancer Causes Control. 2009;20:1039–1053. Epub 2009 Mar 12.
Purpose: Mammographic breast and bone mineral densities (BMD) have been associated with luteal phase hormone concentrations in premenopausal women. We assessed the associations of breast and bone densities with follicular phase hormones and sex hormone binding globulin (SHBG) in premenopausal women, given that follicular phase hormones have been shown to be positively associated with premenopausal breast cancer risk.
Methods: One hundred and ninety-two 40–45-year-old women provided a spot urine and/or blood sample during the follicular phase. Hormone and SHBG concentrations, and bone density were measured and routine mammograms were accessed and digitized to obtain breast density measures. Regression models were fit to assess the associations between hormones and SHBG, and breast and bone densities.
Results: Positive associations were observed between percent breast density and SHBG (p trend = 0.02), as well as estradiol (p trend = 0.08), after controlling for body mass index (BMI), number of pregnancies, and breast feeding history. In addition, a statistically significant inverse association was observed between total testosterone and head BMD (p trend = 0.01), after controlling for BMI.
Conclusions: Associations were observed between breast and bone densities, and serum hormone concentrations during the follicular phase of the menstrual cycle.
Effect of daily fiber intake on reproductive function: The BioCycle Study. Am J Clin Nutr. 2009 Aug 19. [Epub ahead of print]
Background: High-fiber diets have been associated with decreased breast cancer risk, likely mediated by the effect of fiber on lowering circulating estrogen concentrations. The influence of fiber on aspects of reproduction, which include ovulation, has not been well studied in premenopausal women.
Objective: The objective was to determine if fiber consumption is associated with hormone concentrations and incident anovulation in healthy, regularly menstruating women.
Design: The BioCycle Study was a prospective cohort study conducted from 2004 to 2006 that followed 250 women aged 18–44 y for 2 cycles. Dietary fiber consumption was assessed ≤ 4 times/cycle by using 24-h recall. Outcomes included concentrations of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which were measured ≤ 8 times/cycle, and incident anovulation.
Results: Dietary fiber consumption was inversely associated with hormone concentrations (estradiol, progesterone, LH, and FSH; p < 0.05) and positively associated with the risk of anovulation (p = 0.003) by using random-effects models with adjustment for total calories, age, race, and vitamin E intake. Each 5-g/d increase in total fiber intake was associated with a 1.78-fold increased risk (95% CI: 1.11, 2.84) of an anovulatory cycle. The adjusted odds ratio (aOR) of 5 g fruit fiber/d was 3.05 (95% CI: 1.07, 8.71).
Conclusions: These findings suggest that a diet high in fiber is significantly associated with decreased hormone concentrations and a higher probability of anovulation. Further study of the effect of fiber on reproductive health and of the effect of these intakes in reproductive-aged women is warranted.
Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302:750–757.
Context: In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.
Objective: To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.
Design, Setting, and Participants: Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.
Main Outcome Measures: Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.
Results: VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.
Conclusions: Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.
Hyaluronan in vaginal secretions: Association with recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 2009;201:206.e1–5.
Objective: We evaluated whether vaginal concentrations of hyaluronan were altered in women with recurrent vulvovaginal candidiasis (RVVC).
Study Design: Lavage samples from 17 women with acute RVVC, 27 women who were receiving a maintenance antifungal regimen, and 24 control women were tested for hyaluronan and interleukin (IL)-6, IL-12, and IL-23 by enzyme-linked immunosorbent assay.
Results: Median vaginal hyaluronan concentrations were 33.8 ng/mL (range, 21.6–66.3 ng/mL) in women with acute RVVC, 15.0 ng/mL (range, 11.2–50.6 ng/mL) in women who were receiving maintenance therapy, and 4.2 ng/mL (range, 3.6–12.0 ng/mL) in control subjects (p ≤ .02). The vaginal hyaluronan concentration was 27.4 ng/mL (range, 15.4–37.7 ng/mL) when Candida was detected by microscopy and 9.5 ng/mL (range, 7.7–14.6 ng/mL) in microscopy-negative cases (p = .0354). Elevated hyaluronan levels were associated with itching plus burning (40.7 ng/mL) or itching plus discharge (42.1 ng/mL), as opposed to itching only (6.2 ng/mL; p = .0152). Hyaluronan and IL-6 levels were correlated (p = .0009).
Conclusion: Hyaluronan release is a component of the host response to a candidal infection and may contribute to symptoms.
Clinical outcomes from a randomised comparison of Microwave Endometrial Ablation with Thermal Balloon endometrial ablation for the treatment of heavy menstrual bleeding. BJOG. 2009;116:1038–1045. Epub 2009 May 11.
Objective: To compare the clinical outcomes of microwave endometrial ablation and thermal balloon ablation for the treatment of heavy menstrual bleeding.
Design: A double blind randomised controlled trial.
Setting: A UK teaching hospital.
Population: Three hundred and twenty women requesting endometrial ablation.
Methods: Operative data collection and patient completed postal questionnaires were used to ascertain women's satisfaction with outcome, acceptability of each procedure, changes in menstrual symptoms and health related quality of life and additional treatments received.
Main Outcome Measures: Primary outcomes were satisfaction and menstrual scores at 1 year. Secondary outcomes were operative differences, acceptability of treatment and changes in health related quality of life.
Results: Both technologies achieved high levels of satisfaction (−1%, 95% CI (−11, 9)). Menstrual scores were also similar (4%, 95% CI (−7, 19)) Microwave had a significantly shorter operating time, reduced usage of antiemetics and opiate analgesia, increased discharge by 6 hours and fewer device failures.
Conclusions: Both treatments are acceptable to women, with high levels of satisfaction. Microwave is quicker to perform with faster hospital discharge.
Late recognition of pregnancy as a predictor of adverse birth outcomes. Am J Obstet Gynecol. 2009:201:156.e1–6.
Objective: We examined the relationship between the time of recognition of pregnancy and birth outcomes, such as premature births, low birthweight (LBW), admission to the neonatal intensive care unit (NICU), and infant mortality.
Study Design: A secondary analysis was performed using the Pregnancy Risk Assessment and Monitoring System (PRAMS) multistate data from 2000–2004. The sample consisted of 136,373 women who had a live childbirth. Analysis involved multiple logistic regression models, appropriately weighted for point and variance estimation to reflect the complex survey design of the PRAMS using STATA 9.2 (Stata Corp, College Station, TX).
Results: Approximately 27.6% recognized their pregnancy late (after 6 weeks of gestation). Late recognition was significantly associated with an increased odds of having premature births (odds ratio [OR], 1.09; 99% confidence interval [CI], 1.01-1.19), LBW (OR, 1.08; 99% CI, 1.01-1.15), and NICU admissions (OR, 1.12; 99% CI, 1.03-1.21).
Conclusion: These results provide a rationale and an impetus for developing interventions that promote early recognition of pregnancy.
Systematic review: Elective induction of labor versus expectant management of pregnancy. Ann Intern Med. 2009 Aug 18;151(4):252–63, W53–63.
Background: The rates of induction of labor and elective induction of labor are increasing. Whether elective induction of labor improves outcomes or simply leads to greater complications and health care costs is commonly debated in the literature.
Purpose: To compare the benefits and harms of elective induction of labor and expectant management of pregnancy.
Data Sources: MEDLINE (through February 2009), Web of Science, CINAHL, Cochrane Central Register of Controlled Trials (through March 2009), bibliographies of included studies, and previous systematic reviews.
Study Selection: Experimental and observational studies of elective induction of labor reported in English.
Data Extraction: Two authors abstracted study design; patient characteristics; quality criteria; and outcomes, including cesarean delivery and maternal and neonatal morbidity.
Data Synthesis: Of 6117 potentially relevant articles, 36 met inclusion criteria: 11 randomized, controlled trials (RCTs) and 25 observational studies. Overall, expectant management of pregnancy was associated with a higher odds ratio (OR) of cesarean delivery than was elective induction of labor (OR, 1.22 [95% CI, 1.07 to 1.39]; absolute risk difference, 1.9 percentage points [CI, 0.2 to 3.7 percentage points]) in 9 RCTs. Women at or beyond 41 completed weeks of gestation who were managed expectantly had a higher risk for cesarean delivery (OR, 1.21 [CI, 1.01 to 1.46]), but this difference was not statistically significant in women at less than 41 completed weeks of gestation (OR, 1.73 [CI, 0.67 to 4.5]). Women who were expectantly managed were more likely to have meconium-stained amniotic fluid than those who were electively induced (OR, 2.04 [CI, 1.34 to 3.09]).
Limitations: There were no recent RCTs of elective induction of labor at less than 41 weeks of gestation. The 2 studies conducted at less than 41 weeks of gestation were of poor quality and were not generalizable to current practice.
Conclusion: RCTs suggest that elective induction of labor at 41 weeks of gestation and beyond is associated with a decreased risk for cesarean delivery and meconium-stained amniotic fluid. There are concerns about the translation of these findings into actual practice; thus, future studies should examine elective induction of labor in settings where most obstetric care is provided.
First-trimester maternal serum screening and the risk for fetal distress during labor. Am J Obstet Gynecol. 2009:201:166.e1–6.
Objective: The purpose of this study was to assess whether low pregnancy-associated plasma protein-A (PAPP-A) levels in the first trimester are related to the risk of emergency cesarean section delivery (CS) for fetal distress during labor and fetal intrapartum acidemia.
Study Design: We prospectively studied patients who requested first-trimester biochemical screening for Down syndrome.
Results: Among the 1037 women who were enrolled, 152 women (14.7%) had a low first-trimester PAPP-A value, and 855 women (85.3%) had a normal first-trimester PAPP-A value. Excluding elective CS, 19 of 117 women (16.2%) with low PAPP-A values vs 59 of 749 women (7.9%) with normal PAPP-A values underwent CS for concerning fetal status during labor (p = .003; odds ratio, 2.27; 95% confidence interval, 1.30-3.97). This difference remained significant after correction for possible confounders (hypertension, preterm delivery, small for gestational age, labor induction). Among these 78 women, umbilical artery pH was significantly lower in fetuses from mothers with low vs normal PAPP-A values (pH = 7.19 [range, 6.95–7.39] vs pH = 7.26 [range, 7.02–7.39]; p = .022).
Conclusion: Low PAPP-A levels at first-trimester screening are associated independently with higher rates of emergency CS for nonreassuring fetal status during labor and lower pH.