Bone-modifying Agents (BMAs) in Breast Cancer.

Bone-modifying agents (BMAs) are mainstays in breast cancer and prevent and treat osteoporosis in early-stage disease and reduce skeletal metastases complications in advanced disease. There is some evidence to support that BMA also prevents skeletal metastases and improves overall survival. Bone loss occurs with chemotherapy-induced ovarian failure, gonadotrophin-releasing hormone (GnRH) agonists, and aromatase inhibitors. In some women, the bone loss will be of sufficient magnitude to increase the risks of osteoporosis or fractures. Recommended steps in osteoporosis prevention or treatment include risk factor assessment, taking adequate amounts of calcium and vitamin D3, and periodic evaluations with dual-energy x-ray absorptiometry scanning. If clinically indicated by the T-scores and fracture-risk prediction algorithms treat with oral, IV bisphosphonates or subcutaneous denosumab (DEN). Zoledronic acid (ZA) or DEN reduces skeletal metastases complications, including pathological fracture, spinal cord compression, or the necessity for radiation or surgery to bone. Also, both of these drugs have the side-effect of osteonecrosis at a similar incidence. Monthly administration of ZA or DEN is standard, but several recent randomized trials show noninferiority between ZA monthly and every 3-month ZA. Every 3-month ZA is a new standard of care. Similar trials of the schedule of DEN are ongoing. ZA anticancer effect is only in postmenopausal women or premenopausal women rendered postmenopausal by GnRH agonists or bilateral oopherectomy. High-risk women, either postmenopausal or premenopausal, receiving GnRH/oopherctomy should consider adjuvant ZA. There are insufficient data to support DEN in this setting. Herein, this narrative review covers the mechanism of action of BMA, randomized clinical trials, and adverse events, both common and rare.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PURPOSE: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. METHODS: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. RESULTS: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. CONCLUSION: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Assuring Quality Cancer Survivorship Care: We've Only Just Begun.

Clinical practice guidelines, quality metrics, and performance improvement projects are the key tools of the national movement to improve and assure quality cancer care. Each of these evaluation instruments is intended to assess quality from a unique perspective, including that of the individual provider, the practice/hospital, and the health care system. A number of organizations have developed or endorsed quality measures specific to cancer, however, these have not formally included survivorship measures. Fortunately, the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network, the American Cancer Society, and the American College of Surgeons (ACoS) have taken a leadership role in developing survivorship guidelines and quality metrics. Both ASCO and ACoS have focused their efforts on the treatment summary and care plan, a document that was proposed in the 2006 Institute of Medicine report on cancer survivorship. ASCO has proposed a care plan template for implementation and incorporation into the electronic health records (EHR), which will lend itself to structure, process, and outcome measurement. ACoS, conversely, has included the care plan in its cancer program standards with annual evaluation metrics. In addition, ASCO has developed a number of key survivorship-relevant metrics as part of its Quality Oncology Practice Initiative (QOPI), a tool developed to measure quality cancer care and assess adherence to guidelines across academic and community practices. Together, these efforts will direct us to more effective ways to disseminate guideline recommendations and to better methods of assessing quality survivorship care nationally.

Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer.

PURPOSE: Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss. Receptor Activator of Nuclear Factor Kappa-B (RANK)-RANK ligand (RANK-L) signaling balances bone resorption and formation. Osteoprotegerin (OPG) acts as a decoy receptor for RANK, interrupting osteoclast activation and bone resorption. This study examined the relationship between OPG and bone loss in women with CIOF. METHODS: Premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated at chemotherapy initiation, 6 and 12 months. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), follicle stimulating hormone (FSH), ionized calcium, osteocalcin, and OPG were serially measured. CIOF was defined as a negative pregnancy test, FSH levels >30 MIU/mL, and ≥3 months of amenorrhea. RESULTS: Forty women were enrolled; 31 (77.5%) met CIOF criteria. BMD significantly decreased (p < 0.001) in the CIOF group at both time points: LS BMD decreased from a median of 0.993 g/cm(2) to 0.976 g/cm(2) and 0.937 g/cm(2) at 6 and 12 months, respectively. OPG was significantly elevated at 6 months (median increase 0.30 pmol/L, p = 0.015) and then decreased at 12 months to levels still above baseline (median difference 0.2 pmol/L, p = 0.70). CONCLUSIONS: In what was likely a compensatory response to rapid bone loss, CIOF patients' OPG levels increased at 6 months and then decreased at 12 months to values greater than baseline assessments. This phenomenon is described in other diseases, but never before in CIOF.

Quality improvement in breast cancer project: compliance with antiresorptive agents and changing patterns of drug use.

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute participated in NCCN's Quality Improvement in Breast Cancer initiative. The Opportunities for Improvement (OFI) team elected to improve concordance with the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer recommendation that all patients diagnosed with skeletal metastases receive bisphosphonates. Assembling a multidisciplinary team of clinicians, researchers, and administrative stakeholders, the OFI team followed Six Sigma's approach to problem-solving known as DMAIC (define, measure, analyze, improve, and control). Baseline concordance was 79%, which was below the recommended target range. Initial analysis quickly revealed that 5 cases were concordant, resulting in a new baseline of 89%. The key root cause identified for the remaining gap was lack of documentation. The solution included education regarding documentation for existing staff, in addition to hard-wiring the material into new physician orientation, discussion of all patients with bone disease at tumor board meetings, and improved consistency with use of the new electronic medical record system. After implementation, the reported concordance was 92%, and the lack of documentation problem decreased from 11% in the baseline study to 6%. The team concluded that use of the NCCN Oncology Outcomes Database as an opportunity for clinical quality improvement initiatives not only is possible but also should be an essential element of any clinical program looking to continuously improve.

Yoga's impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial.

PURPOSE: To evaluate yoga's impact on inflammation, mood, and fatigue. PATIENTS AND METHODS: A randomized controlled 3-month trial was conducted with two post-treatment assessments of 200 breast cancer survivors assigned to either 12 weeks of 90-minute twice per week hatha yoga classes or a wait-list control. The main outcome measures were lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1ß (IL-1ß), and scores on the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the vitality scale from the Medical Outcomes Study 36-item Short Form (SF-36), and the Center for Epidemiological Studies-Depression (CES-D) scale. RESULTS: Immediately post-treatment, fatigue was not lower (P > .05) but vitality was higher (P = .01) in the yoga group compared with the control group. At 3 months post-treatment, fatigue was lower in the yoga group (P = .002), vitality was higher (P = .01), and IL-6 (P = .027), TNF-α (P = .027), and IL-1ß (P = .037) were lower for yoga participants compared with the control group. Groups did not differ on depression at either time (P > .2). Planned secondary analyses showed that the frequency of yoga practice had stronger associations with fatigue at both post-treatment visits (P = .019; P < .001), as well as vitality (P = .016; P = .0045), but not depression (P > .05) than simple group assignment; more frequent practice produced larger changes. At 3 months post-treatment, increasing yoga practice also led to a decrease in IL-6 (P = .01) and IL-1ß (P = .03) production but not in TNF-α production (P > .05). CONCLUSION: Chronic inflammation may fuel declines in physical function leading to frailty and disability. If yoga dampens or limits both fatigue and inflammation, then regular practice could have substantial health benefits.

Bone health in adult cancer survivorship.

Optimizing health outcomes, including prevention of osteoporotic fractures, is essential for promoting the well-being of the growing number of cancer survivors. Medical providers who participate in the care of cancer survivors should be aware that various cancer treatments may cause bone loss, which can increase the risk of subsequent of osteoporosis. Healthy bone remodeling is a balanced and dynamic equation between new bone formation and bone resorption. Aging, natural menopause, and cancer treatments such as surgical oophorectomy, gonadotropin-releasing hormone agonists, chemotherapy-induced ovarian failure, androgen deprivation therapy, and aromatase inhibitors can all promote bone loss. The WHO Fracture Assessment Tool can be used as a clinical aid to assess an individual's osteoporotic fracture risk, with or without bone mineral density measurements obtained from dual-energy x-ray absorptiometry. Preventative strategies include adequate calcium and vitamin D supplementation and modifying risk factors such as alcohol intake, tobacco use, and lack of exercise. Bisphosphonate therapy and rank-ligand monoclonal antibody therapy are the most commonly used agents for management of bone loss resulting from cancer treatment. This review will summarize the mechanisms by which cancer treatments cause bone loss as well provide screening and treatment recommendations for the management of bone loss.

Premature ovarian failure and body composition changes with adjuvant chemotherapy for breast cancer.

OBJECTIVE: Premature ovarian failure and weight gain are both common in women receiving adjuvant chemotherapy for breast cancer. The objective of this preliminary analysis was to characterize changes in weight and body composition in premenopausal women receiving adjuvant chemotherapy for early stage breast cancer and investigate whether these changes were associated with chemotherapy-induced ovarian failure (CIOF). METHODS: The body composition of 43 premenopausal women with stage I or II breast cancer was measured using dual-energy x-ray absorptiometry within 4 weeks before beginning chemotherapy and after 12 months from baseline. At 12 months, the CIOF was determined using the history of amennorhea for 3 months or more and serum follicle-stimulating hormone. RESULTS: Of the 43 women, 30 (70%) developed CIOF by the 12-month follow-up. Significant weight gain occurred in women with and without CIOF and consisted of fat but not lean mass in the trunk and legs. In women who developed CIOF, truncal fat increased by a median of 1.8 kg (P = 0.0004), whereas truncal lean mass decreased by 0.6 kg (P = 0.02). Women who retained ovarian function gained a median of 0.9 kg (P = 0.06) in truncal fat with no significant change in truncal lean mass. Women with CIOF tended to lose lean mass. Loss of total body lean mass was directly correlated with the decrease in bone density as measured by bone mineral density at the femoral neck (Spearman correlation coefficient, 0.4; P = 0.03). Energy intake decreased similarly in women with and without CIOF (-184 vs -290 kcal, respectively; P = 0.77). CONCLUSIONS: The results of this small preliminary analysis suggest that body composition changes in women receiving adjuvant chemotherapy for breast cancer include an increase in fat mass in the trunk and leg regions without an increase in fat-free mass. Future research with a larger study cohort and longer follow-up is needed to further investigate the role of CIOF in body composition changes in women with breast cancer. Further research is also needed to evaluate the potential effects of body composition changes on breast cancer outcomes.

A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer.

The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.

NCCN Task Force Report: Bone Health in Cancer Care.

Bone health and maintenance of bone integrity are important components of comprehensive cancer care in both early and late stages of disease. Risk factors for osteoporosis are increased in patients with cancer, including women with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors for breast cancer, men receiving androgen-deprivation therapy for prostate cancer, and patients undergoing glucocorticoid therapy. The skeleton is a common site of metastatic cancer recurrence, and skeletal-related events are the cause of significant morbidity. The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force on Bone Health in Cancer Care to discuss the progress made in identifying effective screening and therapeutic options for management of treatment-related bone loss; understanding the factors that result in bone metastases; managing skeletal metastases; and evolving strategies to reduce bone recurrences. This report summarizes presentations made at the meeting.

The LIVESTRONG Survivorship Center of Excellence Network.

INTRODUCTION: The LIVESTRONG Survivorship Center of Excellence Network consists of eight National Cancer Institute-designated Comprehensive Cancer Centers funded by the LAF between 2004 and 2008. The Network was created to accelerate the pace of progress in addressing the needs of the growing survivor community. METHODS: This paper will briefly describe some of the salient issues surrounding the care of cancer survivors, and examine models of survivorship care that are being developed in individual Centers of Excellence (COE) as well as in the overall Network. RESULTS AND CONCLUSIONS: As the recommendations and policies for optimal survivorship care have to be feasible and relevant in the community setting, each COE is partnered with up to three community affiliates. Through these partnerships, the community affiliates develop survivorship initiatives at their institutions with support and guidance from their primary COE.

Applying a conceptual model for examining health-related quality of life in long-term breast cancer survivors: CALGB study 79804.

OBJECTIVES: The Survivor's Health and Reaction study used a quality-of-life model adapted for cancer survivors by Dow and colleagues to identify factors related to global health-related quality of life (HRQL) and to document the prevalence of problems and health-oriented behaviors in a follow-up study of breast cancer patients who participated in CALGB 8541. METHODS: A total of 245 survivors (78% of those invited) who were 9.4-16.5 years post-diagnosis completed surveys that inquired about current HRQL, economic, spiritual, physical and psychosocial concerns, and health-oriented behaviors (e.g. smoking, exercise, and supplement use). A regression model was developed to examine factors related to global HRQL across all domains. RESULTS: The regression model revealed that decreased energy levels (odds ratio (OR)=1.05, 95% confidence interval (CI): 1.03, 1.07), having heart disease (OR=5.01, 95% CI: 1.39, 18.1), having two or more co-morbidities (OR=2.39, 95% CI: 1.10, 5.19), and lower social support (OR=1.03, 95% CI: 1.02, 1.05) were associated with lower global HRQL. Factors related to psychological, spiritual, and economic domains were not predictive of global HRQL. Regarding lifestyle changes, some women reported engaging in health-oriented behaviors since their cancer diagnosis, such as improving eating habits (54%), increasing exercise (32%), and reducing/quitting smoking (20%). The most prevalent problems reported by women at follow-up were menopausal symptoms (64%), such as hot flashes and vaginal dryness, osteoporosis (25%), and lymphedema (23%). CONCLUSION: Suggestions are provided to target interventions, such as provider-based strategies, in order to improve HRQL in long-term breast cancer survivors.

Serum selenium measurements in women with early-stage breast cancer with and without chemotherapy-induced ovarian failure.

Blood selenium has been shown to decline as breast cancer progresses and fluctuate with estrogen. The objective of this study was to determine the effect of estrogen depletion resulting from chemotherapy-induced ovarian failure on serum selenium and selenoproteins in stage I/II premenopausal breast cancer patients. Serum selenium, glutathione peroxidase (GPx) activity, and selenoprotein P (SelP) were measured and a dietary questionnaire was completed at baseline (before chemotherapy) and 6, 12, and 24 months after start of chemotherapy. Twelve months after the start of adjuvant chemotherapy 33 (75%) patients developed ovarian failure (OF) and 11 (25%) retained menstrual function (non-OF). Dietary selenium intake was 30-58% above the Recommended Dietary Allowance for both groups. By six months the mean estradiol (pg/ml) was lower in the OF group than in the non-OF group (32+/-5 versus 140+/-62 pg/ml, p=0.01) and this difference was maintained at 12 and 24 months. However, there was no differences in serum selenium, GPx activity, or SelP in the OF and non-OF groups at 6, 12, and 24 months. Selenium status in premenopausal breast cancer patients, as measured by serum selenium, GPx and SelP, was within the normal range before and following adjuvant chemotherapy, and was not affected by chemotherapy-induced ovarian failure.

NCCN Task Force Report: Bone Health and Cancer Care.

Higher incidences of osteoporosis and osteopenia are found in cancer patients, particularly in women receiving aromatase inhibitors or with chemotherapy-induced ovarian failure, or in men with prostate cancer and androgen deprivation therapy. Therefore, management of long-term bone health is emerging as an important aspect of comprehensive cancer care. Patients with cancer typically have a number of additional risk factors for osteoporosis that should prompt screening, regardless of patient age or sex. Maintaining bone health requires a broad knowledge base, including understanding underlying bone metabolism and how it is affected by both cancer itself and the drugs used to treat cancer, the effect of chemotherapy-induced menopause on bone health, bone markers and imaging techniques used to assess bone health, therapeutic strategies to maintain bone health, and treatment of bone metastases, including surgery for pathologic fractures. Multiple members of the healthcare team may need to be involved in education and care of the patient. This report summarizes discussion of these and other issues regarding bone health and cancer care from the NCCN Bone Health and Cancer Care Task Force meeting in early 2006.

Baseline bone mineral density of the total lumbar spine may predict for chemotherapy-induced ovarian failure.

Age at treatment and the total cumulative dose of cyclophosphamide are established predictors of chemotherapy-induced ovarian failure in premenopausal women with breast cancer. In a prospective trial of 49 women receiving adjuvant chemotherapy, we sought to identify whether other factors including family history of osteoporosis, lifestyle factors, reproductive hormones, bone turnover markers, or bone mineral density (BMD) of the hip or total spine measured before (baseline) and 6 months after chemotherapy increased the risk of ovarian failure. Univariate logistic regression analyses were used to identify the variables related to the risk of ovarian failure, and a multivariate logistic regression model was used to find the best of predictors of ovarian failure among the variables. In the multivariate model a higher total spine BMD at baseline (OR=6.0, p=0.02, 95% CI 1.4-27.3), and a 10% change in estradiol (E2) from baseline to six months (OR=0.80, p=0.02, 95% CI 0.67-0.97) were predictive of ovarian failure adjusted for age. In particular, as total spine BMD at baseline increases by 0.1 g/cm2 the odds of developing chemotherapy-induced ovarian failure increases by 6-fold. The multivariate model provides a good fit to the data (GOF p-value=0.8852), and provides excellent discrimination between those women who will and will not develop ovarian failure (Area under ROC=0.9487). If confirmed in larger data sets, using baseline spinal BMD to identify women who are at higher risk of developing ovarian failure independent of their age would be of value.

Osteopenia and osteoporosis in women with breast cancer.

Osteopenia and osteoporosis are prevalent in women. Epidemiologic studies show that the risk of breast cancer is greater in postmenopausal women with higher bone mineral density (BMD). Standard treatments for breast cancer such as adjuvant chemotherapy or hormonal therapy can increase bone loss, and hence may increase the risk of osteoporosis. Premenopausal women treated with standard adjuvant chemotherapy frequently develop permanent ovarian failure, or early menopause. Ovarian failure is associated with accelerated bone loss, and bisphosphonates may mitigate this bone loss in women treated with adjuvant chemotherapy. Tamoxifen preserves BMD in postmenopausal women; however, in premenopausal women tamoxifen may increase bone loss. Anastrazole, an aromatase inhibitor, is approved for adjuvant treatment of postmenopausal women with early-stage, estrogen receptor-positive breast cancer. With a follow-up duration of less than 5 years, anastrazole-treated women experience increased fractures relative to those treated with tamoxifen. The management of osteopenia and osteoporosis in women with breast cancer generally does not differ from women without breast cancer. Adequate dietary calcium and vitamin D intake, encouraging weight-bearing exercise, and counseling about the relationship between smoking and alcohol and bone loss are all prudent recommendations for overall health and may lessen bone loss and the risk of subsequent osteoporosis. BMD should be measured in women with chemotherapy-induced ovarian failure, and in those on aromatase inhibitors. Bisphosphonates reduce the bone loss associated with chemotherapy-induced ovarian failure, and clinical trials evaluating third-generation bisphosphonates in women with chemotherapy-induced ovarian failure are underway. As many women with breast cancer will be long-term survivors, increasing recognition of maintaining skeletal health is important.

Older women with breast carcinoma are less likely to receive adjuvant chemotherapy: evidence of possible age bias?

BACKGROUND: Older women with breast carcinoma are less likely than younger women to receive adjuvant chemotherapy. The authors hypothesized that after controlling for confounders (i.e., variables related to both age and chemotherapy use) and effect modifiers (i.e., variables that have a significant interaction with age), age would become a less significant factor for predicting adjuvant chemotherapy use. METHODS: Data on 480 women with localized breast carcinoma were entered into the National Comprehensive Cancer Network database at The Ohio State University Medical Center. Women were divided into 3 groups: women age < 50 years (n = 143 [30%]), women ages 50-65 years (n = 216 [45%]), and women age > 65 years (n = 121 [25%]). Chi-square and Wilcoxon rank sum tests were used for univariate analyses of the variables of interest, and logistic regression was used for multivariate analyses. RESULTS: After adjustment for confounders (stage, tumor size, progesterone receptor status, and lymph node involvement) and effect modifiers (namely, estrogen receptor [ER] status), the odds of not receiving chemotherapy for women ages 50-65 years and women age > 65 years with ER-positive breast carcinoma were approximately 6 (odds ratio [OR], 6.4; 95% confidence interval [CI], 3.1-13.3; P < 0.001) and 62 (OR, 62.4; 95% CI, 21.8-178.7; P < 0.001) times greater, respectively, than the odds for women age < 50 years. Women ages 50-65 years with ER-negative breast carcinoma were not significantly different from women age < 50 years with respect to chemotherapy use (OR, 1.9; 95% CI, 0.5-7.3; P = 0.374). However, the odds of not receiving chemotherapy for women age > 65 years with ER-negative breast carcinoma were 7 times (OR, 6.7; 95% CI, 1.5-30.6; P = 0.013) greater than the odds for women age < 50 years. CONCLUSIONS: The results of the current study indicate that based on older age alone, women are less likely to receive adjuvant chemotherapy. In addition, the results suggest that age bias may contribute to undertreatment and lack of accrual of older women into clinical trials.