Menopausal symptoms and adjuvant therapy-associated ... - CiteSeerX

Endocrine-Related Cancer (2008) 15 73–90

REVIEW

Menopausal symptoms and adjuvant therapy-associated adverse events P Hadji Department of Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Baldingerstrasse, 35033 Marburg, Germany (Correspondence should be addressed to P Hadji; Email: [email protected])

Abstract Third-generation aromatase inhibitors (AIs) are replacing tamoxifen as adjuvant therapy in postmenopausal women with hormone-sensitive breast cancer due to their superiority shown in several recent head-to-head trials. Healthy postmenopausal women normally experience age-related side effects, and in postmenopausal women with breast cancer, these symptoms may be exacerbated by adjuvant endocrine therapy. This review evaluates the current literature regarding bone health, lipid metabolism, cardiovascular disease, gynecologic health, and cognition in postmenopausal women receiving adjuvant AI therapy. The AIs – anastrozole, exemestane, and letrozole – are generally well tolerated: most adverse events are mild to moderate and common to menopause. Common short-term AI-associated toxicities are hot flushes, musculoskeletal complaints/arthralgia, and bone loss, all of which can be effectively managed. AIs may lack the cardioprotective and lipid-lowering effects of tamoxifen but, in contrast to tamoxifen, do not increase the risk of serious life-threatening thromboembolic or cerebrovascular events or endometrial cancer. Every patient should be individually assessed with respect to therapy risks and benefits. Lifestyle, comorbidities, and concomitant medications must be considered, and the importance of compliance to adjuvant therapy should be discussed before selecting a treatment regimen. The superior efficacy of adjuvant AI therapy will in most cases outweigh the risk of bothersome side effects that can be prevented or easily managed. Endocrine-Related Cancer (2008) 15 73–90

Introduction In Europe, breast cancer is the most common cancer in females, and two-thirds of breast tumors occur in postmenopausal women aged 55 years and older who may also have age-related comorbidities (e.g., hypertension, arthritis, heart disease, osteoporosis, and diabetes) that could affect treatment decisions and prognosis (Yancik et al. 2001, Tyczynski et al. 2004). The adverse events (AEs) associated with a particular adjuvant therapy thus must be considered when making treatment choices. The antiestrogen tamoxifen had been the standard adjuvant therapy in postmenopausal women with hormone-sensitive (hormone receptor- positive) early breast cancer hazard ratio (HRCEBC) for 20 years (Nolvadex Adjuvant Trial Organization 1983). Tamoxifen therapy not only reduced breast cancer recurrence and mortality but was also associated with an increased incidence of thromboembolic events and endometrial cancer, as well as other bothersome AEs, including vaginal discharge, fluid retention, and hot flushes (Fisher

et al. 1996, Early Breast Cancer Trialists’ Collaborative Group 2005), which increase the likelihood of therapy discontinuation (Demissie et al. 2001). Tamoxifen inhibits the action of estrogen at the estrogen receptor, whereas aromatase inhibitors (AIs) inhibit the aromatase enzyme that converts androgens to estrogen (Brodie et al. 2003). The AIs have a different mechanism of action and a different safety profile that does not include the increased risk of serious AEs, such as thromboembolic events and endometrial cancer (Brodie et al. 2003, Howell et al. 2005, Thu¨rlimann et al. 2005, Coombes et al. 2007). These results come from several AI trials that varied in their safety evaluations. Some classified AEs according to COSTART definitions (Arimidex, Tamoxifen, Alone or in Combination; ATAC), while others used the National Cancer Institute common toxicity criteria (Breast International Group (BIG) 1–98, Intergroup Exemestane Study (IES), MA.17), and still others did not explicitly state the method for reporting and grading of AEs

Endocrine-Related Cancer (2008) 15 73–90 1351–0088/08/015–073 q 2008 Society for Endocrinology Printed in Great Britain

DOI: 10.1677/ERC-07-0193 Online version via http://www.endocrinology-journals.org

P Hadji: Menopausal symptoms and adverse events (Tamoxifen, Exemestane Adjuvant Multicenter (TEAM); Arimidex/Nolvadex (ARNO 95); Austrian Breast and Colorectal Study Group (ABCSG 8); International Breast Cancer Intervention Study (IBIS) II; ZO-FAST, the companion study of the Zometa/ Femara Adjuvant Synergy Trial (Z-FAST); Italian Tamoxifen Anastrozole (ITA); and Adjuvant postTamoxifen Exemestane versus Nothing Applied (ATENA)). Several guidelines now advocate the use of AIs in the adjuvant setting for the management of postmenopausal women with HRCEBC (Goldhirsch et al. 2005, Winer et al. 2005). The third-generation AIs, letrozole, anastrozole, and exemestane, have been approved for the adjuvant treatment of HRCEBC, are displacing tamoxifen as initial adjuvant therapy (Howell et al. 2005, Thu¨rlimann et al. 2005), and are being used as adjuvant therapy following the completion of 2–5 years of tamoxifen (Boccardo et al. 2005, Goss et al. 2005, Jakesz et al. 2005, Coombes et al. 2007). Yet, as adjuvant AI therapy reduces estrogen levels in postmenopausal women even further, such therapy is expected to exacerbate some of the menopausal symptoms women experience as they grow older. Patients and their physicians must weigh the benefits and risks of each therapy and consider comorbidities when making treatment decisions (Theriault et al. 2006). In this review, we discuss some safety concerns associated with adjuvant endocrine therapy and how these AEs, if they develop, may be managed so that patients do not discontinue their therapy.

Fractures and osteoporosis Osteoporosis is a very common condition in postmenopausal women that is associated with low bone density and an increased risk for bone fragility and fracture (Melton 2002, Tuck & Francis 2002). Regarding fractures, about one in two women over the age of 50 is likely to experience such an event in her lifetime (Melton 2002). Estrogen plays a critical role in bone health (Mackey & Joy 2005), which deteriorates with aging (Hadji et al. 2002) and accelerates after menopause because of decreased circulating estrogen (Devine et al. 2005). Substudies of the Women’s Health Initiative Observational Study (NZ93 676) have shown that postmenopausal breast cancer survivors have significantly lower total body bone mineral density (BMD) and total hip BMD (Chen et al. 2005a), as well as an increased risk of clinical fracture, compared with women without a history of cancer (Chen et al. 2005b). 74

Chemotherapy

Chemotherapy-induced ovarian failure, surgical or medical ovarian ablation, and estrogen deprivation therapy in women with HRCEBC have all been shown to result in bone loss (Bruning et al. 1990, Aapro 2004). This was confirmed in a large retrospective study of women with non-metastatic breast cancer (NZ14 604), which showed that anticancer therapy with chemotherapy and hormonal agents increased the risk of osteoporosis/osteopenia (Boyce et al. 2005). Other factors such as poor health status, history of smoking and alcohol abuse, low baseline BMD, prevalent fracture, family history of osteoporosis, tendency for falls, corticosteroid use, as well as the presence of bone metastases, may also influence treatment-related osteoporosis (Boyce et al. 2005, Garreau et al. 2006, Mouridsen 2006). Disease- and treatment-associated skeletal-related events included fracture, spinal compression, bone pain, and hypercalcemia of malignancy. Vertebral fracture risk markedly increased in women with breast cancer (Kanis et al. 1999). Chemotherapy agents such as methotrexate and ifosfamide could potentially induce negative effects on bone metabolism (Pfeilschifter & Diel 2000). In a cross-sectional study (NZ27) to investigate lumbar spine BMD in patients with breast cancer previously treated with adjuvant chemotherapy, 16 patients experienced treatment-related amenorrhea and had 14% lower BMD than did those who maintained menses (Headley et al. 1998). Another study (NZ49) showed that the median percentage decrease of spine BMD was K4.0 between 0 and 6 months and K3.7 between 6 and 12 months in the 35 patients who experienced chemotherapy-induced ovarian failure compared with no significant decrease in BMD in the 14 patients who retained ovarian function (Shapiro et al. 2001). In a study of premenopausal women with breast cancer (NZ73) treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy, changes in BMD, 3 and 5 years after treatment were correlated with menstrual function; however, 3 years of bisphosphonate treatment significantly reduced bone loss in the lumbar spine (Vehmanen et al. 2001). Another study in CMF-treated premenopausal women (NZ148), showed rapid bone loss in women who developed amenorrhea after chemotherapy, compared with only marginal changes in BMD in those with continued menstruation; women older than 40 years of age were at especially high risk (Saarto et al. 1997). Serum estrogen receptor modulators (SERMs) Raloxifene

Results from the Multiple Outcomes of Raloxifene Evaluation trial showed that raloxifene, a selective www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 estrogen receptor modulator, prevents bone loss and reduces the risk for clinical vertebral fracture (relative risk (RR) 0.20; 95% confidence interval (CI) 0.03–0.90; PZ0.034; Qu et al. 2005). Absolute risk reduction (0.17%) was seen as early as 3 months in postmenopausal women with osteoporosis (Qu et al. 2005). In the Continuing Outcomes Relevant to Evista (CORE) trial, raloxifene significantly increased lumbar spine (4.3 and 2.2% from baseline and placebo respectively) and femoral neck BMD (1.9 and 3.0% from baseline and placebo respectively); however, it had no effect on non-vertebral fracture risk after 8 years compared with placebo (Siris et al. 2005). Currently, raloxifene is being investigated in the prevention of primary breast cancer in the Study of Tamoxifen and Raloxifene (STAR) trial; it has been shown to have a risk of fractures similar to tamoxifen and increased musculoskeletal problems compared with tamoxifen (Vogel et al. 2006). Tamoxifen

While tamoxifen has repeatedly proven not to have bone-sparing effects in premenopausal women (Vehmanen et al. 2006), it has demonstrated beneficial effects on bone in postmenopausal women. Two randomized trials showed significant increases in BMD with tamoxifen compared with placebo. A 2-year trial in 140 postmenopausal women found that mean BMD of the lumbar spine increased by 61% per year in women receiving tamoxifen, compared with a 1% decrease per year in those receiving placebo (P!0.001; Love et al. 1992). In another 2-year trial (NZ50), lumbar spine BMD increased during the first year in tamoxifen-treated postmenopausal women and stabilized, compared with decreased BMD in the control group (PZ0.00074; Kristensen et al. 1994). However, some bone loss also occurs naturally as women age or as a consequence of chemotherapy and concomitant medication, and some women on tamoxifen do experience bone loss. A recent study of 118 women who completed 5 years of tamoxifen therapy showed that 23.7 and 41.5% of women had osteoporosis and osteopenia respectively, and 25% of women required treatment with bisphosphonates (Whannel et al. 2006). An international study of 746 women prior to randomization to tibolone found that 11% of women had osteoporosis and 43% had osteopenia after adjuvant endocrine therapy (chemotherapy, tamoxifen, AIs; Bundred et al. 2006a). Aromatase inhibitors

Results of the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) trial showed that, in healthy www.endocrinology-journals.org

women volunteers (NZ90), all three AIs had similar effects on bone biochemical measurements, resulting in increased bone turnover (McCloskey et al. 2006a). Another study in healthy postmenopausal volunteers (NZ77) showed that all three AIs increased levels of bone resorption markers (Goss et al. 2003). Likewise, in a retrospective longitudinal analysis of 1354 women with breast cancer, the prevalence of osteoporosis/osteopenia (8.7 vs 7.1%; PZ0.01) and bone fracture (13.5 vs 10.3%; PZ0.001) was significantly higher in the AI than non-AI group on univariate analysis; similarly, on multivariate analysis, the increase in risk of osteoporosis and fracture was 27 and 21% respectively (Mincey et al. 2006). BMD loss and the risk of fracture and osteoporosis in adjuvant AI trials

In the ATAC trial (NZ6186), fracture rates per 1000 woman-years were 22.6 and 15.6 for anastrozole and tamoxifen respectively, at a median follow-up of 68 months (P!0.0001; Howell et al. 2005). A higher incidence of osteopenia/osteoporosis (11 vs 7%; P!0.0001) and fractures (11 vs 7.7%; P!0.0001), significant BMD loss, and increased bone turnover is also seen with anastrozole, whereas tamoxifen is associated with increased BMD and decreased remodeling. In the ATAC trial bone substudy (NZ167), assessment of lumbar spine and total hip BMD at baseline and 1, 2, and 5 years using dual-energy X-ray absorptiometry (DEXA) showed that significant bone loss occurred throughout the treatment period, with a decline in the rate of loss in years 2 through 5 (Coleman 2006). Patients receiving anastrozole (nZ81) experienced significant decreases in lumbar spine (K8.1%; P!0.0001) and total hip (K7.4%; P!0.0001) BMD compared with patients receiving tamoxifen (nZ86), in whom small increases were observed (Coleman 2006, Eastell et al. 2006). Similarly, in the randomized, double-blind, phase III BIG 1–98 trial (NZ8010), the incidence of fracture was higher in the letrozole arm compared with the tamoxifen arm (5.7 vs 4.0% respectively; P!0.001) after a median follow-up of 25.8 months (Thu¨rlimann et al. 2005). A subset analysis restricted to the monotherapy arm (letrozole 5 years versus tamoxifen 5 years) analysis (nZ4922) of BIG 1–98 at 51-month follow-up confirmed these findings (8.6 vs 5.8% respectively; P!0.001; Coates et al. 2007). The increased risk for bone loss and fracture is also seen when a steroidal AI (exemestane) is used in the switch setting. In the IES (nZ4724), the incidence of fracture (7.0 and 4.9% respectively; PZ0.003) and osteoporosis (9.2 and 7.2% respectively; PZ0.01) was significantly higher with exemestane at a median 75

P Hadji: Menopausal symptoms and adverse events follow-up of 55.7 months (Coombes et al. 2007). In the IES bone substudy (nZ206), patients who switched to exemestane had decreased BMD at the lumbar spine (2.7% reduction, 95% CI 2.0–3.4; P!0.0001) and hip (1.4% reduction, 95% CI 0.8–1.9; P!0.0001) within 6 months of switching, but no significant changes in BMD were observed in patients who continued on tamoxifen. At 2 years, the BMD decrease was 1.0% at the lumbar spine (95% CI 0.4–1.7; PZ0.002) and 0.8% at the hip (95% CI 0.3–1.4; PZ0.003; Coleman et al. 2007). Results of another recent study also showed that switching postmenopausal women from tamoxifen to exemestane led to marked increases in bone turnover markers and reduced BMD (Gonnelli et al. 2007). Studies of AIs versus placebo also report increases in the incidence of fracture risk. At the time of the unblinding of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33, a study evaluating extended adjuvant exemestane therapy after 5 years of tamoxifen, more fractures were reported in patients receiving exemestane (nZ783) than in those receiving placebo (nZ779; 28 versus 20 patients; PZ0.33; Mamounas et al. 2006). Likewise, in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 trial (NZ5187), letrozole was associated with a non-significant increase in the incidence of fracture compared with placebo (5.3 vs 4.6%; PZ0.25), and a small but significant difference in patient-reported diagnosis of new-onset osteoporosis (8.1 vs 6.0%; PZ0.003; Goss et al. 2005; Table 1). In the MA.17 bone substudy (nZ226), patients receiving letrozole showed a significant decrease in total hip (K3.6 vs K0.71%; PZ0.044) and lumbar spine (K5.35 vs K0.70%; PZ0.008) BMD at 24 months, but no patient dropped below the threshold for osteoporosis in total hip BMD (Perez et al. 2006).

Table 1 Adverse events and toxicities in patients in NCIC CTG MA.17 trial (Goss et al. 2005)

Adverse event/toxicity

Letrozole no. (%) (nZ2572)

Placebo no. (%) (nZ2577)

P value

Hypercholesterolemia Vaginal bleeding Arthralgia Sweating Clinical bone fracture New osteoporosis Cardiovascular disease

418 (16) 145 (6) 651 (25) 782 (30) 137 (5.3) 209 (8.1) 149 (5.8)

411 (16) 196 (8) 532 (21) 760 (29) 119 (4.6) 155 (6.0) 144 (5.6)

0.79 0.005 !0.001 0.48 0.25 0.003 0.76

NCIC CTG, National Cancer Institute of Canada Clinical Trials Group.

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Musculoskeletal/joint symptoms Arthralgia and musculoskeletal pain have been reported in postmenopausal women undergoing AI treatment (Morales et al. 2006). A recent survey reported that joint aches were reported as the fourth most troublesome symptom by both tamoxifen and AI users (12 and 23% respectively; PZ0.002), after hot flushes, weight gain, and insomnia (Garreau et al. 2006). Early morning stiffness and hand/wrist pain are other frequently reported musculoskeletal symptoms experienced by postmenopausal women receiving adjuvant AI treatment (Morales et al. 2006). Among patients reporting joint pain in a study of postmenopausal women receiving adjuvant AI therapy, 70% reported worsening of baseline pain after the initiation of AI therapy and 30% developed pain; 50% of patients reported worsening of baseline joint stiffness after the initiation of AI therapy and 50% developed joint stiffness (Crew et al. 2006a). Joint symptoms in adjuvant AI trials

In the ATAC trial, arthralgia was more frequently reported with anastrozole than with tamoxifen (35.6 vs 29.4%; P!0.0001), however, 46% of patients considered such symptoms to be an exacerbation of a preexisting condition (Buzdar 2006a). Only 2.1% of patients receiving anastrozole and 0.9% of those receiving tamoxifen withdrew from the study because of a joint symptom. Carpal tunnel syndrome was more common with anastrozole (3 vs 1%; P!0.0001), but muscle cramps were more common with tamoxifen (4 vs 8%; P!0.0001). Patients in the BIG 1–98 trial receiving initial adjuvant letrozole also had a higher incidence of arthralgia than those receiving tamoxifen (20.3 vs 12.3%; P!0.001; Thu¨rlimann et al. 2005); and initial adjuvant exemestane has also been associated with more bone/ muscle aches than tamoxifen (Asmar et al. 2005). In IES, switching to exemestane was associated with a higher incidence of arthralgia (20.8 vs 15.1%; P!0.0001) and carpal tunnel syndrome (2.8 vs 0.4%; P!0.0001) when compared with continued tamoxifen therapy (Coombes et al. 2007). The increased risk of arthralgia is also seen in trials that compare AIs with a placebo. At the time of unblinding of the NSABP B-33, the most common grade 3/4 toxicities in patients receiving extended adjuvant exemestane or placebo were arthralgia (1.0 vs 0.5%), and bone pain (0.5 vs 0.7%; Mamounas et al. 2006). Likewise, in the MA.17 trial, women who received letrozole had a significantly higher incidence of arthralgia (25 vs 21%; P!0.001) than women receiving placebo, while the incidence of arthritis www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 was similar between the treatment arms (6 vs 5%; PZ0.07; Goss et al. 2005). Clinical management of bone health

The education of patients and health care professionals regarding effective treatment options for the adverse effects of AIs on bone health is critical (Guise 2006). A recent survey showed that patients treated with tamoxifen and AIs report different and significant side effects, and slight differences in the use of medications for effective symptom control, but the costs associated with symptom control were similar and not a major barrier to treatment (Garreau et al. 2006). Arthralgia and joint pain can be bothersome and may lead to impaired mobility; patients need to be advised that constant exercising of joints and the use of exogenous estrogens may alleviate the problem (Chlebowski et al. 2006). AI-associated pain can generally be managed with over-the-counter analgesics and glucosamine (Presant et al. 2006): a recent study also suggests that acupuncture may be effective (Crew et al. 2006b). A study (NZ147) investigating the potential deleterious effect of adjuvant exemestane on bone reported vitamin D deficiency in the majority of patients in both the placebo (56/62) and exemestane (52/59) groups, suggesting that vitamin D deficiency may play a role in the incidence of bone symptoms in postmenopausal women (Lønning et al. 2006). Yet, data from the IBIS II, a breast cancer prevention study of 6000 postmenopausal women at increased risk of breast cancer receiving anastrozole versus placebo, suggest that AI-induced arthralgia is not correlated with 25(OH) vitamin D levels (Singh et al. 2006a,b). Vitamin D deficiency has been shown to increase bone loss and fracture risk (Brazier et al. 1995, Prince et al. 1995), and patient comorbidities may influence treatment-related osteoporosis/osteopenia (Boyce et al. 2005). All patients receiving adjuvant AI therapy should be given calcium and vitamin D supplementation and encouraged to engage in weight-bearing exercise (Morandi et al. 2004). Lifestyle modification and bisphosphonates can improve patient outcome (Guise 2006). Bisphosphonate therapy has shown great benefit in the management of cancer treatment-induced bone loss. In the Z-FAST, 602 postmenopausal women starting adjuvant therapy with letrozole were randomized to receive upfront or delayed zoledronic acid (ZA; Brufsky et al. 2007). The effectiveness and safety of ZA therapy on AI-induced bone loss seen at 12 months was continued at the 24-month assessment (Brufsky et al. 2006, www.endocrinology-journals.org

2007). At month 24, the upfront ZA group (nZ201) showed a mean increase of 1.37% in total hip BMD, while the delayed group (nZ190) showed a mean decrease of 3.24%. Greater changes were seen at the lumbar spine BMD, as the upfront ZA group (nZ200) demonstrated a mean increase of 3.06% and the delayed group (nZ191) showed a mean decrease of 2.89% (Brufsky et al. 2006). Results of ZO-FAST (a companion trial conducted in 28 countries outside North America) and a combined Z-FAST/ZO-FAST analysis also support the use of ZA to manage AI-induced bone loss (Brufsky et al. 2006, Bundred et al. 2006b). The Study of Anastrozole with the Bisphosphonate Risedronate (SABRE) trial is investigating the effect of the bisphosphonate risedronate sodium on BMD and serum lipid profile in postmenopausal women treated with adjuvant anastrozole (Van Poznak et al. 2006). All AIs have been associated with accelerated bone loss and increased risk of fracture, but this should not limit their use. Patients at risk of BMD loss during treatment should be identified and managed according to evolving clinical guidelines (Lester et al. 2005, US Preventive Services Taskforce 2005, Winer et al. 2005, Mouridsen 2006). Current guidelines (American Society of Clinical Oncology) recommend that only women with osteoporosis (T-score ! K2.5) receive bisphosphonate therapy to increase BMD and reduce the risk of fracture. However, as BMD testing is not readily available to all patients, BMD should not be the sole criterion to assess fracture risk; a better approach is to consider other risk factors (Hadji et al. 2007). Postmenopausal women receiving AI therapy should undergo periodic BMD assessment to facilitate early diagnosis and intervention for treatment-related bone loss (Hillner et al. 2003, Winer et al. 2005). DEXA scans for BMD measurement and bone resorption markers (e.g., N-telopeptide, C-telopeptide) have been used to facilitate diagnosis (Brown & Coleman 2002, Coleman 2004). With DEXA scan results of a T-score less than K2.0, patients should take calcium and vitamin D supplementation and a bisphosphonate to prevent fracture. For any patient with a T-score less than K1.5 with at least one additional risk factor (age over 65, family history of hip fracture, low body mass index, personal history of fragility fracture after age 50, oral corticosteroid use longer than 6 months, smoker, and alcohol use), bisphosphonate therapy should be considered. When DEXA scan information is lacking, any patient receiving AIs who has two additional risk factors should receive bisphosphonate treatment to prevent bone loss. 77

P Hadji: Menopausal symptoms and adverse events

Lipid metabolism Obesity is increasing in the European population; more than 48 million adults in Europe and 23 million adults in the European Union have diabetes (Peterson et al. 2005). As breast cancer patients live longer, weight gain after therapy is a common problem that negatively affects serum lipid profiles and increases the risk of diabetes and cardiovascular disease (CVD) (Herman et al. 2005). Menopause also has a negative effect on lipid metabolism: increases in total cholesterol (Stevenson et al. 1993, Tremollieres et al. 1999, Kuh et al. 2005), low-density lipoprotein cholesterol (LDL-C; Matthews et al. 1989, Kuh et al. 2005), and triglycerides (Kuh et al. 2005) and decreases in highdensity lipoprotein cholesterol (HDL-C) (Matthews et al. 1989, Kuh et al. 2005) tend to occur after menopause and are associated with an increased risk of coronary heart disease (Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults 2001). Generally, SERMs such as tamoxifen have been shown to decrease LDL-C and increase HDL-C (Thangaraju et al. 1994, Mannucci et al. 1996, Herrington & Klein 2001), but the AIs have not been reported to have such effects (Mitsuyama et al. 2006). In the LEAP study of healthy postmenopausal women, no difference was found in lipid profiles for either letrozole or exemestane, compared with anastrozole, except for a higher increase in triglycerides with letrozole than anastrozole at 12 weeks (C9.6 vs K2.9%; P!0.05) and a more marked reduction in HDL-C with exemestane than anastrozole at 24 weeks (K13 vs 0.3%; P!0.001); additionally, the HDL:LDL ratio with exemestane was significantly higher than with anastrozole at 24 weeks (17.09 vs 4.6%; P!0.05; McCloskey et al. 2006b). Hypercholesterolemia in adjuvant AI trials

Adjuvant anastrozole therapy has been associated with weight gain (Hori et al. 2006), and an exploratory analysis of non-predefined AEs in the ATAC trial showed that patients receiving anastrozole, compared with tamoxifen, had a higher incidence of hypercholesterolemia (9 vs 3%; P!0.0001) and hypertension (13 vs 11%; PZ0.04; Buzdar et al. 2006b). In the BIG 1–98 trial, hypercholesterolemia was measured more rigorously: total cholesterol was measured at baseline, every 6 months in the first 3 years, yearly for the next 2 years, and 1 year after treatment ended, and hypercholesterolemia appeared as a check-listed box on case report forms (Thu¨rlimann et al. 2005). More patients in the letrozole arm experienced hypercholesterolemia at 78

least once during treatment (43.6 vs 19.2% in the tamoxifen arm), but the majority of cases in both arms were grade 1 (35.1 and 17.3% respectively; Thu¨rlimann et al. 2005). The median total cholesterol did not change significantly from baseline in patients in the letrozole arm but decreased by 13.5% in those in the tamoxifen arm (Thu¨rlimann et al. 2005). The same increase is seen if AIs are given in the switch setting. In the ITA trial, lipid disorders were reported in 9.3% of patients treated with anastrozole versus 4.0% of those receiving tamoxifen (PZ0.04; Boccardo et al. 2005). In the IES, the incidence of hypercholesterolemia was 8.8 and 7.6% in the exemestane and tamoxifen arms respectively (PZ0.14; Coombes et al. 2007). Another randomized study examining body composition and lipid profile in 55 postmenopausal women with primary breast cancer who switched to exemestane after at least 2 years of tamoxifen therapy found that although fat mass decreased significantly by month 12 in women receiving exemestane but not tamoxifen (P!0.01), triglycerides and HDL-C decreased significantly (P!0.01 for both), and LDL-C increased significantly (P!0.01) in the exemestane group (Francini et al. 2006). The AIs may lack the lipid-lowering properties of tamoxifen, but they do not seem to have any detrimental effects on lipid profiles (Monnier 2007). When compared with placebo, an increase in hypercholesterolemia has not been observed. Final results from the MA.17 study showed that hypercholesterolemia occurred at similar rates in both the letrozole and placebo groups (16% each; PZ0.79; Goss et al. 2005). These findings were confirmed in the lipid substudy (nZ347), which found that letrozole did not significantly alter lipid parameters in postmenopausal women who had completed 5 years of adjuvant tamoxifen therapy (Wasan et al. 2005). Of note, the HDL:LDL ratio decreased after the first 6 months of therapy in both the letrozole and placebo arms (no statistically significant differences were noted; Femara package insert 2005). Likewise, another study (NZ147) found that exemestane, compared with placebo, had no major effect on lipids, with the exception of a small decrease from baseline HDL-C (P!0.001) and apolipoprotein A1 (PZ0.004; Lønning et al. 2005). Preliminary results of the ATENA substudy of patients treated with extended adjuvant exemestane, compared with placebo, showed that following 6 months of tamoxifen discontinuation, there were no significant differences between the exemestane and placebo groups for any lipid parameters, consistent with MA.17 findings (Markopoulos et al. 2005). Updated data from the IBIS II study (NZ141) showed no significant difference in mean www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 change in HDL-C, total cholesterol, or triglycerides between the anastrozole and placebo groups (Singh et al. 2006a,b). Thus, all three AIs have a similar impact on lipid parameters and, when compared with placebo, the AIs are not associated with increased hypercholesterolemia or cardiovascular events (Monnier 2007).

Cardiovascular disease In Europe, CVD accounts for more than 1.88 million deaths each year and is the main cause of death in individuals younger than age 75 (44% of deaths in women); stroke is the second most common cause of death, accounting for 1.28 million deaths per year (Peterson et al. 2005). Women with breast cancer are at risk of CVD, and the incidence increases significantly after menopause (Monnier 2007). Postmenopausal women with breast cancer may be more susceptible to certain risk factors associated with CVD, including aging (Coebergh et al. 1999), diabetes (Coebergh et al. 1999, Louwman et al. 2005), and hypertension (Franklin et al. 1997, Coebergh et al. 1999). Tamoxifen

In a trial comparing 2129 patients who received 2 years versus 2046 patients who received 5 years of adjuvant tamoxifen, mortality due to coronary heart disease was significantly reduced in the 5-year group (HR) 0.67, 95% CI 0.47–0.94; PZ0.022; Nordenskjo¨ld et al. 2005). A meta-analysis of published randomized controlled trials showed that tamoxifen significantly decreased death due to myocardial infarction (MI; RR 0.62, 95% CI 0.41–0.93; Braithwaite et al. 2003), and the cardioprotective effects of tamoxifen may confound comparisons of AIs with tamoxifen in assessing the effect of various agents on cardiovascular health. Cardiovascular events in adjuvant AI trials

In ATAC, the incidence of ischemic cardiovascular events was higher in patients treated with anastrozole than in those treated with tamoxifen (4.1 vs 3.4%; PZ0.1; Howell et al. 2005). Angina was mostly mild to moderate and numerically occurred more often in patients receiving anastrozole (71 vs 51%; PZ0.07), while MI occurred in 1% of patients in each arm (PZ0.07; Buzdar et al. 2006b). The BIG 1–98 trial demonstrated a similar incidence of cardiac events in the letrozole and tamoxifen groups (4.1 vs 3.8%; P!0.001; Thu¨rlimann et al. 2005). More women receiving letrozole had grade 3, 4, or 5 cardiac events (2.1 vs 1.1%; P!0.001), but these events were rare (Thu¨rlimann www.endocrinology-journals.org

et al. 2005). In the subset analysis restricted to the monotherapy arms of the BIG 1–98 trial, at 51-month follow-up, the incidence of cardiac events was comparable in the two groups: 134 events (5.5%) versus 122 events (5.0%) with letrozole and tamoxifen respectively. With longer follow-up in almost 5000 patients, the incidence of grade 3–5 cardiovascular events was low in both groups (Coates et al. 2007). Vascular events (hot flushes, ischemic cardiovascular events, deep vein thrombosis, and ischemic cerebrovascular events) occurred more frequently in patients switching to anastrozole than in those who continued on tamoxifen (9.2 vs 8.8%; PZnot reported) in the ARNO 95 trial (NZ979; Kaufmann et al. 2006). Similarly, in the IES, patients switching to exemestane reported more cardiovascular events (excluding venous thromboembolic events) than those continuing on tamoxifen (20.8 vs 18.9%; PZ0.09; Coombes et al. 2007). The incidence of MI was higher in patients receiving exemestane than in those receiving tamoxifen (1.3 vs 0.8%; PZ0.08; Coombes et al. 2007). Yet, when compared with placebo, the AIs do not significantly increase the risk of cardiovascular events, as was shown in MA.17, where the incidence of cardiovascular events was similar with letrozole and placebo (5.8 vs 5.6%; PZ076; Goss et al. 2005). Clinical management

Several clinical trials have reported that although the overall incidence of cardiac events was numerically higher in patients receiving an AI than in those receiving tamoxifen, the differences between groups were not statistically significant (Howell et al. 2005, Jakesz et al. 2005, Thu¨rlimann et al. 2005, Salgado & Zivian 2006, Coombes et al. 2007; Table 2). According to current guidelines, present knowledge is insufficient to fully determine the effect of AIs on CVD and coronary heart disease (Winer et al. 2005) and the risk of long-term side effects (Goldhirsch et al. 2005). The negative impact of cardiovascular risk factors typically seen in older postmenopausal women becomes more evident once adjuvant therapies reduce the rate of breast cancerrelated deaths (Monnier 2007). Although AIs may lack the lipid-lowering and cardioprotective effect of tamoxifen, the risk of cardiovascular events with AIs is well within the range seen in an age-matched, non-breast cancer population (Sourander et al. 1998). Other databases (UK General Practice Research Database, Swedish MI register) have reached similar conclusions (Medicines and Healthcare Products Regulatory Agency 2005). Clinical management includes monitoring cholesterol levels, eating a healthy diet, engaging in regular 79

P Hadji: Menopausal symptoms and adverse events Table 2 Cardiac events in patients receiving tamoxifen versus an aromatase inhibitor (AI) Trial

Cardiac event

AI no. (%)

Intergroup exemestane group (Salgado & Zivian 2006)

Cardiovascular disease other than myocardial infarction Cardiovascular events (excluding venous thromboembolic events) Myocardial infarction

Anastrozole 3 (1)

Ischemic CVD Cardiac event

Anastrozole 127 (4.1) Letrozole 162 (4.1)

Updated intergroup exemestane group (Coombes et al. 2007) Combined results of ABCSG 8 and ARNO 95 (Jakesz et al. 2005) ATAC (Howell et al. 2005) BIG 1–98 (Thu¨rlimann et al. 2005)

Tamoxifen no. (%)

P value

Exemestane 984 (42.6)

913 (39.2)

0.11

Exemestane 483 (20.8)

441 (18.9)

0.09

2 (!1) 104 (3.4) 153 (3.8)

1.0 0.1 0.61

ABCSG, Austrian Breast and Colorectal Cancer Study Group; ARNO, arimidex-nolvadex; ATAC, arimidex, tamoxifen, alone or in combination; BIG, Breast International Group.

exercise, and regulating preexisting hypercholesterolemia with medications (Grundy et al. 2004). All patients at risk of CVD and all patients with breast cancer should be routinely monitored for CVD; lipid-lowering medications may be prescribed (Grundy et al. 2004).

Gynecologic health Hot flushes and night sweats are common menopausal symptoms (Bennett & Degeling 1995). Hot flushes may cause disturbed sleep, depressive symptoms, and significant reductions in quality of life (Bachmann 2005). Sexual dysfunction may also occur as healthy women age (Rosen et al. 1993, Ganz et al. 1999). In a study of 329 healthy women, some common sexual problems included inhibition or anxiety during sexual activity (38.1%), lack of sexual pleasure (16.3%), lack of lubrication (13.6%), and painful intercourse (11.3%), with the latter two problems being significantly more prevalent in postmenopausal women (Rosen et al. 1993). A study of 1134 breast cancer survivors showed that the most consistent and important predictors of sexual health were vaginal dryness, emotional well-being, body image, quality of the partnered relationship, and the presence or absence of sexual problems in the partner (Ganz et al. 1999).

(33.5 vs 38.0%; P!0.001), and night sweats (13.9 vs 16.2%; PZ0.004; Thu¨rlimann et al. 2005). The TEAM study also found that at 12 months, patients receiving tamoxifen, versus those receiving exemestane, had a significantly higher mean hot flush score (PZ0.0253) and more vaginal discharge (P!0.0001), whereas patients receiving exemestane had more vaginal dryness (PZ0.0004) and decreased libido (PZ0.0343; Asmar et al. 2005). In the switch setting, the combined results of the ABCSG 8 and ARNO 95 trials showed no difference between anastrozole- and tamoxifen-treated patients in the incidence of hot flushes (50 vs 48%; PZ0.32), vaginal bleeding/discharge (17 vs 18%; PZ0.93), or endometrial cancer (!1 vs !1%; PZ0.069; Jakesz et al. 2005). In the IES, at a median follow-up of 55.7 months, there was no significant difference in the incidence of hot flushes (42.4% with exemestane versus 39.9% with tamoxifen; PZ0.08), and the incidence of vaginal bleeding was lower in the exemestane than tamoxifen arm (5.2 vs 7.6%; PZ0.002; Coombes et al. 2007). Likewise, in the MA.17 trial, letrozole was associated with less vaginal bleeding than a placebo was (6 vs 8%; PZ0.005) but a greater incidence of hot flushes (58 vs 54%; PZ0.003), while the incidence of vaginal dryness was similar between groups (Goss et al. 2005).

Hot flushes and vaginal symptoms in adjuvant AI trials

In ATAC, the incidence of hot flushes was significantly lower with anastrozole than tamoxifen (35.7 vs 40.9%; P!0.0001), as was vaginal bleeding (5.4 vs 10.2%; P!0.0001; Howell et al. 2005). Conversely, reduced libido (1 vs !1%; PZ0.0001) and dyspareunia (1 vs !1%; PZ0.002) was found in significantly more patients receiving anastrozole than tamoxifen (Buzdar et al. 2006b). In the BIG 1–98 trial, letrozole versus tamoxifen was associated with a lower incidence of vaginal bleeding (3.3 vs 6.6%; PZ0.001), hot flushes 80

Cognition A decline in cognitive ability has been associated with aging. The European Community Concerted Action on the Epidemiology and Prevention of Dementia group calculated prevalence rates for women in nine age groups (30–59, 60–64, 65–69, 70–74, 75–79, 80–84, 85–89, 90–94, and 95–99) based upon pooled data on the prevalence of moderate to severe dementia in several European countries. The results clearly showed that prevalence increased with age (Hofman et al. 1991). www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 A more recent pooled collaborative analysis of European population-based studies found that, in individuals aged 65 years or older, the age-standardized prevalence of dementia (all-cause), Alzheimer’s disease, and vascular dementia was 6.4, 4.4, and 1.6% respectively, with the prevalence of Alzheimer’s disease 0.6% in the 65–69 age group and 22.2% at 90 years of age and older (Lobo et al. 2000). Another analysis reported the prevalence of Alzheimer’s disease in Europe to be very low at younger ages (!2% in the age group 65–70), but then increasing with age and female gender at older ages (up to 46% in French females above 90 years; Moise et al. 2004). Data for the effects of adjuvant AI therapy on cognition are sparse, and more research is needed. In a study comparing patients from the ATAC trial with healthy controls, those receiving anastrozole were more impaired in a processing speed task (PZ0.032) and in a measure of immediate verbal memory (PZ0.026; Jenkins et al. 2004). Another pilot study found more severe cognitive impairment in women taking anastrozole versus those on tamoxifen (Bender et al. 2005), and exemestane was associated with more impaired word finding than tamoxifen (PZ0.0057) in the TEAM study (Asmar et al. 2005). Yet, in the prevention setting, the results from the cognitive substudy (nZ179) of the IBIS-II study found that anastrozole did not have a significant impact on cognitive functioning in postmenopausal women (Jenkins et al. 2006). More studies are needed to evaluate the long-term influence of AIs on cognition, dementia, and Alzheimer’s disease.

Other AEs Some other minor AEs have been reported in adjuvant AI trials. In ATAC, non-predefined AEs (e.g., dry mouth, nail disorders, and fungal infection) occurred more often in patients receiving anastrozole than tamoxifen (Buzdar et al. 2006b). A recent analysis of the ATAC trial showed a significantly greater incidence of dry mouth in patients receiving anastrozole compared with tamoxifen (4 vs 2%; PZ0.003), as well as an increased incidence of

diarrhea (9 vs 7%; PZ0.02; Buzdar et al. 2006b). In the IES, diarrhea (4.2 vs 2.7%; PZ0.0002), gastric ulcer (1.2 vs 0.3%; PZ0.001), paresthesia (9 vs 7%; PZ0.02), and insomnia (3.0 vs 1.2%; P!0.0001) occurred more often in patients receiving exemestane than tamoxifen (Coombes et al. 2007). Some of the AEs reported with exemestane (e.g., diarrhea, visual disturbances) have not been reported with non-steroidal AIs (Aromasin package insert 2005, Coombes et al. 2007). Life-threatening AEs

AIs are associated with fewer serious AEs compared with tamoxifen and lower discontinuation rates due to AEs (Table 3). In ATAC, there was a non-significant trend toward fewer serious AEs leading to death in the anastrozole than in the tamoxifen group (3 vs 4%; PZ0.6; Buzdar et al. 2006b). A similar observation was seen in the switch studies, with fewer incidences of serious or life-threatening AEs in patients who switched to anastrozole than in those who remained on tamoxifen (Boccardo et al. 2005, Kaufmann et al. 2006). In contrast, an excess of life-threatening AEs was observed with adjuvant tamoxifen therapy that occurred early in the first 2–3 years of treatment (Cuzick & Wale 2006, Duffy 2006). Meta-analyses have demonstrated that tamoxifen is associated with significant increases in pulmonary embolism (RR 1.88; 95% CI 1.77–3.01), stroke (RR 1.49; 95% CI 1.16–1.90), and deep vein thrombosis (RR 1.87; 95% CI 1.33–2.64; Braithwaite et al. 2003) and a slightly increased incidence of mortality due to thromboembolic events (15 vs 8 patients; PZNS) and stroke (54 vs 29 patients; PZ0.07; Early Breast Cancer Trialists’ Collaborative Group 2005). The ATAC trial also showed that the incidence of venous thromboembolic events was significantly higher in patients receiving tamoxifen than anastrozole (odds ratio (OR) 0.61; 95% CI 0.46–0.80; P!0.0001; Cuzick & Wale 2006). Trials of letrozole and exemestane showed similar findings (Goss et al. 2005, Jakesz et al. 2005, Thu¨rlimann et al. 2005, Coombes et al. 2007). In the BIG 1–98 trial, the incidence of thromboembolic events was also significantly lower

Table 3 Incidence of serious adverse events (AEs) and discontinuation due to AEs in aromatase inhibitor adjuvant therapy (Braithwaite et al. 2003, Goss et al. 2005, Thu¨rlimann et al. 2005)

Comparator Incidence of serious AEs Discontinuation due to AEs

ATAC

BIG 1–98

IES

MA.17

Anastrozole versus tamoxifen 33 vs 36% 11 vs 14% PZ0.0002

Letrozole versus tamoxifen 1.7 vs 1.7% 11.3 vs 10.4% PZNR

Exemestane versus tamoxifen NR 6 vs 5.2% PZNR

Letrozole versus placebo NR 4.9 vs 3.6% PZ0.019

ATAC, arimidex, tamoxifen, alone or in combination; BIG, Breast International Group; IES, Intergroup Exemestane Study; MA.17, National Cancer Institute of Canada Clinical Trials Group letrozole study; NR, not reported.

www.endocrinology-journals.org

81

P Hadji: Menopausal symptoms and adverse events with letrozole (1.5 vs 3.5%; P!0.001; Thu¨rlimann et al. 2005). Similarly, in the IES, switching to exemestane was associated with significantly reduced incidences of venous thromboembolic events (1.9 vs 3.1%; PZ0.01; Coombes et al. 2007). Tamoxifen use is also associated with a significant increase in the risk of endometrial cancer (RR 2.70; 95% CI 1.94–3.75; Braithwaite et al. 2003). A prospective endometrial assessment in menopausal women demonstrated that AIs as upfront adjuvant therapy had no effect on endometrial thickening; however, if administered as switched therapy after tamoxifen, AIs may reverse tamoxifen-associated endometrial thickening (Garuti et al. 2006). In ATAC, anastrozole was associated with a significantly lower incidence of gynecologic events (endometrial hyperplasia, endometrial neoplasia, cervical neoplasm, and enlarged uterine fibroids; 3 vs 10%; P!0.0001) and endometrial cancer (5/3092 vs 17/3094) than was tamoxifen (Buzdar et al. 2006b). At a mean follow-up of 6 years, the ATAC endometrial sub-protocol found that anastrozole was associated with fewer endometrial abnormalities (most commonly polyp formation) than tamoxifen (27 vs 44%; PZ0.17; Duffy 2006). In BIG 1–98, letrozole versus tamoxifen was associated with fewer endometrial biopsies (2.3 vs 9.1%; P!0.001) and fewer invasive endometrial cancers (0.1 vs 0.3%; PZ0.18; Thu¨rlimann et al. 2005). In IES, fewer serious gynecologic events occurred in women receiving exemestane than tamoxifen (7.0 vs 10.6%; PZ0.0001), and no significant difference was noted in the incidence of endometrial cancer between treatment arms (Coombes et al. 2007). Finally, safety analysis of the ATAC trial showed a surprisingly higher incidence of head and neck cancer with anastrozole than tamoxifen (10/3092 vs 3/3094), as well as a higher incidence of lung cancer (25/3092 vs 16/3094) and lung cancer deaths (15/3125 vs 8/3116; Buzdar et al. 2006b). The mechanism responsible for this increased incidence is unclear. These are very small absolute numbers that have little clinical significance; nonetheless, further analysis and follow-up are warranted.

Efficacy and safety of adjuvant endocrine therapy in older patients Physicians may be hesitant to prescribe adjuvant AIs, because they may consider them no more effective than tamoxifen or possibly unsafe in this population (Mustacchi et al. 2007, Passage & McCarthy 2007); older patients are more likely to have serious comorbidities, as well as increased risk for CVD and dying of other causes. Older patients often receive less aggressive treatment than younger patients (Rao et al. 2007), but a study of 118 women aged over 80 years with breast 82

cancer showed that the women treated with letrozole had better progression-free survival than those treated with tamoxifen (progression was 5/64 and 24/54 respectively; Garimella et al. 2006). In the BIG 1–98 trial, letrozole, compared with tamoxifen, significantly reduced the risk of recurrence by 21% in patients aged 65 years or older (HR 0.79; 95% CI 0.64–0.97; PZ0.02; Thu¨rlimann et al. 2005), while in the ATAC trial, anastrozole reduced the risk of recurrence by only 7% in women aged 65 years and older (HR 0.93; 95% CI 0.80–1.08) when compared with tamoxifen (Arimidex package insert 2005). A recent analysis from the BIG 1–98 trial only on the patients in the monotherapy arms (NZ4922) showed that letrozole provided consistent benefit over tamoxifen irrespective of age (!65–75 years and older; Crivellari et al. 2007). In MA.17, letrozole reduced the risk of recurrence by 27% in women aged 50 years and older (HR 0.73; 95% CI 0.55–0.98; Goss et al. 2005). A follow-up MA.17 analysis showed that in patients aged 70 years and older who were in good health, letrozole yielded benefits in disease-free and distant disease-free survival similar to those seen in younger patients, without increased toxicity versus placebo (Muss 2006). Overall survival was significantly shorter in patients aged 70 years and older (perhaps due to non-breast cancer death), but patients in this age group with nodepositive disease had a significant improvement in overall survival with letrozole (PZ0.04). There was no difference in toxicity by age between letrozole and placebo in patients of 70 years old and older and, at 36 months, quality of life in these patients was similar in both letrozole and placebo groups (Muss 2006).The results suggest that older patients generally benefit from AI therapy and should be considered for letrozole after 5 years of tamoxifen (Muss 2006).

Compliance with adjuvant endocrine therapy Compliance in patients with all chronic diseases is low, with about 50% of patients adhering to recommended treatment regimens (World Health Organization 2003). Two German studies found that mean compliance was low with daily and weekly bisphosphonate use (37.7 and 51.7% respectively) for patients with osteoporosis (Bartl et al. 2005), and about one-third to one-half of patients on weekly versus daily bisphosphonate therapy discontinued treatment after one prescription (31.3 vs 45.8% respectively; Bartl et al. 2006). Likewise, a retrospective cohort analysis found that statin use decreased over time, from 79% in the first 3 months to 42% after 120 months (Benner et al. 2002). A study showed that a greater belief in the necessity of treatment correlated with higher www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 reported adherence (RR 0.21; P!0.01), whereas greater concern regarding dependence or long-term effects correlated with lower adherence (RR 0.33; P!0.01; Horne & Weinman 1999). A meta-analysis has shown that therapy non-compliance was responsible for 5.5% of hospitalizations in the United States (Sullivan et al. 1990), illustrating that non-compliance can lead to serious health risks. Tamoxifen is associated with poor tolerability; 23–40% of patients discontinue therapy (Demissie et al. 2001). A study of 462 women (65 years and older) with stage I–IIIA breast cancer showed that 31% of those who started tamoxifen therapy failed to complete the recommended 5-year course (Lash et al. 2006). Another study found that 50% (489/974) of women discontinued tamoxifen during 5 years of follow-up (Owusu et al. 2006). In a study of 516 women aged 65 years and older, tamoxifen discontinuation was more likely in women with neutral or negative beliefs about tamoxifen (OR 3.0; 95% CI 1.6–5.6; Fink et al. 2004). A study of 131 women with stable breast cancer found that women who disliked taking medication reported significantly less adherence (PZ0.001; Atkins & Fallowfield 2006). Self-reported non-adherence to tamoxifen was associated with the belief that nothing would be gained by taking the drug, whereas adherence was associated with the belief that tamoxifen would prevent breast cancer; side effects were the main reason reported for not taking tamoxifen (Grunfeld et al. 2005). Tamoxifen adherence rates were significantly lower in the youngest, oldest, non-white, and mastectomy patients, whereas adherence rates were significantly higher in patients who saw an oncologist in the year before the initiation of tamoxifen (Partridge et al. 2003). Noncompliance also occurs with adjuvant AI therapy. A study evaluating adherence to adjuvant anastrozole therapy (NZ1498) found that 20% of women may be suboptimally adherent during the first 12 months of therapy (Partridge et al. 2006). A smaller study of women with breast cancer receiving anastrozole (nZ44), letrozole (nZ10), or exemestane (nZ2) found that treatment-related arthralgia and/or bone pain was severe enough to cause 20% of patients to discontinue AI therapy (Presant et al. 2006). Yet, an investigation of adherence and persistence patterns in 16 900 patients treated with adjuvant endocrine therapies found that AI usage is increasing, and that individuals who switched from tamoxifen to an AI persisted longer on therapy (Martin et al. 2006). For example, a study of 104 postmenopausal women who were experiencing distressing side effects while taking adjuvant tamoxifen and then switched to letrozole found that, after 6 weeks, 66% of the women preferred to remain on letrozole (Thomas et al. 2006). www.endocrinology-journals.org

A retrospective observational study (nZ128) reported that of 51 patients switched from one agent to another, almost half (45%) did so because of AEs, and the majority (78.4%) switched from tamoxifen to an AI after a mean of 36 months (Schwartzberg et al. 2006). AEs can be quite troublesome to patients and may result in treatment discontinuation. Physicians need to actively identify and treat AEs before patients decide to discontinue therapy, but patients should be informed of any therapyassociated AEs that may develop before treatment is initiated. Educating the patient beforehand will help manage patient expectations and beliefs about the benefits of therapy. Physicians also should emphasize the importance of compliance to therapy and how it affects the patient’s outcome before starting therapy. A recent study shows that increased duration of drug usage is associated with improved survival in breast cancer patients, so clearly, these drugs cannot be effective in patients who do not take their therapy (McCowan et al. 2007).

Conclusion Clinical trials show that all AIs are superior to tamoxifen in terms of reducing recurrence risk, and some, like letrozole, are also superior to tamoxifen in terms of reducing the risk of distant metastases, especially early on in the course of therapy (Howell et al. 2005, Thu¨rlimann et al. 2005, Coombes et al. 2007, Mauriac et al. 2007). The AIs are generally well tolerated and have similar safety profiles, with the majority of AEs being mild to moderate and common to menopause. Common short-term AI-associated toxicities included hot flushes, musculoskeletal complaints/arthralgia, and bone loss, which are all predictable and can be effectively managed. Results from the Z-FAST and ZO-FAST studies have shown that initial use of concomitant ZA with adjuvant AI therapy is a safe and effective way to prevent bone loss. Although AIs lack the cardioprotective and lipidlowering effects of tamoxifen, they have not been determined to have a detrimental impact on cardiac health. In contrast to tamoxifen, the AIs also do not increase the risk of serious life-threatening thromboembolic and cerebrovascular events and endometrial cancer. Patients and doctors should engage in a dialogue about possible side effects and the importance of compliance to therapy before initiating AI treatment, so that fully informed decisions can be made (Salgado & Zivian 2006). Individual patient assessment with respect to therapy risks and benefits is critical. Lifestyle factors, comorbidities, and concomitant medications must all be considered. Proper management of AEs, if they develop, can greatly improve compliance and, ultimately, patient outcome. 83

P Hadji: Menopausal symptoms and adverse events

Acknowledgements Editorial support was provided by phase Five Communications Inc (New York, N710011, US).

References Aapro MS 2004 Long-term implications of bone loss in breast cancer. Breast 13 S29–S37. Arimidex (package insert) 2005. Wilmington, DE: AstraZeneca. Aromasin (package insert) 2005. New York, NY: Pfizer. Asmar L, Cantrell J, Vukelja SJ, Pippen J, O’Shaughnessy J, Blum JL, Brooks R, Mull S, Ilegbodu D & Jones S 2005 Final analysis of a planned comparison of menopausal symptoms in 1618 patients receiving either exemestane (E) or tamoxifen (T) in a blinded adjuvant hormonal study. Breast Cancer Research and Treatment 94 S97 (Abstract 2039). Atkins L & Fallowfield L 2006 Intentional and non-intentional non-adherence to medication amongst breast cancer patients. European Journal of Cancer 42 2271–2276. Bachmann GA 2005 Menopausal vasomotor symptoms. A review of causes, effects and evidence-based treatment options. Journal of Reproductive Medicine 50 155–165. Bartl R, Goette S, Hadji P & Hammerschmidt T 2005 Persistence and compliance with daily and weeklyadministered bisphosphonates for osteoporosis treatment in Germany. Presented at: 5th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 16–19, Rome, Italy. (Abstract P195). Bartl R, Go¨tte S, Hadji P & Hammerschmidt T 2006 Adha¨renz mit ta¨glichen und wo¨chentlichen oralen bisphosphonaten in der osteoporosetherapie. Deutsche Medizinische Wochenschrift 131 1257–1262. Bender CM, Sereika SM, Ryan CM, Casillo FE, Vogel VG, Berga SL, Cohen SM, Rastogi P & Brufsky AM 2005 Memory impairments with anastrozole versus tamoxifen therapy in women with early stage breast cancer. Breast Cancer Research and Treatment 94 S274 (Abstract 6074). Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC & Avorn J 2002 Long-term persistence in use of statin therapy in elderly patients. Journal of the American Medical Association 288 455–461. Bennett D & Degeling D 1995 The Meaning of Midlife: A Positive Approach to Total Health. Sydney: Angus & Robertson, 26. Boccardo F, Rubagotti A, Puntoni M, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D & Rinaldini M 2005 Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian tamoxifen anastrozole trial. Journal of Clinical Oncology 23 5138–5147. Boyce SP, Mincey B, Duh M, Marynchenko M, Raut MK, Brandman J & Perez EA 2005 Risk of osteoporosis/osteopenia among women with breast cancer receiving anticancer therapy (ACT). Journal of Clinical Oncology 23 665.

84

Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R & Col NF 2003 Meta-analysis of vascular and neoplastic events associated with tamoxifen. Journal of General Internal Medicine 18 937–947. Brazier M, Kamel S, Maamer M, Agbomson F, Elesper I, Garabedian M, Desmet G & Sebert JL 1995 The markers of bone remodeling in the elderly subject: effect of vitamin D insufficiency and its correction. Journal of Bone and Mineral Research 10 1753–1761. Brodie AH, Jelovac D & Long B 2003 The intratumoral aromatase model: studies with aromatase inhibitors and antiestrogens. Journal of Steroid Biochemistry and Molecular Biology 86 283–288. Brown JE & Coleman RE 2002 Assessment of the effects of breast cancer on bone and the response to therapy. Breast 11 375–385. Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Dong M, Schenk N, Lacerna L & Perez E 2006 An integrated analysis of zoledronic acid (ZA) for prevention of aromatase inhibitor associated bone loss (AIBL) in postmenopausal women (PMW) with early breast cancer (BCa) receiving adjuvant letrozole (LET). Breast Cancer Research and Treatment 100 S25 (Abstract 107). Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, Hohneker J, Lacerna L, Petrone S & Perez EA 2007 Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. Journal of Clinical Oncology 25 829–836. Bruning PF, Pit MJ, de Jong-Bakker M, van den Ende A, Hart A & van Enk A 1990 Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. British Journal of Cancer 61 308–310. Bundred NJ, Helmyr P, Kenemans P, Kubista E, von Schoultz B, Vassilopoulos-Sellin R, Sismondi P, Foidart J, Beckmann MW, Yip C & Egberts J 2006a Incidence of osteoporosis in breast cancer patients–baseline data from the LIBERATE trial. Breast Cancer Research and Treatment 100 S112 (Abstract 2095). Bundred N, Campbell I, Coleman R, DeBoer R, Eidtmann H, Frassolati A, Liombart A, Monnier A, Neven P & Dias R 2006b Zoledronic acid in the prevention of cancer treatment-induced bone loss in postmenopausal women receiving letrozole as adjuvant therapy for early breast cancer (ZO-FAST study). European Journal of Cancer 4 48 (Abstract 12). Buzdar A, Howell A, Cuzick J, Wale C, Distler W, HoctinBoes G, Houghton J, Locker GY & Nabholtz JM 2006a Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncology 7 633–643. Buzdar A & on behalf of the ATAC Trialists’ Group 2006b Clinical features of joint symptoms observed in the arimidex, tamoxifen, alone or in combination (ATAC) trial. Journal of Clinical Oncology 24 15s (Abstract 551).

www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 Chen Z, Maricic M, Pettinger M, Ritenbaugh C, Lopez AM, Barad DH, Gass M, LeBoff MS & Bassford TL 2005a Osteoporosis and rate of bone loss among postmenopausal survivors of breast cancer. Cancer 104 1520–1530. Chen Z, Maricic M, Bassford TL, Pettinger MS, Ritenbaugh C, Lopez AM, Barad DH, Gass M & LeBoff MS 2005b Fracture risk among breast cancer survivors: results from the Women’s Health Initiative Observational Study. Archives of Internal Medicine 165 552–558. Chlebowski RT, Johnson KC, Kooperberg C, Hubbell A, Lane D, O’Sullivan M, Cummings S, Rohan T, Yasmeen S & Khandekar J 2006 The Women’s Health Initiative Randomized Trial of calcium plus vitamin D: effects on breast cancer and arthralgias. Journal of Clinical Oncology 24 930s (Abstract LBA6). Coates AS, Keshaviah A, Thu¨rlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M et al. 2007 Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrineresponsive early breast cancer: update of study BIG 1–98. Journal of Clinical Oncology 25 486–492. Coebergh JW, Janssen-Heijnen ML, Post PN & Razenberg PPA 1999 Serious comorbidity among unselected cancer patients newly diagnosed in the southeastern part of The Netherlands in 1993–1996. Journal of Clinical Epidemiology 52 1131–1136. Coleman RE 2004 Hormone- and chemotherapy-induced bone loss in breast cancer. Oncology 18 16–20. Coleman RE & on behalf of the ATAC Trialists’ Group 2006 Effect of anastrozole on bone mineral density: 5-year results from the arimidex, tamoxifen, alone or in combination (ATAC) trial. Journal of Clinical Oncology 24 5s (Abstract 511). Coleman RE, Banks LM, Girgis SI, Kilburn LS, Vrdoljak E, Fox J, Cawthorn SJ, Patel A, Snowdon CF, Hall E et al. 2007 Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncology 8 119–127. Coombes RC, Kilbrun LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, van de Velde CJH, Delozier T, Alvarez I et al. 2007 Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial. Lancet 369 559–570. Crew KD, Apollo A, Greenlee H, Raptis G, Braffman L, Fuentes D & Hershman DL 2006a Prevalence of joint symptoms in postmenopausal women on aromatase inhibitors for early stage breast cancer. Breast Cancer Research and Treatment 100 S235 (Abstract 5068). Crew KD, Capodice J, Greenlee H, Raptis GR, Blozie K, Sierra A, Braffman L, Fuentes D & Hershman DL 2006b Effect of acupuncture on joint symptoms related to

www.endocrinology-journals.org

adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients. Breast Cancer Research and Treatment 100 S236–S237 (Abstract 5071). Crivellari D, Sun Z, Coates AS, Price KN, Thu¨rlimann B, Mouridsen H, Mauriac L, Forbes JF, Castiglione-Gertsch M & Goldhirsch A 2007 Aromatase inhibitors (AI) for elderly patients: efficacy, compliance and safety according to patient age in the BIG 1–98 trial. Journal of Clinical Oncology 25 501s (Abstract 9033). Cuzick J, Wale C & on behalf of the ATAC Trialists’ Group 2006 A detailed analysis of the benefits of anastrozole over tamoxifen for venous thromboembolic events (VTEs) after 5 years treatment. Breast Cancer Research and Treatment 100 S24 (Abstract 104). Demissie S, Silliman RA & Lash TL 2001 Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. Journal of Clinical Oncology 19 322–328. Devine A, Dick IM, Dhaliwal SS, Naheed R, Beilby J & Prince RL 2005 Prediction of incident osteoporotic fractures in elderly women using the free estradiol index. Osteoporosis International 16 216–221. Duffy S & on behalf of the ATAC Trialists’ Group 2006 Anastrozole is associated with a lower risk of endometrial abnormalities than tamoxifen: first report of the ATAC trial endometrial sub-protocol at 6 years follow-up. Breast Cancer Research and Treatment 100 S190 (Abstract 4055). Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2005 Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 1687–1717. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G & Adams JE 2006 Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the anastrozole, tamoxifen, alone or in combination (ATAC) trial (18233230). Journal of Bone and Mineral Research 21 1215–1223. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001 Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Journal of the American Medical Association 285 2486–2497. Femara (package insert) 2005. East Hanover, NJ: Novartis Pharmaceuticals. Fink AK, Gurwitz J, Rakowski W, Guadagnoli E & Silliman RA 2004 Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor-positive breast cancer. Journal of Clinical Oncology 22 3309–3315. Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM et al. 1996 Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. Journal of National Cancer Institute 88 1529–1542. Francini G, Petrioli R, Montagnani A, Cadirni A, Campagna S, Francini E & Gonnelli S 2006 Exemestane after tamoxifen as

85

P Hadji: Menopausal symptoms and adverse events adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids. British Journal of Cancer 95 153–158. Franklin SS, Gustin W IV, Wong ND, Larson MG, Weber MA, Kannel WB & Levy D 1997 Hemodynamic patterns of agerelated changes in blood pressure. The Framingham Heart Study. Circulation 96 308–315. Ganz PA, Desmond KA, Berlin TR, Meyerowitz BE & Rowland JH 1999 Predictors of sexual health in women after a breast cancer diagnosis. Journal of Clinical Oncology 17 2371–2380. Garimella V, Radhakrishna S, Rao VSR, Fox JN, Mahapatra T, Chaturvedi A & Drew PJ 2006 Comparison of primary letrozole vs tamoxifen therapy in women over the age of 80 years with breast cancer. Breast Cancer Research and Treatment 100 S191 (Abstract 4058). Garreau JR, Delamelena T, Walts D, Karamlou K & Johnson N 2006 Side effects of aromatase inhibitors versus tamoxifen: the patients’ perspective. American Journal of Surgery 192 496–498. Garuti G, Cellani F, Centinaio G, Montanari G, Nalli G & Luerti M 2006 Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors. Gynecological Oncology 103 599–603. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thu¨rlimann B & Senn H-J 2005 Meeting highlights: international expert consensus on the primary therapy of early breast cancer. Annals of Oncology 16 1569–1583. Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G & Nuti R 2007 Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 40 205–210. Goss PE, Thomsen T, Banke-Bochita J & Hadji P 2003 Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover and lipid metabolism in healthy volunteers. Breast Cancer Research and Treatment 82 5101 (Abstract 427). Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI et al. 2005 Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. Journal of National Cancer Institute 97 1262–1271. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr & Stone NJ 2004 Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arteriosclerosis, Thrombosis, and Vascular Biology 24 e149–e161. Grunfeld EA, Hunter MS, Sikka P & Mittal S 2005 Adherence beliefs among breast cancer patients taking tamoxifen. Patient Education and Counseling 59 97–102. Guise TA 2006 Bone loss and fracture risk associated with cancer therapy. Oncologist 11 1121–1131.

86

Hadji P, Rabe T, Ortmann O, Mueck AO, von Holst T, Emons G & Schulz K-D 2002 Mo¨glichkeiten und ¨ strogene Grenzen der Osteoporose-pra¨vention durch O und Gestagene. Gebfra 62 436–445. Hadji P, Aapro M, Brufsky A, Tubiana-Hulin A, Guise T & Body JJ 2007 Practical guidance for the prevention of aromatase inhibitor-associated bone loss in women with breast cancer. Breast Cancer Research and Treatment 106 (Suppl 1) 537 (Abstract 504). Headley JA, Theriault RL, LeBlanc AD, VassilopoulouSellin R & Hortobagyi GN 1998 Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Investigation 16 6–11. Herman DR, Ganz PA, Petersen L & Greendale GA 2005 Obesity and cardiovascular risk factors in younger breast cancer survivors: The Cancer and Menopause Study (CAMS). Breast Cancer Research and Treatment 93 13–23. Herrington DM & Klein KP 2001 Effects of SERMs on important indicators of cardiovascular health: lipoproteins, hemostatic factors, and endothelial function. Women’s Health Issues 11 95–102. Hillner B, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A et al. 2003 American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. Journal of Clinical Oncology 21 4042–4045. Hofman A, Rocca WA, Brayne C, Breteler MM, Clarke M, Cooper B, Copeland JR, Dartigues JF, da Silva Droux A, Hagnell O et al. 1991 The prevalence of dementia in Europe: a collaborative study of 1980–1990 findings. Eurodem Prevalence Research Group. International Journal of Epidemiology 20 736–748. Hori Y, Akizuki M & Nishimura R 2006 Comparison of adverse effects on lipid metabolism of Anastrozole with tamoxifen in the adjuvant setting for postmenopausal women with early breast cancer. European Journal of Cancer 4 94 (Abstract 172). Horne R & Weinman J 1999 Patients’ beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. Journal of Psychosomatic Research 47 555–567. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY & Tobias JS 2005 ATAC Trialists’ Group. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365 60–62. Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samoniqq H et al. 2005 ABCSG and the GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 455–462.

www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 Jenkins V, Shilling V, Fallowfield L, Howell A & Hutton S 2004 Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study Psychooncology 13 61–66. Jenkins V, Atkins L, Ambroisine L, Fleissig A, Fallowfield L & Howell A 2006 Preliminary results from the IBIS II (prevention) cognitive sub-protocol. Breast Cancer Research and Treatment 100 S238 (Abstract 5076). Kanis JA, McClosekey EV, Powles T, Paterson AHG, Ashley S & Spector T 1999 A high incidence of vertebral fracture in women with breast cancer. British Journal of Cancer 79 1179–1181. Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I & Von Minckwitz G 2006 Survival benefit of switching to anastrozole after 2 years’ treatment with tamoxifen versus continued tamoxifen therapy: The ARNO 95 study. Journal of Clinical Oncology 24 14s (Abstract 547). Kristensen B, Ejlertsen B, Dalgaard P, Larsen L, Nistrup Holmegaard S, Transbol I & Mouridsen HT 1994 Tamoxifen and bone metabolism in postmenopausal lowrisk breast cancer patients: a randomized study. Journal of Clinical Oncology 12 992–997. Kuh D, Langenberg C, Hardy R, Kok H, Cooper R, Butterworth S & Wadsworth MEJ 2005 Cardiovascular risk at age 53 years in relation to the menopause transition and use of hormone replacement therapy: a prospective British birth cohort study. British Journal of Obstetrics and Gynaecology 112 476–485. Lash TL, Fox MP, Westrup JL, Fink AK & Silliman RA 2006 Adherence to tamoxifen over the five-year course. Breast Cancer Research and Treatment 99 215–220. Lester J, Dodwell D, McCloskey E & Coleman R 2005 The causes and treatment of bone loss associated with carcinoma of the breast. Cancer Treatment Reviews 31 115–142. Lobo A, Launer LJ, Fratiglioni L, Anderson K, Di Carlo A, Breteler MMB, Copeland JRM, Dartigues J-F, Jagger C, Martinez-Lage J et al. 2000 Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54 S4–S9. Lønning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES, Paolini J et al. 2005 Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. Journal of Clinical Oncology 23 4847–4849. Lønning P, Geisler J, Krag LE, Lokkevik E, Risberg T, Hagen AI, Schlichting E, Eide GE & Di Salle E 2006 Vitamin D deficiency: a threat to bone health in breast cancer patients during adjuvant treatment with aromatase inhibitors. Journal of Clinical Oncology 24 16s (Abstract 554). Louwman WJ, Janssen-Heijnen MLG, Houterman S, Voogd AC, van der Sangen MJC, Nieuwenhuijzen GAP & Coebergh JWW 2005 Less extensive treatment and inferior prognosis for breast cancer patient with comorbidity: a population-based study. European Journal of Cancer 41 779–785.

www.endocrinology-journals.org

Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP & DeMets DL 1992 Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. New England Journal of Medicine 326 852–856. Mackey JR & Joy AA 2005 Skeletal health in postmenopausal survivors of early breast cancer. International Journal of Cancer 114 1010–1015. Mamounas E, Jeong J-H, Wickerham L, Smith R, Geyer C, Ganz P, Land S, Hutchins L, Eisen A, Ingle J et al. 2006 Benefit from exemestane (EXE) as extended adjuvant therapy after 5 years of tamoxifen (TAM): intent-to-treat analysis of NSABP B-33. Breast Cancer Research and Treatment 100 S22 (Abstract 49). Mannucci PM, Bettega D, Chantarangkul V, Tripodi A, Sacchini V & Veronesi U 1996 Effect of tamoxifen on measurements of hemostasis in healthy women. Archives of Internal Medicine 156 1806–1810. Markopoulos C, Chrissochou M, Michailidou A, Tzoracoleftherakis E, Xepapadakis G, Papadiamantis J, Misitzis J, Zobolas V, Bafaloukos D & Gogas H 2005 Effect of exemestane on the lipidemic profile of post-menopausal operable breast cancer patients following 5–7 years of adjuvant tamoxifen: preliminary results of the ATENA substudy. Anticancer Drugs 16 879–883. Martin B, Barghout V & Hutchins L 2006 Compliance and persistence of tamoxifen and aromatase inhibitors in breast cancer patients. European Journal of Cancer 4 96–97 (Abstract 179). Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW & Wing RR 1989 Menopause and risk factors for coronary heart disease. New England Journal of Medicine 321 641–646. Mauriac L, Keshaviah A, Debled M, Mouridsen H, Forbes JF, Thu¨rlimann B, Paridaens R, Monnier A, La´ng I, Wardley A et al. 2007 Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial. Annals of Oncology 18 859–867. McCloskey E, Hannon R, Lakner G, Clack G, Miyamoto A & Eastell R 2006a The letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial: a direct comparison of bone biochemical measurements between aromatase inhibitors (AIs) in healthy postmenopausal women. Journal of Clinical Oncology 24 16s (Abstract 555). McCloskey E, Hannon R, Lakner G, Clack G, Miyamoto A, Finkelman R & Eastell R 2006b Complete data from the letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamic (PD) ‘LEAP’ trial: direct comparison of safety parameters between aromatase inhibitors (AIs) in healthy postmenopausal women. Breast Cancer Research and Treatment 100 S111 (Abstract 2092). McCowan C, Shearer J, Dewar JA, Thompson AM, Donnan D, Crilly M & Fahey TP 2007 Tamoxifen adherence and its relationship to mortality in women with breast cancer. European Journal of Cancer 5 164 (Abstract 1213). Medicines and Healthcare Products Regulatory Agency (MHRA) 2005 Publication Assessment Report Femara

87

P Hadji: Menopausal symptoms and adverse events 2.5 mg tablet. http://www.mhra.gov.uk/home/groups/l unit1/documents/websiteresources/con2023055.pdf. Accessed July 13, 2006. Melton LJ III 2002 Epidemology worldwide. Endocrinology and Metabolism Clinics of North America 32 1–13. Mincey BA, Duh MS, Thomas SK, Moyneur E, Marynchencko M, Boyce SP, Mallet D & Perez EA 2006 Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clinical Breast Cancer 7 127–132. Mitsuyama S, Yanagida Y, Doihara H, Komaki K, Kusama M, Ikeda T, Kimura M, Sano M & Miyauchi K 2006 A multi-center study of the effects of toremifene (TOR) and anastrozole (ANA) on serum lipids and bone metabolism in postmenopausal patients with estrogen receptor (ER) positive breast cancer: Interim report. (Abstract 645) Journal of Clinical Oncology 24 39s. Moise P, Schwarzinger M, & Um M-Y 2004 Dementia Care in 9 OECD Countries: a comparative analysis. OECD. http://www.oecd.org/dataoecd/10/52/33661491.pdf. Accessed May 21, 2007. Monnier A 2007 Comparing AI cardiovascular safety data: trial comparators and outcomes. Presented at: 10th Conference on Primary Therapy of Early Breast Cancer, March 14–17, St Gallen, Switzerland. Abstract 109. Morales L, Pans S, Paridaens R, Westhovens R, Timmerman D, Verhaeghe J, Wildiers H, Leunen K, Amant F, Berteloot P et al. 2007 Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Research and Treatment 104 87–91. Morandi P, Rouzier R, Altundag K, Buzdar AU, Theriault RL & Hortobagyl G 2004 The role of aromatase inhibitors in the adjuvant treatment of breast carcinoma: the M. D. Anderson Cancer Center evidence-based approach. Cancer 101 1482–1489. Mouridsen H 2006 Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women. Current Medical Research and Opinion 22 1609–1621. Muss HB 2006 The benefits of letrozole in postmenopausal women with early stage breast cancer who have had five years of tamoxifen are independent of age. Breast Cancer Research and Treatment 100 S23 (Abstract 102). Mustacchi G, Cazzaniga ME, Pronzato P, Dc Matteis A, Di Costanzo F & Floriani I 2007 Breast cancer in elderly women: a different reality? Results from the NORA study Annals of Oncology 18 991–996. Nolvadex Adjuvant Trial Organisation 1983 Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet 1 257–261. Nordenskjo¨ld B, Rosell J, Rutqvist L-E, Malmstro¨m P-O, Bergh J, Bengtsson N-O, Hatschek T, Wallgren A & Carstensen J 2005 Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. Journal of National Cancer Institute 97 1609–1610.

88

Owusu C, Buist D, Field T, Lash TL, Thwin S & Silliman R 2006 Tamoxifen discontinuance among women aged 65 years and older with estrogen receptor positive breast cancer. Journal of Clinical Oncology 24 39s (Abstract 648). Partridge AH, Wang PS, Winer EP & Avorn J 2003 Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. Journal of Clinical Oncology 21 602–606. Partridge AH, LaFountain A, Taylor B & Asnis-Alibozek A 2006 Adherence with adjuvant anastrozole therapy among women with early stage breast cancer. Breast Cancer Research and Treatment 100 S186 (Abstract 4044). Passage KJ & McCarthy NJ 2007 Critical review of the management of early-stage breast cancer in elderly women. Internal Medicine Journal 37 181–189. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE et al. 2006 Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. Journal of Clinical Oncology 24 3629–3635. Peterson S, Peto V, Rayner M, Leal J, Luengo-Fernandez R & Gray A 2005 European cardiovascular disease statistics. London: British Heart Foundation. http://www.ehnheart.org/files/statistics%202005092711A.pdf. Accessed May 21, 2007. Pfeilschifter J & Diel IJ 2000 Osteoporosis due to cancer treatment: pathogenesis and management. Journal of Clinical Oncology 18 1570–1593. Van Poznak C, Hannon RA, Clack G et al. 2006 The SABRE (study of anastrozole with the bisphosphonate risedronate) study: the effects of risedronate on BMD and bone metabolism in postmenopausal women using anastrozole as adjuvant therapy for hormone receptor-positive early breast cancer first results. Breast Cancer Research and Treatment 100 S191–S192 (Abstract 4061). Presant C, Kelly C, Bosserman L, Upadhyaya G, Vakil M, Horns R, Ebrahimi B, Yeon C, Howard F, Rios A et al. 2006 Aromatase inhibitor (AI)-associated arthralgia (A) and bone pain (BP): frequency and characterization in clinical practice. Journal of Clinical Oncology 24 334s (Abstract 6137). Prince RL, Dick I, Devine A, Price RI, Gutteridge DH, Kerr D, Criddle A, Garcia-Webb P & St John A 1995 The effects of menopause and age on calcitropic hormones: a crosssectional study of 655 healthy women aged 35 to 90. Journal of Bone and Mineral Research 10 835–842. Qu Y, Wong M, Thiebaud D & Stock JL 2005 The effect of raloxifene therapy on the risk of new clinical vertebral fractures at three and six months: a secondary analysis of the MORE trial. Current Medical Research and Opinion 21 1955–1959. Rao VS, Garimella V, Hwang M & Drew PJ 2007 Management of early breast cancer in the elderly. International Journal of Cancer 120 1155–1160.

www.endocrinology-journals.org

Endocrine-Related Cancer (2008) 15 73–90 Rosen RC, Taylor JR, Leiblum SR & Bachmann BA 1993 Prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecological clinic. Journal of Sex & Marital Therapy 19 171–188. Saarto T, Blomqvist C, Valimaki M, Ma¨kela¨ P, Sarna S & Elomaa I 1997 Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. Journal of Clinical Oncology 15 1341–1347. Salgado BA & Zivian MT 2006 Aromatase inhibitors: side effects reported by 622 women. Breast Cancer Research and Treatment 100 S168 (Abstract 3131). Schwartzberg LS, Cobb P, Kulig K, Johns A, Fu D-Y & Fortner BV 2006 Variation from clinical guideline recommendations in practice patterns of community based adjuvant hormonal therapy (AHT) in early stage breast cancer (ESBC). Breast Cancer Research and Treatment 100 S196–S197 (Abstract 4076). Shapiro CL, Manola J & Leboff M 2001 Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. Journal of Clinical Oncology 19 3306–3311. Singh S, Howell A & Cuzick J 2006a Vitamin D levels among patients with arthralgia: results from IBIS-II breast cancer prevention study. Breast Cancer Research and Treatment 100 S61 (Abstract 1068). Singh S, Richmond B, Howell A & Cuzick J 2006b Effect of anastrozole on cholesterol fractions in postmenopausal women with high risk of breast cancer: results from IBIS-II breast cancer prevention study. Breast Cancer Research and Treatment 100 S57–S58 (Abstract 1055). Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, Stock JL, Song J, Qu Y, Kulkarni PM et al. 2005 Continuing Outcomes Relevant to Evista (CORE) Investigators. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. Journal of Bone and Mineral Research 20 1514–1524. Sourander L, Rajala T, Ra¨iha¨ I, Ma¨kien J, Erkkola R & Helenius H 1998 Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). (Erratum in: Lancet 1999; 353: 330) Lancet 352 1965–1969. Stevenson JC, Crook D & Godsland IF 1993 Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 98 83–90. Sullivan SD, Kreling DH & Hazlet TK 1990 Noncompliance with medication regimens and subsequent hospitalizations: a literature analysis and cost of hospitalization estimate. Journal of Research in Pharmaceutical Economics 2 19–33. Thangaraju M, Kumar K, Gandhirajan R & Sachdanandam P 1994 Effect of tamoxifen on plasma lipids and lipoproteins in postmenopausal women with breast cancer. Cancer 73 659–663.

www.endocrinology-journals.org

Theriault RL, Biermann JS, Brown E et al. 2006 NCCN task force report: bone health and cancer care. Journal of the National Comprehensive Cancer Network 4 S1–S20 (quiz, S21–S22). Thomas RJ, Marshall C, Williams M et al. 2006 Switching to adjuvant letrozole improves hot flushes, mood and quality of life in the tamoxifen intolerant subgroup. Annals of Oncology 17 ix93 (Abstract 264P). Thu¨rlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M et al. 2005 Breast International Group (BIG) 1–98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. (Erratum in: N Engl J Med 2006; 354: 2200) New England Journal of Medicine 353 2747–2757. Tremollieres FA, Pouilles JM, Cauneille C & Ribot C 1999 Coronary heart disease risk factors and menopause: a study in 1684 French women. Atherosclerosis 142 415–423. Tuck SP & Francis RM 2002 Osteoporosis. Postgraduate Medical Journal 78 526–532. Tyczynski JE, Plesko I, Aareleid T, Primic-Zakelf M, Dalmas M, Kurtinaitis J, Stengrevics A & Parkin DM 2004 Breast cancer mortality patterns and time trends in 10 new EU member states: mortality declining in young women, but still increasing in the elderly. International Journal of Cancer 112 1056–1064. US Preventive Services Taskforce 2005 Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Annals of Internal Medicine 142 855–860. Vehmanen L, Saarto T, Elomaa I, Ma¨kela¨ P, Va¨lima¨ki M & Blomqvist C 2001 Long-term impact of chemotherapyinduced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients: the effect of adjuvant clodronate treatment. European Journal of Cancer 37 2373–2378. Vehmanen L, Elomaa I, Blomqvist C & Saarto T 2006 Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. Journal of Clinical Oncology 24 675–680. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL 3rd et al. 2006 National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P2 trial. (Epub 2006 Jun 5. Erratum in: JAMA 2006; 296: 2926. JAMA 2007; 298: 973) Journal of the American Medical Association 295 2727–2741. Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, DeAngelis D et al. 2005 The influence of letrozole on serum lipid concentrations

89

P Hadji: Menopausal symptoms and adverse events in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Annals of Oncology 16 707–715. Whannel KJ, McLellan A, Wilson CR & Doughty JC 2006 The need for DXA assessment of breast cancer patients following 5 years tamoxifen prior to starting an aromatase inhibitor. Breast Cancer Research and Treatment 100 S187 (Abstract 4046). Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB et al. 2005 American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant

90

therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. Journal of Clinical Oncology 23 619–629. World Health Organization 2003 Adherence to long-term therapies: evidence for action. Geneva, Switzerland. http://www.who.int/chronic_conditions/adherencereport/en. Accessed May 21, 2007. Yancik R, Wesley MN, Ries LAG, Havlik RJ, Edwards BK & Yates JW 2001 Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. Journal of the American Medical Association 285 885–892.

www.endocrinology-journals.org