Adjuvant Therapy For Postmenopausal Women Research Articles

Management of side effects of aromatase inhibitors (AIs) during adjuvant therapy for postmenopausal women with HR+ breast cancer: Analysis of French practices

e11593 Background: Aromatase inhibitors (AIs) are widely used as adjuvant therapy for HR+ breast cancer. Most frequently reported side effects are joint pain, osteoporosis and lipid disorders. Our aim was to describe how physicians in their clinical practice manage these side effects at initiation of treatment and during follow-up. Methods: Multicentric survey conducted in October 2008 by Internet among a sample of 293 physicians specialized in breast cancer management prescribing adjuvant AIs in post-menopausal women with HR+ breast cancer Results: At initiation of AI treatment, 97 % of the physicians interviewed declared informing their patients of the possible occurrence of joint pain; corresponding figures were 81 % for the increased risk of osteoporotic fractures, 66 % for lipid disorders, 59 % for asthenia, and only 16% for cognitive disorders. At initiation, 71% of the physicians assess fracture history, 83 % prescribe BMD, and 60 % lipid tests. Co-prescription of drugs in association with AIs from the onset of treatment is uncommon (24% of physicians interviewed), vitamin D and calcium being the most frequent prescription (19%); prescription of bisphosphonates was less frequently declared (10%). During the course of treatment, 90% of physicians assess BMD at least once, 41% repeat BMD two years after and 41% adapt monitoring of BMD according to the initial result. Lipid tests are monitored every six months by 29% of physicians, and every year by 29%. In case of joint pain, the initial therapeutic management includes: prescription of an analgesic and/or an anti-inflammatory for 66% of physicians, change of AI for 28%; the switch for tamoxifene is mentioned by only 1%. As a second step in case of failure of the initial measures, adjuvant treatment is modified by 70 % of physicians: change of AI by 50 %, switch for tamoxifene by 20 %. Conclusions: The possible side effects of aromatase inhibitors are taken into account by physicians from the initiation of treatment. They perform themselves the monitoring of the patient during follow-up, including the search for side effects. Bone-joint adverse events are managed by oncologists while the care of lipid disorders is transferred to the primary care physician. No significant financial relationships to disclose.

Modalities of prescription of aromatase inhibitors (AI) in adjuvant therapy for postmenopausal women with HR+ breast cancer: Analysis of daily practices in France

e11619 Background: Aromatase inhibitors (AIs) are widely used as adjuvant therapy for HR+ breast cancer. This survey is an overview of clinical daily practices in France Methods: Multicentric survey conducted in October 2008 by Internet among a sample of 293 physicians specialized in breast cancer management (oncologists, radiotherapists, surgeons) prescribing adjuvant AIs in post-menopausal patients with HR+ breast cancer Results: When started upfront, 87% of physicians expressed that the optimal duration of AIs treatment is 5 years, and 7 % more than 5 years. Nevertheless only, 33% of physicians inform their patients of a total duration of AIs therapy of 5 years, and 66% of a possible adjustment according to the evolution of the scientific knowledge during the five years. AIs are prescribed after the end of chemotherapy by 97% of physicians, after the end of radiotherapy by 83%, and during radiotherapy by 15%. When started after two years of tamoxifen, 71 % of physicians expressed that the optimal duration of AIs treatment is 3 years, 22% 5 years, and 3% more than five years. When started after five years of tamoxifen, 48% of physicians expressed that the optimal duration of AIs treatment is less than three years, 15% 3 years, 15% 5 years, and 2% more than five years. The optimal duration of treatment with aromatase inhibitors is still subject to question for 73% of the physicians interviewed Conclusions: In France, most physicians declared an optimal duration of treatment with aromatase inhibitors in adjuvant setting in HR+ breast cancer in line with guidelines and/or approved indications. However, the optimal duration of treatment is still subject to question for many physicians No significant financial relationships to disclose.

A woman's heart

Adjuvant therapy in postmenopausal women with breast cancer may contribute to the expression of underlying cardiovascular disease or expose the heart to additional toxicities. Tamoxifen remains an important component of endocrine therapy for breast cancer, although major clinical trials of the aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane suggest that these agents are more effective and better tolerated alternatives to tamoxifen. The AIs inhibit the conversion of androgens to estrogen in postmenopausal women; consequently, their mechanism of action differs from that of tamoxifen. Accordingly, although it has been observed that tamoxifen has some favorable effects on cardiovascular risk, such as reducing total cholesterol levels, because of its partial estrogen-agonist properties, no such effects exist for the AIs. Some studies, particularly those that compare the AIs with tamoxifen, have suggested a less favorable impact of adjuvant AI therapy on cardiovascular risk. Comorbid conditions, including cardiovascular disease, emerge as competing causes of death as women with breast cancer continue to live longer, and the potential impact of adjuvant therapies on cardiovascular risk becomes an increasingly important consideration for clinicians. Cancer 2009. (c) 2009 American Cancer Society.

0242 Cost effectiveness analysis of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer

0242 Cost effectiveness analysis of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer

Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: meta-analyses of randomized trials of monotherapy and switching strategies.

Abstract Abstract #12 Background: Meta-analyses (EBCTCG, Lancet 2005; 365:2687) have established in estrogen receptor (ER) positive breast cancer (BC) that 5 yrs of adjuvant tamoxifen (Tam) substantially reduces recurrence and mortality. The aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have been studied in prospective trials in postmenopausal patients (pts) in comparison with Tam either as initial monotherapy (Cohort 1) or after 2 to 3 years of Tam in a switching strategy (Cohort 2); both to a total of 5 years (yrs) of endocrine therapy.
 Methods: Outcomes data submitted to EBCTCG were used in separate meta-analyses of Cohort 1 (trials: ATAC, BIG 1-98/IBCSG 18-98) and of Cohort 2 (trials: ABCSG 8, ARNO 95, IES/BIG 2-97, ITA). The primary analysis involved pts with tumors reported to be ER positive with endpoints of BC recurrence (all, local only, contralateral BC only, distant), death with and without recurrence, any death. Subgroup analyses included progesterone receptor (PgR) status, age, tumor grade and nodal status. All p-values were 2-sided.
 Results: Highlights include: Cohort 1: 9,856 pts with 50,000 woman-years of follow-up. At 5 yrs, AI therapy was associated with an absolute 2.7% (standard error [SE] 0.7) decrease in BC recurrence (10.7% vs 13.4%, relative decrease 20% [SE 5], p=0.00004). There appeared to be greater proportional decreases in isolated local recurrence (30% [SE 10], p=0.003) and in contralateral disease (38% [SE 12], p=0.003) than in distant recurrence (12% [SE 6], p= 0.04). AIs yielded an absolute 1.0% (SE 0.5) decrease in BC mortality (5.5% vs 6.5%, relative decrease 7% [SE 7], p=0.28). Cohort 2: 9,015 pts with 33,000 woman-years of follow-up. At 6 yrs from treatment divergence (i.e., 8-9 yrs from diagnosis), AI therapy was associated with an absolute 3.5% (SE 1.1) decrease in BC recurrence (12.6% vs 16.1%, relative decrease 29% [SE 6], p<0.00001). There appeared to be greater proportional reductions in isolated local recurrence (40% [SE 13], p=0.002) and in contralateral disease (35% [SE 16], p=0.03) than in distant recurrence (24% [SE 7], p= 0.001). AIs yielded an absolute 1.6% (SE 0.8) decrease in BC mortality (6.3% vs 8.0%, relative decrease 22% [SE 9], p=0.02). Subset analyses with respect to PgR status, age, tumor grade and nodal status revealed no apparent heterogeneity between the proportional reductions in recurrence and no indication of an increase or decrease in non-breast deaths with AIs in either cohort 1 or 2.
 Conclusions: In 2 separate meta-analyses considering both the initial monotherapy setting and the switching setting after 2 to 3 yrs of Tam, AIs produced significantly lower BC recurrence rates compared with Tam. Additional follow-up data will provide important information on long-term survival. Meta-analyses can be helpful even in the era of relatively large clinical trials. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 12.

Effects of switching aromatase inhibitors on arthralgia: the ATOLL study.

Abstract Abstract #1142 Background: Aromatase inhibitors (AIs) are standard adjuvant therapy in postmenopausal women (PMW) with hormone receptor-positive breast cancer (HR+BC). The estrogen-deficient environment induced by AIs may predispose women to increased bone loss and arthralgia. Switching from one AI to another has been shown to improve arthralgia. However, clinical trial data documenting the course of joint pain symptoms in switching studies has been sparse. The Articular Tolerance of Letrozole (ATOLL) study evaluates the tolerability of letrozole (L) in patients who were switched from anastrozole (A) due to severe joint pain.
 Objectives: This study included PMW with HR+BC who experienced severe joint pain with A requiring discontinuation and then switched to L. The aim of the study was to (i) determine the incidence of L discontinuation due to joint pain (ii) identify predictive factors for L tolerance.
 Methods: Only PMW with HR+ BCwho experienced severe joint pain on A requiring discontinuation were eligible for this 6-month prospective open-label, multi-centre trial. Treatment with L was initiated following a 1 month washout period. Pain assessment was done by a oncologist just prior to L initiation and after six months of follow up. Outcomes were based on patient reports of joint pain after initiating L. A central review was done by a rheumatologist. Statistical evaluations were determined on a 95% CI, and correlations were performed using a Cox model.
 Results: 179 PMW with HR+ breast cancer (mean age 61.3 ± 8.4) were eligible. The mean duration of A treatment prior to discontinuation was 14.6 ± 10.59 months with 126 (73.7%) on A for more than 6 months. At the end of the 6 month follow-up, 128 patients (71.5%) remained on L and continued by choice while 51(28.5%) patients discontinued L due to worsening of joint pain;73.5% patients discontinued due to arthralgia and 21% due to muscle pain . Hands, knees and spine were the most commonly affected joints. There was no association between L discontinuation with age, duration of menopause, socio-demographic status or previous joint disorders including osteoarthritis. The predictor of L discontinuation was significant only for the duration of the previous A treatment (p=0.04).
 Conclusion: These data suggest switching from anastrozole to letrozole may help to maintain the benefit of AI therapy in patients who complain with severe joint pain and support the reported findings of Renshaw et al that more than 50% of women obtained relief of joint pain by switching from one AI to another. Symptomatic arthralgia due to prolonged use of A reduced the usefulness of switching to L in this patient cohort, therefore, switching from one AI to the other at the onset of symptoms may help to maintain the benefit of AI therapy in patients who complain of severe joint pain. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1142.

A review of the use of exemestane in early breast cancer

Exemestane is a third-generation aromatase inhibitor, which has proven to be a useful drug in the treatment of early stage breast cancer. Several clinical trials have been performed or are currently underway using exemestane as adjuvant therapy in postmenopausal women, which will be the indication reviewed here. A relative reduction in risk of breast cancer recurrence or death of 24% has been shown with exemestane compared with tamoxifen when given after 2 to 3 years of tamoxifen. This corresponded to a 3.3% absolute reduction in recurrence or death at the end of 5 years, for a number needed to treat of 30. The main use of exemestane in the adjuvant setting is as an alternative to tamoxifen, and toxicities are discussed in relation to tamoxifen toxicities. In general, patients receiving exemestane experience less hot flashes and more arthralgias in comparison to tamoxifen, while there is also a reduction in venous thromboembolic events and vaginal bleeding. Patients on exemestane as a group do not appear to have a significantly changed quality of life in comparison to tamoxifen, while having a statistically significant benefit in preventing breast cancer recurrence.

Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

Adjuvant endocrine therapy reduces the risk of recurrence and improves survival among women with hormone receptor–positive breast cancer (1). Because most breast cancers, especially those among postmenopausal women, are hormone receptor positive, hundreds of thousands of women worldwide initiate adjuvant endocrine treatment each year. Historically, the standard recommendation for such patients has been 5 years of therapy with the selective estrogen receptor modulator tamoxifen (1). Two large randomized clinical trials—the Breast International Group Trial 1–98 (BIG 1–98) (2) and the Arimidex, Tamoxifen Alone or in Combination trial (3)—have shown that initial adjuvant endocrine treatment with aromatase inhibitors yields improved disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor–positive breast cancer. These findings have led many oncologists to adopt aromatase inhibitors as their preferred initial adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer (4). However, interpretation of these trial results is complicated by new pharmacogenomic data that suggest that the clinical benefit of tamoxifen may vary according to the cytochrome P450 (CYP) 2D6 genotype of the patient (5–7). CYP2D6 is the cytochrome P450 isoform that is mainly responsible for catalyzing the conversion of tamoxifen to endoxifen (8), the tamoxifen metabolite that is thought to be the primary mediator of estrogen-dependent suppression of cell proliferation (9). The CYP2D6 gene has multiple allelic variants, some of which, including the *4 allele, result in the loss of CYP2D6 enzyme function. Population genetic studies (10–12) have revealed that variations in the CYP2D6 gene sequence correspond to pharmacogenomic variations in endoxifen levels among women taking tamoxifen. For example, in a study of 80 newly diagnosed breast cancer patients who were beginning tamoxifen treatment, Jin et al. (10) found that those who carried either the homozygous (*4/*4) or the heterozygous (wt/*4) variant genotype of CYP2D6 had statistically significantly lower mean plasma endoxifen levels (20.0 and 43.1 nM, respectively) than those who carried the homozygous wild-type (wt/wt) genotype (78.0 nM). Additional studies have also supported the finding of a CYP2D6 gene dose effect on plasma concentrations of endoxifen (11,12). These data prompted a Food and Drug Administration advisory panel to recommend in October 2006 that a warning label be added to tamoxifen; the panel cited the new pharmacogenomic studies (5,12) indicating that the drug is less effective in women who carry a mutation in one of the enzymes used to metabolize tamoxifen than in those who do not. Both of the landmark clinical studies (2,3) that revealed improved disease-free survival outcomes for up-front adjuvant treatment with aromatase inhibitors vs tamoxifen accrued patients irrespective of their CYP2D6 gene mutation status. Given the link between CYP2D6 mutation status and compromised clinical outcomes among mutation carriers on tamoxifen, it is likely that aromatase inhibitors would be the preferred treatment for a woman with deficiencies in tamoxifen metabolism, such as those heterozygous (wt/*4) or homozygous (*4/*4) for the *4 mutation of CYP2D6. However, for women who do not carry a CYP2D6 gene mutation that affects tamoxifen metabolism, the decision about which type of adjuvant endocrine therapy to undergo is not as clear. To date, no genotype analysis of patients who participated in the randomized trials comparing adjuvant tamoxifen with aromatase inhibitors has been performed. However, it is reasonable to infer that if these trials had been restricted to women with wild-type tamoxifen metabolism, the women in the tamoxifen arms would have had better outcomes than those that were reported. To study the magnitude of difference between reported outcomes on tamoxifen and the estimated efficacy of tamoxifen in patients with-out CYP2D6 gene mutations, we constructed a decision-analytic model using data from CYP2D6 pharmacogenomic studies and used the model to evaluate whether an aromatase inhibitor or tamoxifen is the optimal initial treatment choice for the large majority of postmenopausal women who do not carry a mutation that affects the function of the CYP2D6 enzyme.

The role of endocrine therapies in reducing risk of recurrence in postmenopausal women with hormone receptor-positive breast cancer

Hormone receptor-positive breast cancer is increasingly considered a chronic disease, as there remains an ongoing risk of local and distant relapse for years after diagnosis. While early recurrence risk peaks 2-3 years post diagnosis, the majority of breast cancer recurrences and deaths occur following 5 years of adjuvant tamoxifen. Aromatase inhibitors have achieved greater relative reductions in recurrence risk than tamoxifen alone and are now widely recommended as adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer. Although both anastrozole and letrozole have demonstrated superior disease-free survival compared with tamoxifen, letrozole to date offers the greatest significant reduction in the risk of distant metastases in patients with hormone-sensitive breast cancer. Anastrozole and exemestane also reduce local and distant recurrence risk in the "switch setting" following 2-3 years of tamoxifen. Extended adjuvant letrozole, given after 5 years of tamoxifen, significantly reduces local and distant recurrence as well as mortality in patients with node-positive disease. Specialist nurses and nurse practitioners facilitate informed choice for breast cancer patients through explaining treatment options and side effects; they thus need an understanding of which treatment strategies reduce recurrence risk, especially the risk of distant metastases.

Aromatase inhibitors in early breast-cancer treatment: The story so far

This paper describes the clinical evidence for using the aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, as adjuvant therapy for postmenopausal women with early breast cancer. Efficacy data for AIs are reviewed across different treatment strategies (initial, switched, sequenced or extended adjuvant therapy). Although trials are still ongoing, AIs have demonstrated superiority over tamoxifen in terms of disease-free survival and recurrence as initial therapy, and benefits in overall survival in switched or extended strategies. However, comparisons of efficacy data across trials are confounded by methodological differences between trials. To address this problem, mathematical models have been developed which allow for inter-trial comparisons. Results from these models indicate that initial adjuvant therapy with an AI is superior to initial therapy with tamoxifen, and suggest that initial AI therapy is better than starting tamoxifen and then switching to an AI. Further clinical trials are needed to ascertain the optimal length of treatment with an AI.

Choosing early adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer: Aromatase inhibitors versus tamoxifen

Aims The aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole have demonstrated superior disease-free survival (DFS) over tamoxifen in several trials. As the choice of adjuvant endocrine treatment for early breast cancer (EBC) is evolving from tamoxifen to the AIs, this review compares the AIs with tamoxifen to help surgeons choose a treatment plan that provides the greatest reduction of recurrence risk for their patients. Methods MEDLINE was searched to identify relevant literature on the adjuvant use of tamoxifen and AIs in EBC. Results Despite the use of adjuvant tamoxifen, recurrence is a persistent threat to women with hormone-sensitive EBC. Trials of the AIs versus tamoxifen have established that patients benefit from longer DFS, and in some cases distant DFS, after the use of an AI as initial adjuvant therapy, as switch therapy following 2–3 years of tamoxifen, or as extended adjuvant therapy following 5 years of tamoxifen. The AIs are well tolerated, with a different safety profile than that of tamoxifen in all these settings. Trials addressing the optimal regimen and treatment duration for AIs are also underway. Conclusions The advantage in DFS associated with AIs over tamoxifen use should prompt physicians and patients to consider the use of an AI as the initial adjuvant endocrine therapy or, alternatively, switching patients who currently take tamoxifen to an AI for the remainder of adjuvant endocrine therapy. Prolonging the period of adjuvant therapy with letrozole after 5 years of tamoxifen reduces recurrence and is associated with a survival advantage in node-positive patients.

Menopausal symptoms and adjuvant therapy-associated adverse events

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.

Pre‐treatment with anastrozole may be the optimal treatment sequence with radiotherapy for breast cancer

AbstractAim: The aim of this study was to assess the in vitro effect of sequencing of irradiation and anastrozole on MCF‐7aro breast cancer cell line proliferation. Adjuvant tamoxifen therapy for breast cancer is often delayed until after completion of radiotherapy because of the potential inhibition of radiation cytotoxicity and normal tissue radiation effects. Aromatase inhibitors like anastrozole are now indicated as the first‐line adjuvant therapy for postmenopausal women, but there are little data regarding the optimum sequencing order of radiotherapy and aromatase inhibitors.Methods: Using reverse transcription polymerase chain reaction we confirmed the aromatase gene expression for MCF‐7aro cells. Comprehensive dose–response curves for MCF‐7aro were established for anastrozole and ionizing radiation (IR). Cell proliferation and colony survival were assayed for a 2 Gy fraction of IR administered either before or during incubation with 1.4 μmol/L anastrozole.Results: Compared to radiation alone, the relative day 7 cell proliferation with anastrozole exposure commenced before radiation exposure is 0.59 (95% CI 0.51–0.67) versus anastrozole exposure commenced after radiation exposure, which is 0.83 (95% CI 0.69–0.96), rank sum P = 0.007. Colony survival assays also support the possibility that pre‐radiation anastrozole treatment enhances the effects of irradiation. There was no evidence of radiation resistance as a result of pre‐radiation treatment with anastrozole.Conclusion: The initiation of anastrozole before irradiation may enhance radiosensitivity and local control for adjuvant breast irradiation.

The use of third-generation aromatase inhibitors and tamoxifen in the adjuvant treatment of postmenopausal patients with hormone-dependent breast cancer: evidence based review

(1) Worldwide, breast cancer is the most common type of cancer in women, and the second most frequently diagnosed cancer overall.(2) Since its approval approximately 20 years ago, a 5-year course of tamoxifen has been the standard adjuvant therapy for patients with hormone-dependent breast cancer.(3) Recently, data from large randomised clinical trials have indicated that the third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen as adjuvant therapy in postmenopausal women with operable breast cancer when given either initially, or sequentially following initial tamoxifen therapy, within the first five years post-operatively.(4) One large randomised trial demonstrated that administration of letrozole to high-risk (node-positive) postmenopausal patients who have completed 5 years' adjuvant tamoxifen further prevents late recurrences and contralateral breast cancer, contrary to the lack of obvious benefit of extending tamoxifen treatment to 10 years found in another large randomised study.(5) Aromatase inhibitors and tamoxifen should not be administered concomitantly as this does not provide additional benefit, and a large, randomised study demonstrated reduced disease-free survival with the combination of anastrozole plus tamoxifen compared with anastrozole alone.(6) Further studies are required to establish whether the third-generation aromatase inhibitors prolong overall survival compared with tamoxifen, to evaluate their long-term efficacy and tolerability profiles, and to determine the optimal treatment duration with these agents.

Aromatase Inhibitors and Arthralgias: A New Frontier in Symptom Management for Breast Cancer Survivors

Aromatase inhibitors (AIs) have become widely used as adjuvant therapy for postmenopausal women with hormone receptor– positive breast cancer. Although the optimal schedule and duration remain unclear, current guidelines endorse the inclusion of AI treatment at some point during adjuvant therapy for most postmenopausal women with estrogen receptor–positive breast cancer. Because of the incidence and demographics of breast cancer, hundreds of thousands of breast cancer patients throughout the world will start AI therapy each year. As a class, AIs are generally safe drugs and are reasonably well tolerated by most patients. They have been studied in very large adjuvant trials with careful documentation of both toxicity and patient compliance. The majority of symptoms associated with aromatase inhibition are related to the profound estrogen deprivation that arises as a consequence of AI therapy. These symptoms include hot flashes, night sweats, vaginal dryness, and sexual dysfunction. A particular concern among postmenopausal women has been bone health, including osteopenia, osteoporosis, and osteoporotic fracture, all of which are accelerated by AIs. Serial monitoring of bone mineral density and supplemental calcium, vitamin D, and exercise are recommended to minimize loss of bone density in women receiving AI therapy. Given that AI treatment has become more common, clinical experience has suggested another unique musculoskeletal adverse effect of AI therapy: arthralgias. Arthralgia is defined as pain in one or more joints, and is distinguished from arthritis, which suggests inflammation of the joint caused by structural damage, infection, autoimmunity, or metabolic conditions. Arthralgias may be difficult to gauge in older breast cancer patients with early-stage breast cancer owing to the high prevalence of degenerative joint disease and of nonspecific muscle and joint aches. In patients with stage IV breast cancer, the frequency of bone metastases also confounds easy measurement of drug-associated musculoskeletal symptoms. The pivotal trials of AIs as treatment for metastatic breast cancer documented musculoskeletal complaints in 4% to 13% of women receiving AI therapy. The first report linking AI therapy to arthralgia was a letter to the editor of the Journal of Clinical Oncology (JCO) in 2001, describing a series of patients with metastatic breast cancer treated with AI therapy in the United Kingdom. Among 77 women starting AI therapy for metastatic breast cancer, 16% developed new joint pains, mostly of moderate grade, prompting one in four of these women to stop AI therapy because of symptoms. In each case, cessation of AI therapy resolved the joint pain. The most common sites of joint pain were hands, knees, hips, back, and shoulders. The seminal studies of adjuvant AI therapy such as the Arimidex, Tamoxifen, Alone or in Combination, Breast International Group 1-98, Intergroup Exemestane Study, and National Cancer Institute of Canada trial MA17, captured data on adverse effects of AI and tamoxifen as treatment-related toxicity. Bone and joint symptoms were categorized in a variety of different ways in the toxicity reporting of the major adjuvant AI trials, including classification as arthritis, joint pain, or musculoskeletal disorders, to name several examples. Estimates for the incidence of musculoskeletal problems in these trials range from 5% to 36% among patients receiving AI therapy, and from 4% to 29% among women taking tamoxifen. These broad ranges reflect both the variety of definitions of arthritis, arthralgia, and bone pain, and the potentially confounding effect of widely prevalent nonspecific bone symptoms. Formal surveys of patients continuing protocol treatment in the adjuvant AI trials showed comparable global quality of life among women taking either AI or tamoxifen/placebo therapies, suggesting that whatever musculoskeletal symptoms patients were experiencing, they had on average a modest impact on dayto-day function and activity. Nonetheless, growing clinical experience suggests that AI therapy can be associated with a particular clinical syndrome of arthralgias, and breast cancer specialists are becoming more familiar with these symptoms. Typical sites of discomfort include the hands (fingers and wrists), arms, knees, and feet, pelvic and hip bones, and back. In our experience, patients describe stiffness, achiness, or pain that is usually symmetric, may be associated with mild thickening of the soft tissues (for instance, rings do not fit as before), and is temporally associated with onset of AI therapy. Symptoms may be most noticeable on awakening, and often improve with morning activities. Patients frequently make gestures such as squeezing or flexing their joints to show affected areas, and often mention that they feel they have “aged” abruptly. The true prevalence of such symptoms among breast cancer survivors is not known, and thus the report from Crew et al at JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 25 SEPTEMBER 1 2007

Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective

In the primary core analysis of BIG 1-98, a randomized, double-blind trial comparing 5 years of initial adjuvant therapy with letrozole versus tamoxifen in postmenopausal women with hormone receptor-positive (HR+) early breast cancer, letrozole significantly improved disease-free survival by 19% and reduced the risk of breast cancer recurrence by 28% and distant recurrence by 27%. A Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained with 5 years of initial adjuvant therapy with letrozole versus tamoxifen from a Canadian healthcare system perspective. Probabilities of recurrence and side effects for tamoxifen were based on published results of BIG 1-98 and other published population-based studies. Corresponding probabilities for letrozole were calculated by multiplying probabilities for tamoxifen by estimated relative risks for letrozole versus tamoxifen from BIG 1-98. Other probabilities, costs of breast-cancer care and treatment of side effects, and health-state utilities were obtained from published studies. Costs and QALYs were estimated over the lifetime of a cohort of postmenopausal women with HR+ early breast cancer, aged 60 years at initiation of therapy, and discounted at 5% annually. Compared with tamoxifen, letrozole yields an additional 0.368 life-years (12.453 vs. 12.086) and 0.343 QALYs (11.582 vs. 11.239). These benefits are obtained at an additional cost of Can$ 8,110 (Can$ 30,819 vs. Can$ 22,709). Cost per QALY gained for letrozole versus tamoxifen is Can$ 23,662 (95% CI Can$ 15,667-Can$ 52,014). In postmenopausal women with HR+ early breast cancer, initial adjuvant treatment with letrozole is cost-effective from the Canadian healthcare system perspective.

News & Notes

AbstractSwitch from tamoxifen to anastrozole improves outcomes in early breast cancerPostmenopausal women who have taken tamoxifen for two years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing to receive tamoxifen, according to the results of the ARNO 95 trial.1 This open‐label trial randomised post menopausal women who had undergone primary surgery for oestrogen receptor‐positive early breast cancer and had received two years of continuous tamoxifen therapy (20 or 30mg/day) to treatment with anastrozole (1mg/day; n=489) or to continue with tamoxifen (20 or 30mg/day; n=490) for an additional three years. The primary endpoint of the study was disease‐free survival (including local or distant recurrence, new contralateral breast cancer, or death); secondary end‐points included overall survival and toxicity. Disease‐free survival was improved in women who switched to anastrozole compared with those who continued with tamoxifen (HR 0.66; 95% CI 0.44‐1.00; P=0.049). Estimated three‐year disease‐free survival rates were 93.5% for anastrozole and 89.3% for tamoxifen. Switching to anastrozole was associated with improved overall survival compared with continuing on tamoxifen (HR 0.53; 95% CI 0.28‐0.99; P=0.045). Fewer patients who switched to anastrozole reported serious adverse events (22.7 vs 30.8%) compared with those who continued on tamoxifen, mainly because more patients in the tamoxifen group had endometrial events (OR 0.66; 95% CI 0.49‐0.89; P=0.0065). The authors conclude that patients switched to anastrozole after an initial period of tamoxifen therapy experience significant improvements in terms of disease‐free and overall survival. The results provide additional evidence that five years of tamoxifen is no longer the optimum adjuvant therapy for postmenopausal women with hormone‐receptor‐positive early breast cancer. 1. Kaufmann M, Jonat W, Hilfrich J, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after 2 years of treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study. J Clin Oncol, published early online, 11 June 2007; doi: 10.1200/JCO.2006.08.8054.BASHH 10th annual NCCG conferenceThe 10th annual conference for nonconsultant career grade doctors in genitourinary medicine will be held at Loughborough University on 14 and 15 September 2007.The provisional programme includes: What's new in NSU? Prostatitis Sexual behaviour in MSM: emerging issues HPV vaccines Topical issues in O&G Post‐exposure prophylaxis. Further details are available on the BASHH website: www.bashh.org/committees/nccg/index.asp Copyright © 2007 Wiley Interface Ltd.

Cost‐effectiveness of switching to exemestane versus continued tamoxifen as adjuvant therapy for postmenopausal women with primary breast cancer

Sequential tamoxifen/exemestane therapy reportedly improves disease-free survival in women with primary breast cancer compared with continued tamoxifen therapy. The objective of the current study was to assess the cost-effectiveness of switching to exemestane after 2 to 3 years of tamoxifen versus continued tamoxifen in postmenopausal women with primary breast cancer for a total of 5 years of adjuvant therapy. A Markov model based on the Intergroup Exemestane Study (IES) population compared switching to exemestane versus continued tamoxifen for 2.5 years of therapy and 5 years of postadjuvant therapy follow-up. Disease progression and hazards ratios (HR) for recurrence and survival were determined from datasets (IES and the Surveillance, Epidemiology, and End Results program of the National Cancer Institute) and from the published literature. An expert panel validated treatment patterns, outcomes, and resource utilization. Direct medical costs were included based on published sources. Cost-effectiveness ratios were determined, and extensive sensitivity analyses were conducted. Exemestane was found to be more effective than tamoxifen alone with regard to disease-free survival (2.6% absolute improvement), life-years gained (0.1028 LY), and quality-adjusted life-years gained (0.1195 QALY), at an additional cost of 2,889 Can dollars per person over 7.5 years. Incremental cost-effectiveness ratios were 28,119 Can dollars/LY gained and 24,185 Can dollars/QALY gained. The model was most sensitive to distant recurrence HR but was robust to variations in clinical, cost, and utility parameters. Switching to adjuvant exemestane after 2 to 3 years of tamoxifen is cost-effective in postmenopausal women with primary breast cancer.

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?