Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003862 (arthralgia)
 7,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Letrozole (Femara), a nonsteroidal, third-generation aromatase inhibitor administered orally once daily, has shown efficacy in the treatment of postmenopausal women with early-stage or advanced, hormone-sensitive breast cancer. In early-stage disease, extending adjuvant endocrine therapy with letrozole (beyond the standard 5-year period of tamoxifen) improved disease-free survival; compared with placebo there was a 43% relative reduction in disease recurrences or new contralateral breast tumours at a median follow-up of 2.4 years. The results of 4 months' neoadjuvant treatment with letrozole or tamoxifen in postmenopausal women with untreated primary disease favour letrozole. In advanced breast cancer, letrozole was superior to tamoxifen as first-line treatment; time to disease progression was significantly longer (9.4 vs 6.0 months, p < 0.0001) and objective response rate was significantly greater with letrozole, but median overall survival was similar between groups. For second-line therapy of advanced breast cancer that had progressed on antiestrogen therapy, letrozole showed efficacy equivalent to that of anastrozole and similar to or better than that of megestrol acetate. Letrozole is generally well tolerated and has a similar tolerability profile to tamoxifen; the most common treatment-related adverse events were hot flushes, nausea and hair thinning. In patients with tumours that had progressed on antiestrogen therapy, letrozole was tolerated as least as well as, or better than, anastrozole or megestrol acetate. In the trial of extended adjuvant therapy, adverse events reported more frequently with letrozole than placebo were hot flushes, arthralgia, myalgia and arthritis. The long-term effects of letrozole on bone mineral density or lipid profile have not been determined and these parameters may require monitoring. In several pharmacoeconomic modelling studies from various public healthcare system perspectives, letrozole was considered a cost effective choice for first-line (vs tamoxifen) or second-line (vs megestrol acetate) treatment for advanced breast cancer in postmenopausal women. In conclusion, letrozole 2.5 mg/day is effective in the treatment of postmenopausal women with early-stage or advanced breast cancer. The efficacy, cost effectiveness and favourable tolerability profile of letrozole are reflected in current treatment guidelines recommending the drug as first-line therapy for advanced breast cancer. Letrozole is superior to tamoxifen for first-line treatment and is at least as effective as standard second-line treatments in disease that has progressed on antiestrogen therapy. For early-stage disease, letrozole is superior to tamoxifen in the neoadjuvant setting, and prolongs disease-free survival when administered after the standard 5-year period of adjuvant tamoxifen therapy.
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PMID:Letrozole: a review of its use in postmenopausal women with breast cancer. 1516 28

The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.
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PMID:Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. 1581 48

The aromatase inhibitors deplete oestrogen by inhibiting aromatase, the enzyme that synthesises oestrogen from androgens. They are effective as therapies for breast cancer only in postmenopausal women whose tumours express oestrogen or progesterone receptors. As adjuvant therapy, tamoxifen and the aromatase inhibitors have similar efficacy in the first 5 years of treatment. Aromatase inhibitors can be used as an alternative to tamoxifen in women with symptomatic intolerance or a contraindication to tamoxifen. Early data suggest that switching to an aromatase inhibitor after 2-5 years of tamoxifen therapy is beneficial in women with high-risk disease. Aromatase inhibitors are associated with more hot flushes than placebo, but with fewer hot flushes, less endometrial toxicity and venous thromboembolism, and more arthralgia, myalgia and bone fracture than tamoxifen.
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PMID:The aromatase inhibitors in early breast cancer: who, when, and why? 1639 38

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1alpha recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor alpha (RXRalpha), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1-dependent, PGC-1alpha-stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression.
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PMID:Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. 1635 89

Letrozole is a highly selective, nonsteroidal, third-generation aromatase inhibitor approved for first-line and extended adjuvant therapy in postmenopausal women with hormone-responsive, early-stage breast cancer. Binding of letrozole to the haeme component of the cytochrome P450 subunit of aromatase inhibits estrogen biosynthesis throughout the body. As first-line adjuvant therapy in approximate, equals 8000 postmenopausal women with hormone-responsive, early-stage breast cancer, once-daily letrozole 2.5mg significantly prolonged disease-free survival (DFS; primary endpoint) and reduced the risk of relapse at distant sites relative to once-daily tamoxifen 20mg in the ongoing Breast International Group 1-98, double-blind, multinational trial. The median duration of follow-up for this primary core analysis was 25.8 months. Extended adjuvant therapy with once-daily letrozole 2.5mg significantly prolonged DFS relative to placebo treatment at a median follow-up of 30 months (primary endpoint) in the MA-17 trial in approximate, equals 5000 postmenopausal women who were disease free after 4.5-6 years of tamoxifen therapy for hormone-responsive, early-stage breast cancer. Letrozole treatment for up to 5 years was generally well tolerated in this clinical setting. As first-line treatment, relative to tamoxifen, letrozole was associated with a significantly lower incidence of venous thromboembolitic events, vaginal bleeding, hot flushes and night sweating, whereas the incidence of cardiac failure, bone fractures and arthralgia was higher in letrozole recipients.
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PMID:Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. 1652 26

Tamoxifen has been the gold standard adjuvant therapy for the treatment of postmenopausal women with hormone-receptor-positive (HR+) early breast cancer for many years. Tamoxifen treatment is limited to 5 years because of the development of de novo and acquired resistance, and an ongoing risk of adverse events, including endometrial cancer, thromboembolic events, and gynecological symptoms with long-term use. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole, and exemestane, are displacing tamoxifen as the first-choice therapy for HR+ early breast cancer, and are now recommended as the preferred therapy by national and international guidelines. Recent randomized trials have demonstrated that the AIs are more effective than tamoxifen in preventing disease recurrence when used in substitution and sequential strategies in the early adjuvant setting, and letrozole has been shown to be more effective than placebo in the extended adjuvant setting (after 5 years of tamoxifen therapy). Trial safety data show that the overall tolerability of AIs is similar to that of tamoxifen, with adverse events being predictably characteristic of estrogen deprivation; however, some important differences in adverse event profiles between tamoxifen and the AIs have been demonstrated. In addition to antiestrogenic effects, tamoxifen acts as an estrogen agonist in some tissues, which can lead to serious side effects not associated with the AIs, which prevent estrogen biosynthesis. A lower incidence of gynecological and thromboembolic events is observed in patients taking AIs, and fewer cases of endometrial cancer are seen compared with tamoxifen. Adverse events that are more frequent with adjuvant AI therapy compared with tamoxifen include arthralgia and myalgia, bone loss, and effects on the cardiovascular system and blood lipids. The effects of AIs on bone are predictable and may be easily managed, where necessary, with bisphosphonates. Studies examining the effects of AIs on the cardiovascular system and lipid profiles, including in the extended adjuvant setting, suggest that these adverse events may be due to the absence of a protective effect of tamoxifen rather than true AI toxicity. Further studies are required to determine the long-term safety of AI therapy in postmenopausal women with HR+ early breast cancer.
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PMID:Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective. 1721 90

Postmenopausal patients with hormone-sensitive breast cancer may be eligible for adjuvant hormone therapy. - For years, tamoxifen was the treatment of choice. - However, the side effects associated with tamoxifen, such as endometrial cancer and thromboembolic disorders, and the search for more effective agents have led to the introduction of new hormonal therapies. - The results of randomised trials with the third-generation aromatase inhibitors anastrozole, exemestane and letrozole demonstrate improved efficacy compared to tamoxifen. - Using aromatase inhibitors, the disease-free survival is prolonged and recent data from some studies also show a benefit in overall survival. - Aromatase inhibitors are associated with specific side effects consisting of osteoporosis/increased incidence of fractures and myalgia/arthralgia.
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PMID:[Optimal adjuvant hormone therapy in postmenopausal women with hormone-sensitive mammary carcinoma: tamoxifen and the aromatase inhibitors anastrozole, exemestane and letrozole]. 1731 17

Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. Clinical trials have assessed 5 years of AI therapy, either as an alternative to tamoxifen for primary adjuvant therapy of breast cancer, or after 5 years of adjuvant tamoxifen. Treatment of 2-3 years' duration after 2-3 years of tamoxifen has also been studied. AI therapy brings side effects related to estrogen deprivation, and this side effect profile differs in clinically relevant ways from that seen with tamoxifen. In particular, the selective estrogen receptor modulatory effects of tamoxifen contribute to menopausal symptoms, vaginal discharge, and the rare but worrisome risks of thromboembolism and uterine carcinoma. By contrast, the low levels of estrogen achieved with aromatase inhibition contribute to menopausal symptoms, vaginal dryness and sexual dysfunction, and accelerated bone demineralization with risk of osteoporosis and osteoporotic fracture. Clinical experience also suggests that AI therapy is associated with a novel musculoskeletal side effect consisting of an arthralgia syndrome. The actual incidence of AI-associated arthralgias or musculoskeletal symptoms is not known, though such symptoms are quite prevalent and appear more commonly with AI use than with tamoxifen. Arthralgias can be a reason for discontinuation of AI treatment. The possible mechanisms of AI-associated arthralgia are unclear. Estrogen deficiency causes bone loss, which in turn contributes to arthralgia. Less well-studied functions of estrogen include regulating immune cells and cytokines involved in bone remodeling, and modulating pain sensitivity at the level of the central nervous system. Arthralgia and arthritis have seldom been rigorously differentiated in clinical trials of AIs. Assessment of inflammatory and rheumatologic markers, as well as detailed evaluation of patient symptoms using appropriate quality-of-life instruments, may be warranted in order to understand both the symptoms and the etiology of the arthralgia syndrome. Treatment options for arthralgia (primarily non-steroidal anti-inflammatory drugs) are currently inadequate, but areas of active research include high-dose vitamin D and new-targeted therapies to inhibit bone loss.
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PMID:Aromatase inhibitor-associated arthralgia syndrome. 1736 3

To summarise the advances in the hormonal treatment of post-menopausal metastatic breast cancer, this paper reviews the published literature regarding the randomised trials comparing aromatase inhibitors (AIs) versus tamoxifen as a first-line therapeutic choice, or AIs versus megestrole acetate (MEG) as a second-line option. The pooled analysis of these authors on AI versus MEG as a second-line option for post-menopausal metastatic breast cancer suggested that AIs do not add any significant benefit over MEG in terms of overall response rate (ORR) and time to progression. According to the Cochrane Database, use of an AI as a second-line therapy versus any other endocrine therapy (mostly MEG) has shown a significant benefit in terms of overall survival, but not for progression-free survival, clinical benefit (CB) or ORR. Concerning the authors' comparisons between AIs versus tamoxifen as a first-line endocrine option in post-menopausal women with metastatic breast carcinoma, AIs seem to be superior to tamoxifen, with a significant benefit in terms of ORR, CB and time to progression being observed in favour of AIs over tamoxifen with fixed effects estimates. According to the Cochrane Database, there was an advantage to the use of AIs over tamoxifen in terms of progression-free survival and CB, but not for overall survival or ORR. With regards to toxicity, AIs show similar levels of hot flushes and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. Weight gain, dyspnoea and peripheral oedema seem to be more frequent with MEG. At present, there is no proved overall survival difference in patients who are treated first with an AI and then with tamoxifen compared with the opposite sequence. In the metastatic setting, results are limited and are based on retrospective analyses.
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PMID:Aromatase inhibitors in post-menopausal metastatic breast carcinoma. 1759 87

In postmenopausal women with hormone receptor-positive early-stage breast cancer, the use of aromatase inhibitors (AIs) to suppress estrogen is associated with improved clinical outcomes compared with tamoxifen therapy. Women receiving such endocrine therapy may experience treatment-related side effects that negatively affect health-related quality of life (QoL) and adherence to therapy. In published clinical trials and in clinical practice, adverse events (AEs) constitute the main reason for nonadherence to endocrine treatment. Serious AEs are sometimes resolved by switching to a different agent, whereas other side effects can often be managed to allow patients to remain on therapy without sacrificing QoL. Across all adjuvant endocrine trials, regardless of the treatment received, vasomotor symptoms such as hot flashes are the most common side effects. Other frequently reported side effects, such as vaginal discharge, vaginal dryness, dyspareunia, and arthralgia, vary in prevalence between tamoxifen and AIs. Here we provide an overview of reported AEs of adjuvant endocrine therapy, focusing on those that are amenable to pharmacologic or nonpharmacologic management without treatment discontinuation. Also highlighted are specific management strategies that may improve patient QoL and thereby optimize adherence to therapy, which in turn might improve patient outcomes.
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PMID:Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. 1787 3


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