Safety Of Aromatase Inhibitors Research Articles

Aromatase inhibitors for uterine fibroids

Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Albeit generally benign, uterine fi broids can have a major impact on women's health and quality of life by contributing to abnormal uterine bleeding and causing pelvic pressure symptoms (such as increased urinary frequency, pelvic pain and constipation). Traditional treatments for symptomatic fi broids include a variety of surgical techniques. However, because of the high recurrence rate, as well as possible pain and infertility caused by the formation of postoperative adhesions, this approach may not be advisable. Safer and more effective medical therapy has long been awaited. Both in vitro studies and clinical trials have suggested that use of the aromatase inhibitors (AIs), a class of anti-oestrogens, might inhibit fi broid growth, thereby eliminating the need for surgery. To evaluate the effectiveness and safety of aromatase Inhibitors (AIs) in women with uterine fibroids. We searched the following databases (from inception to August 21, 2013): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and PsycINFO. In addition, the reference lists of included trials were searched, and experts in the field were contacted. Randomised controlled trials (RCTs) in women of reproductive age comparing the effects of any AI versus placebo, no treatment or any medical treatment/surgery were included. Selection of eligible trials, assessment of trial quality and data extraction were performed independently by two review authors. If data were available, we planned to calculate odds ratios (ORs) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CIs). Only one trial involving 70 participants was included. This trial did not report our primary review outcome (relief of symptoms of fibroids). The only secondary review outcomes reported by this trial were adverse effects (hot flushes) and reduction in fibroid size. Significantly fewer women reported hot flushes in the letrozole group than in the GnRHa group (0/33 vs 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a gonadotrophin-releasing hormone (GnRH) agonist (GnRHa) by 32% after 12 weeks of treatment; these proportions were not significantly different. The included trial did not report data on fibroid volume in a form that permitted calcuation of an odds ratio. Morevoer it was unblinded and included only 60/70 women in analysis. Evidence is insufficient to support the use of AI drugs in the treatment of women with uterine fibroids.

Combination treatment with aromatase inhibitor and capecitabine as first- or second-line treatment in metastatic breast cancer.

e11016 Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and oral fluoropyrimidines in estrogen receptor (ER)-positive cell lines enhance antitumor efficacy. This might be explained by reduction of ER-induced growth signaling in addition to decrease in estrogen production. This retrospective analysis of a cohort of patients with metastatic breast cancer (MBC) evaluates the efficacy and safety of combined AI with capecitabine. Methods: Patients with hormone receptor-positive MBC treated with this combination were evaluated and outcomes were compared to women treated with capecitabine (conventional dose) or AI as monotherapy. The administered total dose of capecitabine was 2000 mg. per day in combination with AI. Results: Of 93 patients evaluated, 37 received the combination treatment, 27 capecitabine and 29 an AI. Combination was used in 26 patients as first-line treatment and 11 as second-line. At the time of progression, 92% had a performance status of ≤2 and 58% of patients had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow-up was 23 months (m). The median PFS of first-line treatment was significantly better for the combination (PFS not-reached vs.3.0 m for capecitabine and 13.0 m for AI, p&lt;0.0001). For second-line treatment, the PFS was longer in the combination compared to capecitabine and AI (PFS not reached vs. 6.0 m vs.13.0 m, respectively, p=0-041). For the entire cohort, OS was not reached. The most common adverse events for the combination group were grade 1 and 2 hand-foot syndrome (65%), grade 1 fatigue (52%) and grade 1 diarrhea (5%). Only one grade 3 hand-foot syndrome event was reported. Conclusions: Combination treatment with capecitabine and AI used as first-line treatment or second-line improved PFS compared to treatment with either single agent. The combination was safe and rendered dismal toxicity. Prospective randomized clinical trials should evaluate the use of the combination of capecitabine and an AI in advanced breast cancer in order to confirm our findings.

P1-16-01: A Randomized, Double-Blinded, Controlled Study of Exemestane vs. Anastrozole for the First-Line Treatment of Postmenopausal Japanese Women with Hormone Receptor Positive Advanced Breast Cancer.

Abstract Background The steroidal irreversible aromatase inhibitor (AI) exemestane (E), the non-steroidal reversible AI anastrozole (A) and tamoxifen (T) are approved for the first-line treatment of the postmenopausal women with hormone receptor (HR) positive advanced breast cancer (ABC) in Japan. Although there are some studies which compare the efficacy and safety of AIs and T in the first-line disease setting, the number of studies that compare efficacy and safety of AIs is limited. We conducted this multicenter, randomized, double-blinded non-inferiority study, to evaluate the time to progression (TTP) in HR positive ABC randomized to therapy with E or A. Methods Patients (pts) who were ≥20 years [yrs], postmenopausal, ECOG PS ≤1 and had HR positive ABC that recurred after the adjuvant therapy or metastatic disease settings were eligible and randomized (1:1) to 25 mg/day of E or to 1 mg/day of A. Data were evaluated for non-inferiority of E compared to A defined as the upper limit of a two-sided 95% confidence interval (CI) of the hazard ratio (HR) of TTP being less than or equal to 1.25. The primary endpoint was TTP assessed by the independent radiological images review committee (RIRC). Secondary endpoints included TTP by investigator, time to treatment failure, overall survival (OS), objective response rate (ORR), clinical benefit rate, and safety. Results A total of 298 pts from 58 sites were randomized to E (n=149; mean age: 63.4 yrs) or A (n=149; mean age: 64.0 yrs). The mean BMI for the E and A arms were 23.0 kg/m2 and 23.6 kg/m2, respectively. Six pts (2 pts in E arm, 4 pts in A arm) were excluded from the full analysis set due to lack of evaluation for anti-tumor response after study medication started. Median TTP (as per RIRC) was 13.8 months (M) vs. 11.1 M for E vs. A, respectively (HR 1.007; 95% CI: 0.771−1.317). Median TTP (Investigator) was 13.8 M vs. 13.7 M for E vs. A, respectively (HR 1.059; 95% CI: 0.816−1.374). The median OS for A treated pts was 60.1 M, OS for E was not reached (as of data cut-off: December 8, 2010). ORR for E was 43.9% (95% CI: 35.3−52.8) and 39.1% (95% CI: 30.6−18.1) for A. Other analyses, including sub-population analyses are ongoing. The incidence of treatment related adverse events (AEs) in E arm was 71.1% (n=106) and in A arm 59.7% (n=89); the AEs were mostly grade 1 and 2 in 61.7% (n=92) and 53.7% (n=80) of pts respectively. They were expected and manageable. Treatment related SAEs were similar in both groups: 6 (4.0%) in E arm and 5 (3.4%) in A arm. The most common AEs for E were hot flushes (22.1%), arthralgias (16.8%), musculoskeletal stiffness (11.4%) and γ-GTP increased (10.1%); in A arm, hot flushes (14.8%) and arthralgia (16.8%) were observed in &amp;gt;10% pts. Conclusions Although median TTP (RIRC) of E is slightly improved compared with that of A, the result of TTP did not meet the non-inferiority criteria. There were no significant differences found between E and A in ORR. Although AEs in E were numerically higher, the observed AE profiles were similar to those previously reported for E and A. This study shows that E is comparable to A in efficacy and safety. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-16-01.

Current role and safety profile of aromatase inhibitors in early breast cancer

The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.

Aromatase Inhibitors to Augment Height: Continued Caution and Study Required

Aromatase inhibitors (AIs) are a class of drugs that prevent conversion of androgens to estrogens, and that are approved in the United States as adjunctive treatment of estrogen receptor-positive breast cancer. Because ultimate fusion of the growth plates is estrogen-dependent in both boys and girls, AI administration may help to slow down epiphysial maturation and allow for greater height potential. Research trials in children with short stature have predominantly been done in Finland and Florida. Despite the apparent efficacy described by these groups, only ˜110 children worldwide have been treated with AIs in research protocols (and usually concomitant with other growth-promoting agents) as of the end of 2008 (and none to final height). That said, many children are being treated with AI’s in the United States outside of research protocols. Furthermore, little is known about the short- and long-term safety of AIs in children. Thus, it is imperative that there be well-designed, long-term studies of efficacy and safety of AI use in pediatric populations.Conflict of interest:None declared.

Aromatase inhibitors for female infertility: a systematic review of the literature

Ovulation induction remains a milestone in the treatment of women with anovulatory infertility. Clomiphene citrate (CC) is considered the first line treatment for induction of ovulation in women with polycystic ovary syndrome (PCOS), while it may be used for ovulation induction in unexplained infertility. Aromatase inhibitors (AI) have been introduced as a new treatment option that could challenge CC for ovulation induction. A systematic review of the literature was conducted in order to highlight the efficacy and safety of AI in female infertility. Current data from randomized and non-randomized trials suggest that AI may have a role in ovulation induction regimens in PCOS patients, as well as for ovarian stimulation, since they achieve comparable clinical pregnancy rates to CC. Furthermore, when combined with gonadotrophins, AI improve the ovarian response of poor responders and reduce the gonadotrophin dose required. However, the current review is based on small trials with a limited number of patients. If solid data from future large adequately powered randomized trials support current evidence regarding efficacy and safety, AI might offer a new treatment choice for infertile women.

Efficacy and safety of aromatase inhibitors in early breast cancer

Background: Third-generation aromatase inhibitors (AIs) are surfacing as the standard adjuvant treatment for postmenopausal women with hormone receptor positive breast cancer over tamoxifen but their long-term effects are still under investigation. Objective: In the light of current information, what factors should health practitioners take into consideration when prescribing AIs to patients? Methods: Results of several randomized controlled adjuvant clinical trials were reviewed to assess the efficacy of treatment and their subprotocols focusing on quality of life and skeletal health to highlight the safety concerns. Conclusion: To prevent early recurrences, AIs should be considered as the upfront hormonal treatment of choice. They are also recommended for use as a switching strategy after 2 – 3 years of tamoxifen and as extended adjuvant treatment after 5 years of tamoxifen. The adverse events experienced are manageable and overall quality of life is not compromised; however, bone density must be monitored for patients at risk and appropriate bone-protection supplements need to be taken.

Summary of aromatase inhibitor clinical trials in postmenopausal women with early breast cancer

Five years of adjuvant therapy with tamoxifen was considered the gold-standard treatment for postmenopausal women with estrogen receptor-positive breast cancer for many years. Data from a core group of clinical trials investigating the safety and efficacy of aromatase inhibitors (AIs) have challenged this perception. These studies were designed to evaluate the safety and efficacy of AIs in the following clinical settings: 1) as initial adjuvant therapy (the Arimidex, Tamoxifen, Alone or in Combination trial, Breast International Group Trial 1-98), 2) in a "switched setting" after 2 to 3 years of treatment with tamoxifen (Arimidex-Nolvadex 95, the Austrian Breast and Colorectal Cancer Study Group 8 [ABCSG 8] trial, the Italian Tamoxifen Anastrozole study, the Intergroup Exemestane Study), and 3) in extended settings (National Cancer Institute of Canada Trial MA.17, ABCSG 6a, National Surgical Adjuvant Breast and Bowel Project 33). The efficacy data from these studies suggested that AIs have added substantial benefit in terms of disease outcome. AIs were tolerated well, and patients who received them experienced fewer thrombolic events and less endometrial cancer, hot flashes, night sweats, and vaginal bleeding compared with patients who receive tamoxifen. However, patients who received tamoxifen had less skeletal events and accelerated bone resorption compared with women who received AIs. AIs should be considered when planning a patient's endocrine therapy, taking into account the differences in tolerability and end-organ effects of the classes of endocrine therapy. Outstanding issues to optimize AI therapy include identifying the optimal duration, agent, and patients for these therapies.

Safety of aromatase inhibitors in the adjuvant setting

Safety of aromatase inhibitors in the adjuvant setting

Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer

Adjuvant endocrine therapy plays an important role in the management of hormone-receptor-positive early breast cancer, and has increased life expectancy for millions of women. Many patients receive adjuvant treatment for at least 5 years following tumor resection, hence good long-term safety is important for endocrine agents to gain widespread acceptance. Tamoxifen has been used as adjuvant therapy for early breast cancer for many years, and safety data have been well documented, but a poor risk:benefit profile limits treatment duration to 5 years. Increased efficacy over tamoxifen and good tolerability have recently made the third-generation aromatase inhibitors (AIs) the first-choice agents for adjuvant endocrine therapy; however, it is currently not known whether AI therapy, like tamoxifen, will be limited to 5 years. Many side effects of endocrine therapy, such as hot flushes and mood disturbances, are related to estrogen deprivation and are common to tamoxifen and AIs, reflecting the mechanism of action of these drugs. In addition, tamoxifen has estrogenic effects that are beneficial in some tissues: tamoxifen lowers serum cholesterol levels and protects against bone loss and cardiovascular disease, but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic disease. As AIs lack estrogenic activity, they are not associated with these serious adverse events. Clinical trials comparing AIs with tamoxifen in the adjuvant setting have shown that AIs are well tolerated and are associated with a lower incidence of gynecological symptoms and hot flushes than tamoxifen. However, AIs are associated with musculoskeletal side effects, such as arthralgia, myalgia and bone loss, but these events are preventable or manageable. The effects of AIs on lipid metabolism and the cardiovascular system are still debatable, but placebo-controlled trials provide no evidence to suggest that AIs adversely affect these systems. Furthermore, the AIs allow women to maintain a good quality of life, comparable with women receiving tamoxifen or placebo, and are a cost-effective therapeutic option. Ongoing trials will provide more information regarding the long-term effects of AI therapy and will provide comparative data on the efficacy and safety of the different AIs, thereby helping to determine the optimal treatment strategy for these highly effective and well-tolerated drugs.

Inhibidores de la aromatasa en el tratamiento adyuvante de pacientes postmenopáusicas con cáncer de mama. Metanálisis

To evaluate the efficacy and safety of aromatase inhibitors (AIs) as adjuvant hormonal therapy for postmenopausal patients with hormone receptor positive breast cancer compared with tamoxifen therapy, or as a subsequential treatment to this therapy. We carried out a bibliographical search using the Medline database and papers presented at the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium conferences. The efficacy parameters evaluated were disease-free survival (DFS) and overall survival (OS), measured after the follow-up period for each of the tests analysed. The data selected were subjected to a stratified meta-analysis according to the different strategies used to introduce the AIs. The Mantel-Haenszel odds ratio (MH OR; at 95% CI) was calculated for each of the parameters evaluated. The principal side effects with respect to toxicity, described in the various comparative clinical trials, have been listed in a table. Compared to tamoxifen, AIs have been shown to increase DFS both as a first-line therapy (MH OR = 0.83; 95% CI: 0.76-0.92) and when sequentially administered for 2-3 years following 2-3 years of tamoxifen treatment (MH OR = 0.65; 95% CI: 0.57-0.75). Similarly, their use after 5 years of tamoxifen therapy also produces an increase in DFS (MH OR = 0.63; 95% CI: 0.51-0.77). As for OS, a statistically significant difference is obtained only when the AI is administered following 2-3 years of tamoxifen treatment (MH OR = 0.77; 95% CI: 0.64-0.94). In comparison with tamoxifen, AIs reduce the incidence of thromboembolic and gynaecologic events, although they increase bone toxicity. The clinical studies evaluated show the consistent benefits of AIs at different adjuvant treatment stages; however, we have been unable to establish the optimum moment for their introduction due to the absence of direct comparisons between the different strategies. We now need to focus on the selection of patient sub-groups which could benefit from their use as a first-line therapy, the long-term toxicity of AIs, and their capacity to increase OS, regardless of the strategy followed, after a longer monitoring period. In light of the evidence available, bearing in mind certain limitations, we propose criteria for the use of AIs in daily clinical practice.

Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2–3 years of tamoxifen.The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures.

Bone safety of aromatase inhibitors versus tamoxifen

Bone loss may be a potential side effect of implementing aromatase inhibitors in the adjuvant setting. Current evidence suggests a minor bone loss during treatment with the steroidal aromatase inhibitor exemestane compared to placebo and a nonsignificant increase in fracture rate during treatment with exemestane when compared to tamoxifen. Such a difference could be due to the bone-sparing effects of tamoxifen. For the nonsteroidal inhibitors letrozole and anastrozole, the MA17 study revealed a nonsignificant increase in fracture rate for letrozole compared to placebo. In contrast, both anastrozole and letrozole were found to significantly increase fracture rate compared to tamoxifen when administered as monotherapy or given sequentially. While an increased fracture rate may have detrimental effects, evidence suggests that enhanced bone loss may be preventable through careful bone mineral density (BMD) assessment and treatment with bisphosphonates.