弗隆治疗绝经后晚期乳腺癌的疗效观察

弗隆是第三代非甾体类高选择性芳香化酶抑制剂，其具有高选择性，对他莫昔芬（三苯氧胺，tamoxifen，TAM）或其他抗雌激素药物治疗无效的绝经后晚期乳腺癌仍有较好的疗效，我科于1998年11月-2004年4月参加国际多中心比较弗隆与TAM一线治疗绝经后晚期乳腺癌的P025项目．临床上共应用弗隆治疗绝经后晚期乳腺癌38例，现将临床疗效和安全性观察结果报告如下．     

乳腺癌的预防

乳腺癌发病率逐年增高,一级预防是重点,主要复习乳腺癌的预防措施,包括基因检测、饮食调控、改变生活方式及化学药物预防,如三苯氧胺、雷洛昔芬、芳香化酶抑制剂和灭活剂等。     

临床常用的乳腺癌内分泌治疗药物

乳腺癌是一种激素依赖性的全身性疾病，其治疗手段有手术、放疗、化疗和内分泌治疗，其中内分泌治疗以其独特的作用和有效性受到了越来越多的关注。长期以来，三苯氧胺（tamoxifen，TAM）被视为内分泌治疗的标准选择，但近年来新型的芳香化酶抑制剂（AIs）向TAM的传统地位发起了强有力的挑战。此外，促黄体激素释放激素（LH—RH）类似物和孕激素类药物，共同构成了目前乳腺癌内分泌治疗的基本药物，对乳腺癌的内分泌治疗药物方面的咨询也越来越多，本文就现有的乳腺癌内分泌治疗药物作一简要介绍。     

芳香化酶抑制剂在乳腺癌内分泌治疗中的应用

乳腺癌的治疗,目前主要采取以手术为主,化疗、放疗、内分泌治疗和分子靶向治疗等为辅的综合治疗模式。而内分泌治疗在乳腺癌治疗中的地位越来越受到人们的重视,尤其是芳香化酶抑制剂（AIS）的问世,其在辅助治疗方面存在潜在的益处,直接挑战三苯氧胺在内分泌治疗方面的作用。     

乳腺癌内分泌治疗研究进展

内分泌治疗用于乳腺癌已有100多年的历史,具有疗效确实、耐受性良好的特点,已在各期激素受体阳性乳腺癌的辅助治疗中占据重要地位。目前,三苯氧胺仍是绝经前患者的标准用药,绝经后患者则首选芳香化酶抑制剂。本文就近年来进行的多个大宗临床试验,对乳腺癌内分泌治疗研究进展做一综述。     

乳腺癌内分泌药物治疗的研究进展

乳腺癌是严重影响妇女身心健康甚至危及生命的恶性肿瘤之一。传统的乳腺癌内分泌治疗药物是作用于雌激素环节的雌激素受体调节剂、芳香化酶抑制剂,但芳香化酶抑制剂的选择性较差,有中度的治疗相关毒性,如高血脂、骨丢失、肝脂肪化等,因此需要开发具有组织选择性、高效低毒的芳香化酶抑制剂。此外,新型的甾体硫酸酯酶抑制剂也已成为有效的激素依赖性乳腺癌(HDBC)治疗药物,氨基磺酸酯基团被证实是这类药物中的药效团。本文综述了芳香化酶抑制剂和硫酸酯酶抑制剂的研究进展。     

乳腺癌的内分泌药物两则

三苯氧胺为非淄体抗雌激素抗肿瘤药,主要适用于晚期乳腺癌,为停经后病例的首选药物,还可作为有效的预防药。氨鲁米特为芳香化酶抑制剂,主要适用于雌激素受体阳性绝经后晚期乳腺癌。三苯氧胺治疗失败时,氨鲁米特可作为二线治疗药物。本文介绍两药的药理作用、临床应用、应用方法和不良反应。     

乳癖宁贴膏与三苯氧胺联合治疗乳腺增生症78例分析

目的 观察乳癖宁贴膏与三苯氧胺联合治疗乳腺增生症的临床疗效。方法 将78例乳腺增生症患者随机分为治疗组和对照组，治疗组采用乳癖宁贴膏外用与口服三苯氧胺片综合治疗，对照组口服乳康片．观察治疗前后临床症状、体征变化，黄体期血清雌二醇和孕酮含量变化；比较两组临床效果。结果 治疗组总有效率92．86％，对照组总有效率75．00％。结论 三苯氧胺与乳癖宁贴膏联合应用起效快、复发率低，临床疗效显著。     

新型抗肿瘤药物依西美坦

依西美坦为第三代甾体类芳香化酶抑制剂，临床上治疗绝经后妇女晚期乳腺癌，作用机制为与芳香化酶底物结合位占不可逆结合使芳香化酶失活。本文综述了依西美坦的化学合成、药理作用及临床应用。     

乙氧苯柳胺在家兔体内的主要代谢产物

采用高效液相色谱法对家兔口服乙氧苯柳胺（Ｎ－（４－乙氧苯基）－２－羟基苯甲酰胺）后在尿中的代谢物进行了分离与检测．用β－Ｄ－葡糖苷酸酶和该酶加专属性抑制剂葡糖二酸－１，４－内酯分别对尿样进行水解处理，发现该药的主要代谢物为β－Ｄ－葡糖醛酸结合物，其含量超过尿中代谢物总量的８０％．利用色谱保留值和紫外双波长吸收比对酶解后的主要生成物进行定性分析，证明该代谢物为乙氧苯柳胺葡糖醛酸结合物（Ｎ－（４－乙氧苯基）－苯甲酰胺－２－Ｏ－葡糖苷酸）．此外，在家兔给药后０～１２ｈ尿样中未检测出乙氧苯柳胺原形药物及其可能的代谢产物水杨酸．     

Safety issues surrounding the use of aromatase inhibitors in breast cancer

Third generation aromatase inhibitors (AIs) are now established therapy in advanced oestrogen receptor (ER)-positive breast cancer. As the use of AIs expands to include adjuvant treatment of early breast cancer and breast cancer prevention, tolerability and effects on other organs such as bone will become as important as the antitumour properties of the drugs. In direct comparisons with tamoxifen, AIs have a better toxicity profile with fewer patients stopping therapy because of drug-related side effects. There is a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen. Although published information about the side effects of AIs is scarce, it is likely that they will have adverse effects on bone and possibly also on lipid metabolism. Subprotocols of ongoing adjuvant trials are investigating these effects. It is likely that the choice of which third generation AI to use will be largely determined by its tolerability and safety profile, since it is likely that the currently available drugs have similar efficacy.     

Putting the cardiovascular safety of aromatase inhibitors in patients with early breast cancer into perspective: a systematic review of the literature

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.     

Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women

ABSTRACT

Objective: Third-generation aromatase inhibitors (AIs) are effective and generally well-tolerated as adjuvant therapy. These AIs are now being introduced for the adjuvant treatment of postmenopausal patients with estrogen-receptorpositive early-stage breast cancer. However, questions remain about their long-term safety. This paper summarizes the adverse events reported in third-generation AI trials and comments on the appropriate management of these drug-induced adverse events in patients.

Methods: Papers relating to anastrozole, exemestane, and letrozole were identified through Medline searches, and proceedings of recent oncology meetings were also reviewed to capture relevant emerging data.

Results: The most commonly reported adverse events associated with adjuvant AI therapy include hot flushes and musculoskeletal complaints/arthralgia. The incidence of endometrial cancer and thromboembolic events is significantly lower with an AI than with tamoxifen. However, there is a small but significant increase in the risk of osteoporosis and fractures with AI therapy. A potential negative effect on the cardiovascular system, specifically on lipid metabolism, has not been conclusively demonstrated. No significant differences in overall quality of life were observed in studies comparing AIs with tamoxifen or placebo.

Conclusion: AIs alone and sequenced after tamoxifen are an appropriate option for adjuvant endocrine therapy for most postmenopausal patients with hormone-responsive breast cancer. The incidence of some side effects such as endometrial cancer, stroke, or pulmonary embolism associated with tamoxifen is decreased. Monitoring and management of bone loss associated with AI treatment are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of AIs on lipid metabolism and cardiovascular health.     

Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women

OBJECTIVE: Third-generation aromatase inhibitors (AIs) are effective and generally well-tolerated as adjuvant therapy. These AIs are now being introduced for the adjuvant treatment of postmenopausal patients with estrogen-receptor-positive early-stage breast cancer. However, questions remain about their long-term safety. This paper summarizes the adverse events reported in third-generation AI trials and comments on the appropriate management of these drug-induced adverse events in patients. METHODS: Papers relating to anastrozole, exemestane, and letrozole were identified through Medline searches, and proceedings of recent oncology meetings were also reviewed to capture relevant emerging data. RESULTS: The most commonly reported adverse events associated with adjuvant AI therapy include hot flushes and musculoskeletal complaints/arthralgia. The incidence of endometrial cancer and thromboembolic events is significantly lower with an AI than with tamoxifen. However, there is a small but significant increase in the risk of osteoporosis and fractures with AI therapy. A potential negative effect on the cardiovascular system, specifically on lipid metabolism, has not been conclusively demonstrated. No significant differences in overall quality of life were observed in studies comparing AIs with tamoxifen or placebo. CONCLUSION: AIs alone and sequenced after tamoxifen are an appropriate option for adjuvant endocrine therapy for most postmenopausal patients with hormone-responsive breast cancer. The incidence of some side effects such as endometrial cancer, stroke, or pulmonary embolism associated with tamoxifen is decreased. Monitoring and management of bone loss associated with AI treatment are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of AIs on lipid metabolism and cardiovascular health.     

Aromatase inhibitors: a new reality for the adjuvant endocrine treatment of early-stage breast cancer in postmenopausal women

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.     

Aromatase inhibitors in post-menopausal metastatic breast carcinoma

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.     

Aromatase inhibitors in post-menopausal metastatic breast carcinoma

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.     

Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer

BACKGROUND: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and sequencing strategies and extended adjuvant therapy. METHODS: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1-98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed. CONCLUSION: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.     

Aromatase inhibitors: a safety comparison

For almost three decades, tamoxifen has been the mainstay of hormonal therapy in breast cancer patients, but now the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are emerging as potential alternatives, associating greater clinical efficacy with a more favourable overall safety profile than tamoxifen. AIs are associated with a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen, although they are known to affect bone turnover and possibly lipid metabolism. As the available AIs have similar efficacy, it is likely that safety and tolerability profiles will have an impact on agent selection in clinical practice. Therefore, it is important that differences in the safety profiles of the third-generation AIs are understood.     

Aromatase inhibitors: a safety comparison

For almost three decades, tamoxifen has been the mainstay of hormonal therapy in breast cancer patients, but now the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are emerging as potential alternatives, associating greater clinical efficacy with a more favourable overall safety profile than tamoxifen. AIs are associated with a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen, although they are known to affect bone turnover and possibly lipid metabolism. As the available AIs have similar efficacy, it is likely that safety and tolerability profiles will have an impact on agent selection in clinical practice. Therefore, it is important that differences in the safety profiles of the third-generation AIs are understood.