Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Aromatase inhibitors
General information
The development of newer antiestrogens continues in the hope of attaining a better benefit to harm balance, particularly in the adjuvant treatment of early breast cancer after the menopause [ , ]. The third-generation aromatase inhibitors inhibit the production of estrogen [ ]. Anastrozole and letrozole are non-steroids, and exemestane (a steroid with some androgenic activity) is a derivative of the androgen androstenedione, the natural substrate of aromatase. Early findings were positive, as demonstrated by a first analysis of the ATAC (“Arimidex, Tamoxifen Alone or in Combination”) trial, with a median follow-up of 33 months and a safety analysis after as many as 37 months of treatment [ ]. The latest safety analysis seemed to confirm that endometrial cancer vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all occurred less often in the anastrozole group, whereas musculoskeletal disorders and fractures continued to occur less often in the tamoxifen group. However, there is still debate about whether the aromatase inhibitors have significant advantages over tamoxifen [ ]; proponents argue that they are associated with fewer adverse effects (including endometrial cancer as well as those listed above) than tamoxifen [ ]. However, although they may cause fewer hot flushes, gynaecological, and thromboembolic adverse effects than tamoxifen, they may cause more musculoskeletal complications and sexual dysfunction. There is also variability in the actions of the different aromatase inhibitors, and they are not interchangeable [ ].
Comparative studies
Aromatase inhibitors versus tamoxifen
Letrozole (Femar®) and its congeners, notably anastrozole (Arimidex®) and exemestane (Aromasin®), suppress aromatase-induced estrogen production in postmenopausal women and have been approved in many countries to treat both early and advanced breast cancer [ ]. They cannot suppress estrogen production by the ovary and are therefore of no value in earlier life, but they now represent a serious alternative to tamoxifen in cases of endometrial and mammary malignancy [ , ]. While tamoxifen was for many years the gold standard adjuvant endocrine therapy for early breast cancer, its role is being challenged by the newest aromatase inhibitors. Whatever its merits, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major adverse effect of the inhibitors is bone loss, which may increase the risk of osteoporotic fractures and bone pain.
Several studies have justified the conclusion that aromatase inhibitors as monotherapy or sequentially to tamoxifen can improve the prospects of relapse-free survival in postmenopausal women with early breast cancer [ ]. Extensive studies of anastrozole in cases of hormone receptor-positive breast cancer suggest that it is closely similar to tamoxifen in both efficacy and safety [ ]. Recent work also suggests that these treatments are cost-effective [ ]. The cost-effectiveness of long-term adjuvant letrozole after a course of tamoxifen has also been stressed by economists examining the matter on behalf of Britain’s National Health Service [ ]. Several studies have compared the aromatase inhibitors with tamoxifen as adjuvant hormone therapy in postmenopausal women. Using these drugs, either alone or after tamoxifen, reduces the risk of cancer recurrence more than tamoxifen alone for 5 years. For postmenopausal women whose cancers are estrogen and/or progesterone receptor-positive, most experts now recommend using an aromatase inhibitor at some time during adjuvant therapy. Two separate meta-analyses of clinical trials have each reached the same conclusion. However, questions remain regarding the best treatment regimen [ , ].
The aromatase inhibitors tend to have fewer serious adverse effects than tamoxifen, with no risk of uterine cancers and a low incidence of thrombosis. However, they can cause joint stiffness and/or pain involving a number of joints simultaneously, while the risk of osteoporosis and fractures may justify a prior bone density test in view of the possibility of corrective treatment, for example with a bisphosphonate [ ].
Whether under particular conditions tamoxifen or an aromatase inhibitor should be preferred is still disputed. However, at present both tamoxifen and aromatase inhibitors have their place and their proponents [ ]. Quality of life is generally good for up to 3 years of follow-up with either treatment. Vasomotor and sexual complaints remain problematic, although they occur in only a small proportion of women. However, in one woman who had had amenorrhea for 5 years during tamoxifen treatment the introduction of letrozole in normally accepted doses resulted within 2 weeks in resumption of menstruation [ ].
In a survey of 452 patients on long-term treatment the most troublesome symptoms in of users tamoxifen and aromatase inhibitors included hot flushes (35% versus 30% respectively), weight gain (14% versus 15%), insomnia (17% versus 17%), and joint aches (12% versus 23%); 48% of users of aromatase inhibitors switched medication to improve symptoms compared with only 37% of users of tamoxifen [ ].
Organs and systems
Cardiovascular
Of 8028 postmenopausal women with receptor-positive early breast cancer who were randomly assigned double-blind to letrozole, tamoxifen, or a sequence of these agents for 5 years, 7963 were included in an analysis of cardiovascular events over a median follow-up time of 30 months [ ]. There was a similar overall incidence of cardiac adverse events (letrozole 4.8%; tamoxifen 4.7%), but more grade 3–5 events with letrozole (2.4% versus 1.4%), an excess that was only partly attributable to prior hypercholesterolemia. There were more thromboembolic events with tamoxifen (3.9% versus 1.7% overall and 2.3% versus 0.9% for grade 3–5 events). There were no significant differences between tamoxifen and letrozole in the incidence of hypertension or cerebrovascular events.
The risk of venous thromboembolism in women taking anastrozole is lower than that in women taking tamoxifen (1.6% versus 2.4%) [ ], but still higher than in the untreated population. Cases of pulmonary embolism have been reported in an 80-year-old woman taking anastrozole [ ] and a 72-year-old woman taking letrozole [ ].
Sensory systems
Retinal hemorrhages were sought in 35 women taking anastrozole 1 mg/day, 38 taking tamoxifen 20 mg/day, and 53 controls [ ]. There were retinal hemorrhages within the posterior pole in four of those taking anastrozole and none of the controls or those taking tamoxifen. Two of those taking anastrozole had a flame hemorrhage in the retinal nerve fiber layer and two had a blot hemorrhage deeper in the retina.
Psychiatric
A case report suggests the need for caution when using aromatase inhibitors in women with a past history of postpartum affective disorder or bipolar disorder.
-
A 60-year old woman, who had had an episode of severe depression after the birth of her only child 32 years before, had a mastectomy for breast cancer followed by radiotherapy and chemotherapy (anastrozole for 6 weeks and then letrozole) [ ]. While taking anastrozole she had a labile mood, increased activity, tremulousness, and difficulty in sleeping. These symptoms disappeared after anastrozole was withdrawn. While taking letrozole she had an acute irritable activated mood elevation, which then subsided into prolonged major depression after withdrawal of letrozole. These effects occurred during co-prescription of amitriptyline at a low dose for increased urinary frequency.
As with postpartum mania, the primary mechanism of this effect may be an acute reduction in circulating estrogen concentrations.
Metabolism
In 55 overweight or obese postmenopausal women who took tamoxifen (n = 27) or exemestane (n = 28) for 1 year, frat mass fell significantly with exemestane but not tamoxifen. Triglycerides and high-density lipoprotein cholesterol fell significantly and low-density lipoprotein cholesterol rose significantly with exemestane [ ].
In 147 postmenopausal women with early breast cancer who took exemestane in a placebo-controlled study, exemestane caused modest reductions in high-density lipoprotein cholesterol and apolipoprotein, but had no major effect on lipid profile, homocysteine concentrations, or coagulation [ ].
In 122 postmenopausal patients with metastatic breast cancer who were randomized to exemestane 25 mg/day (n = 62) or tamoxifen 20 mg/day (n = 60), neither exemestane nor tamoxifen had adverse effects at 8, 24 or 48 weeks on concentrations of total cholesterol, HDL cholesterol, apolipoproteins A1 or B, or lipoprotein a [ ]. Exemestane lowered triglyceride concentrations while tamoxifen increased them.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here