Aromatase enzyme is expressed significantly in endometrial stromal cells and it is physiologically responsible of the oestrogens synthesis; it induces, in consideration of its expression, the proliferation of tumour cells, and this phenomenon leads to the transformation of neoplastic tissue . Aromatase inhibitors cause a block of the activity of the aromatase cytocrome p-450 enzyme by binding the heme group, which leads to a decrease of the oestrogens synthesis and blood concentrations. Aromatase inhibitors play a significant role in post-menopause, when the gonadic oestrogens have low blood-concentration due to the inactivity of hypothalamic-pitituary-ovarian axis. In all post-menopausal women, the reduction of the conversion of testosterone to oestrogen decreases by 90% . Anastrozole is a non-steroidal aromatase inhibitor of third-generation, which is able to bind the enzyme with a reversible mechanism, hence inhibiting it completely (99% of the enzyme activity appears to be blocked) [17, 18]. However, as our previous literature review showed, the use of aromatase inhibitors has a moderate clinical benefit in case of recurrent/advanced EC . Nevertheless, the work of Gao et al., demonstrated that the use of aromatase inhibitors appears to be a possible therapy in endometrial cancer in early stages, based on the literature review of previously data . Also Thangavelu et al. demonstrated that the markers of proliferation (KI-67 protein) and apoptosis (bcl2 protein) decrease in those patients with EC which underwent to anastrozole as a neaodiuvant therapy . These considerations are the biological and biochemical bases for the rational of the administration of anastrozole in aged women, not suitable for surgery. In fact, the EC type 1 is commonly diagnosed in early stages in several patients; nevertheless, there is a group of patients in which surgical treatment (which is a better therapeutic option in this stage of disease) is not feasible for different reasons such as advanced age and comorbidities. In these cases, the neaodiuvant/palliative therapy is the best therapeutic option for these patients, in order to give them an alternative therapy for the management of the symptoms of EC.
Our preliminary trial shows that anastrozole can be a valid therapeutic option as a palliative therapy in the treatment of EC in elderly women which improves not only the quality of life of these patients, but also helps them to relieve the disease-related symptoms. Anastrozole administration appears to be effective as a palliative therapy in all of the patients enrolled in our trial with EC type 1. In fact, this treatment causes a good clinical response in 87.5% of the cases (the patients died for other reasons were included) and only one patient demonstrated stable disease. Moreover, the treatment allowed a good control of endometrial disease without any need for surgery intervention, which would have been difficult in relation to the patients’ advanced age and frequently present co-morbidities. Anastrozole therapy may prevent the onset of further recurrences and the progression of endometrial cancer. Physical well-being and compliance to the therapy was evident in all of our patients, in relation to a well-tolerated therapy and a low report of side effects in this particular category of elderly women. In fact, the hormone therapy resulted in a subjective well-being and an easiness of administration which are both important aspects to consider in all aged patients. As the QLQ-C30 questionnaire reported, the global health increased significantly twelve months after beginning the therapy, which highlighted the clinical benefit of this palliative therapy for elderly women with EC. The global improvement and the reduction of the symptoms (especially vaginal bleeding) are associated with a radiological and physical response to the therapy, also in case of a stable disease. The psychological and physical benefit of this therapy, in our opinion, also regards the wellness of the sleep with a decrease of insomnia at six and twelve months. The significant increase of appetite loss and fatigue, according to our opinion, are not related to the side effects of the therapy with anastrozole, but could more likely be related to the age of the patient; in fact, the women enrolled in this study were very aged patients, in which it is known that the sense of fatigue and the appetite decrease are typical of this age. The unchanged values reported in the other items of questionnaire are probably related to the early stage of disease. In fact, EC being confined to the uterus, does not cause significant appearance of pain or clinical manifestations which cause distress in the patient. The use of anastrozole also permits to avoid the risk of surgery in elderly women. Laparoscopic or laparotomic hysterectomy with bilateral salpingo-ophorectomy is possibly associated with delayed healing, lymphedema, infection, haemorrhages, and an increase of hospitalization and post-operatory complications. Nevertheless, the rate of surgery in patients aged more than 80 years is similar of the one stated in younger women . Any possible complications of surgical procedure in older women decrease their quality of life, especially in women with several comorbidities .
In according with Valenzano Menada et al. , endometrial thickness during the administration of anastrozole decreased significantly and the mean reduction was 4.5 mm in those patients with previous breast cancer treated with anastrozole and tamoxifen, while in our case the volume reduction of endometrial thickness was 9.25 mm. Probably this value can be related to a different endometrial tissue considered in these trials. In our opinion the endometrial cancer cell, in which the aromatase enzyme is active, has a better response and reports a significant reduction in its volume, especially considering those patients who did not assume any previous hormonal therapy, which may influence the biological mechanisms of endometrial growth.
However, it’s important to highlight that the surgery in elderly women is not contraindicated only by age factor, in relation to its potential benefit . Mini-invasive surgery and robotic laparoscopy demonstrated a large benefit in elderly women in terms of reduction of complications [26, 27]. Also, in consideration of any possible role of neaodiuvant chemotherapy and radiotherapy, Eggeman et al.,  in their work, described that elderly women with EC generally refuse this kind of treatment because radiotherapy and chemotherapy are not recommended by the physicians, in relation of performance status and medical diseases of the patients.
The use of anastrozole also decreases the risks of surgery and the adverse effects of other hormonal therapy, such as megestrole acetate, and neoadiuvant chemotherapy or radiotherapy, and it appears an easy and safe palliative therapy also in case of symptomatic women with a short life expectancy; these data confirm that the therapy is acceptable in elderly women and it can prove to be beneficial in those patients with the same conditions. Also, the use of aromatase therapy may be preferable due to the comorbidity typical of advanced age and also less adverse effects, which appear to be fewer than other hormonal therapies. The benefits of levonorgestrol releasing IUS system (Mirena) demonstrated the efficacy in the treatment of EC and in the decrease of malignancies progression in those patients which were at high risk for surgical procedure . However, the use of oral therapy deletes the discomfort caused by the insertion of IUS system, and the possible incompliance by aged women for this kind of medical dispositive. Considering progestagens for the treatment of endometrial cancer, their role is known since 1950s. These drugs appear to have an anti-oestrogen activity by decreasing ER, by increasing oestrogen dehydrogenase enzyme, and by blocking the production of new receptors in endometrial tissue . In case of endometrial cancer, the use of progestagens, such as medroxyprogesterone acetate approved by FDA, demonstrated to facilitate a regression in EC (60–70% of cases) [31, 32]. However, several sides effects are reported by the use of these drugs, such as weight gain, hypertension, oedema, increases of blood sugar level, sleeps discomfort, tremor, bowel disturbance, and the most dangerous adverse effects such as thrombosis and pulmonary emboli [32, 33]. Further trials should be focused to relate the use of aromatase inhibitors and progestin therapy in the endometrial cancer treatment.
The most important limit of our study was the small sample of women enrolled in this pilot study. Nevertheless, the prolonged follow-up of these patients demonstrated that this therapy is an interesting palliative option in all patients not eligible to the standard therapy, and this data is supported by the safety, easiness of administration and the good compliance reported by all our patients. Moreover, another weak point of this study is the application of EORTC-QLQC30 in aged women; in fact, the accuracy of this questionnaire probably lapses in the case of very elderly patients because many items are either interpreted in relation of the pathological and physical conditions of the patients and do not reflect the real condition of the woman. Furthermore, larger and multicentric studies are necessary to confirm our data.