Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies.

Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Progesterone therapy obtains overall response rates ranging from 11% to 25% in patients with endometrioid-type tumours, and oral medroxyprogesterone acetate 200mg daily appears to be a reasonable therapeutic option for those lesions that are well differentiated and/or have a high progesterone receptor (PgR) content. However, the activity of progestins is often compromised by the down-regulation of PgR within the target tissues, and therefore therapeutic strategies designed to enhance PgR expression are warranted. Little data are currently available about the new aromatase inhibitors and selective estrogen receptor modulators. As for chemotherapy, the combination of doxorubicin [DOX]+cisplatin [CDDP] achieves overall response rates ranging from 34% to 60%, and the addition of paclitaxel (TAX) seems to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. A phase III study is currently comparing TAX+DOX+CDDP versus the less toxic combination of TAX+carboplatin. Chemotherapy is active against both endometrioid-type carcinoma and uterine serous papillary carcinoma. However, this latter endometrial malignancy is less chemosensitive than the histologically similar high-grade serous ovarian carcinoma. Interesting fields of research are represented by investigational agents directed against specific intracellular signal transduction pathways involved in the proliferation, invasiveness and metastatic spread of endometrial cancer. Mammalian target of the rapamycin (mTOR) inhibitors, epidermal growth factor receptor inhibitors (gefitinib, erlotinib, lapatinib, the monoclonal antibody cetuximab), imatinib, the monoclonal antibody trastuzumab, and the Clostridium perfrigens enterotoxin are currently under evaluation as molecularly targeted therapies for endometrial cancer. Further investigations addressed to better understand the signal transduction pathways that are disregulated in endometrial carcinogenesis could identify novel biological targets suitable for tailored therapies.