We read with great interest the article of Kacan et al. entitled “Everolimus as an mTOR Inhibitor Suppresses Endometriotic Implants: an Experimental
Rat Study” [1] published in your journal.
The authors surgically induced endometriosis by the autotransplantation of uterine
tissue in the peritoneal cavity of 24 rats. The animals were randomized in three groups,
receiving oral everolimus, oral anastrozole, or intravenous saline solution for 14
days. Histological evaluation was done by the endometriosis score (according to Keenan
et al. [2]) and immunohistochemical examination was performed by using antibodies against vascular
endothelial growth factor (VEGF), CD117 and BAX. The post-treatment analysis of endometriotic
implants revealed that anastrozole and everolimus succeeded in significantly decreasing
their growth and size with no difference in histological and immunohistochemical results
between the two drugs. The authors noted at histology that the number of ovarian follicles
was not negatively altered by everolimus, differently from anastrozole that, as evidenced
in literature, tends to decrease it [3].
The rational of the study is based on the evidence of the pivotal role of mTOR in
angiogenesis and growth of endometriotic implants [4]. The results of the therapy are in line with a previous study performed on the animal
model [5], in which Leconte et al. found that also the administration of temsirolimus (intraperitoneal
3 mg/kg), another mTor inhibitor, for 2 weeks led to significant decreases in endometriosis
implants growth.
Although the authors should be congratulated for their laboratory findings, we would
like to raise some concerns on the administration of mTor inhibitors, and in particular
everolimus, in the clinical treatment of endometriosis. Everolimus is approved by
Food and Drug Administration (FDA) for the treatment of advanced tumors, such as advanced
kidney cancer, progressive or metastatic pancreatic or gastrointestinal neuroendocrine
tumors, and it is currently being also evaluated in gynecological cancers. Moreover,
its use is indicated for immunosuppression after solid organ transplant [6].
Although in oncologic setting it has been reported that patients with specific mutations
(i.e. PIK3A, PTEN) tend to have higher benefit receiving mTor pathway inhibitors,
a first non-negligible problem is that there are no validated predictive biomarkers
for patientsʼ selection and for monitoring drug efficacy [7]. A second concern is related to the fact that in the experiment endometriotic implants
were surgically induced only in peritoneum of rats, and not in other localizations.
Thus, it appears unlikely that drugs acting on angiogenesis-related pathways, such
as mTor, may treat the symptoms caused by large nodules of deep infiltrating endometriosis
(DIE), which are mainly composed of fibromuscular tissue, and may have already been
present for some years.
More importantly, drugs targeting mTor pathway may cause adverse effects [8], including a large variety of metabolic, hematological, respiratory, renal and dermatological
toxicities. These sometime serious side effects explain the notable rate of drug discontinuation
in clinical trials for advanced cancer. Although some of them, such as oral stomatitis
(30 – 60% of patients) or pneumonitis, seem to increase with the dosage of the drug,
the majority are idiosyncratic and unpredictable, and may also occur from days to
years after the beginning of the therapy. These adverse effects may be tolerable in
oncological therapy, where the primary endpoints are disease-free survival and overall
survival, but it appears difficult to accept them in young women with endometriosis
where the goal is improving the quality of life. In fact, endometriosis is a chronic
benign disease that requires a long-term therapy combining clinical efficacy (preventing
recurrence, controlling pain symptoms) with acceptable costs and toxicity. Given this
background, it seems unlikely that everolimus may have a relevant role in the future
treatment of women with endometriosis.
