The role of mifepristone in the management of meningiomas: A systematic review of literature
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263232
Source of Support: None, Conflict of Interest: None
Keywords: Hormonal treatment, meningioma, mifepristone, multiple, recurrent, unresectable
Key Message: There is a potential role of mifepristone in the treatment of multiple or unresectable meningiomas. The available literature shows that the use of mifepristone as a hormonal agent for meningiomas has produced mixed results. The "diffuse meningiomatosis" group showed a good response. The long-term mifepristone administration was well tolerated in most of the patients. However, the possible mechanisms of action of mifepristone on meningioma cells must be studied in further detail by in-vitro studies, which may help in the identification of a mifepristone responsive subset of meningioma.
Meningiomas are the second most common intracranial tumors and account for approximately one-third of all primary intracranial tumors. Almost 70–80% of meningiomas are benign (World Health Organisation [WHO] grade 1), 20–30% are atypical or borderline (grade 2), and 1–2% are malignant (grade 3)., One to nine percent of patients with meningiomas have multiple lesions.[3–5] The incidence of meningiomas is high in females, and their growth has been shown to be hormone dependent, as is observed in breast cancer cells. As expected, the size of meningiomas has been documented to increase during pregnancy and to decrease with termination of pregnancy. Moreover, recurrence is documented in successive pregnancies. In contrast to breast cancer cells, meningioma cells show more progesterone receptors (PRs) than estrogen receptors (ERs) and stain positive with monoclonal antibodies directed against PRs. Blankenstein et al., using immunological methods in the human meningioma cytoplasm, found that the staining intensity increases with increase in the number of PRs. PRs are also found to be high in multiple meningiomas when compared to single lesions.
Surgery plays a central role in the treatment of meningiomas, and the recurrence rate depends upon the extent of resection. Convexity meningiomas being amenable to complete resection are found to have a low recurrence rate (3%), whereas up to 19% and 34% recurrence is reported in parasellar and sphenoid wing meningiomas, respectively.[9–11] Moreover, surgery becomes challenging in patients having multiple meningiomas. Hence, it is important to investigate the role of other therapeutic agents, including hormonal agents, with antineoplastic properties, such as the role of tamoxifen in patients with breast cancer. Mifepristone (also known as RU-486), developed by a French pharmaceutical company in the early 80s for inducing medical abortion, has significant activity against glucocorticoids and PRs. The activity on PRs requires a lower dose of mifepristone compared to the activity on glucocorticoid receptors. Even though the precise mechanism by which mifepristone blocks PR is not known, several tissue culture and clinical studies are available in the literature to identify the role of mifepristone in meningiomas. The aim of this systematic review was to evaluate the role of mifepristone in the treatment of meningiomas (particularly in lesions that are multiple or unresectable) and to study its side effects and safety profile.
Searching the relevant literature
The studies were searched on PubMed using the key words “mifepristone” and “meningioma.” The references of the relevant studies were also used to complement the initial search.
Study eligibility criteria
The studies satisfying the following criteria were included:
Review articles and letter to editors were excluded. Studies from across the globe were selected matching the above criteria, without any preference for a particular geographical region. The study eligibility was assessed by two independent observers (RS and VK) and disagreements were resolved with the opinion of a third independent observer (KG).
After searching the literature, 71 articles were identified on PubMed and Cochrane library. Seven articles were selected to be included in the study based on the inclusion and exclusion criteria. Out of these 7 studies, 6 were retrospective case series and 1 was a randomized controlled trial. The summary of the literature search strategy has been illustrated in [Figure 1].
All clinical studies were focused upon to determine the role of mifepristone in the treatment of meningiomas. In addition, 2 studies primarily described the adverse effect profile of long-term mifepristone therapy in different patient populations and discussed the monitoring of these adverse events. In all studies, the study population included patients with unresectable, recurrent (who underwent prior surgery or radiotherapy), or multiple meningiomas. The salient features of individual clinical trials are discussed in [Table 1] and [Table 2].
In all studies, 200 mg of mifepristone was administered, since this dose of the drug has been shown to achieve an antiprogesterone effect without significant antiglucocorticoid effect. Dexamethasone was also given along with mifepristone (either during the first 2 weeks or throughout the whole course) to reduce the hormonal side effects and adrenal insufficiency. Treatment was given for a period ranging from 2 to 31 months except in one study where some patients received treatment for more than 3 years, with one patient receiving mifepristone for more than 13 years. Follow-up was done by neurological and ophthalmological examination, as well as radiological evaluation. Some authors also conducted a gynecological examination and regular hematological and biochemical investigations to document the side effects.
One double-blind phase 3 multicentric randomized controlled trial was also included in our review. It included cases with histologically confirmed primary, recurrent, residual, or unresectable meningiomas who had a measurable disease, as assessed by computed tomography (CT) or magnetic resonance imaging (MRI); received radiotherapy for the disease at least 1 year before the study enrolment (unless radiotherapy was either inappropriate because of tumor location or declined by the patient); had documented evidence of disease recurrence or progression within 2 years of random assignment; and, the performance status of patients was between 0–2.
In 1991, Grunberg et al., evaluated the role of mifepristone in 14 patients with an unresectable meningioma. One of the 14 patients refused further treatment, and therefore, the response was assessed in 13 patients. Five patients (2 males and 3 premenopausal females) showed tumor regression (5/13; 38%) and 3 of them (23%) had associated symptomatic improvement. Five patients (38%) had a stable disease, and disease progressed in the remaining 3 (23%) patients. Two patients with disease progression were found to have a malignant histology. The same group in 2006 reported a favorable response in 8 out of a total of 28 (28%) patients, which included 13 patients from the study of 1991. Out of these 8 patients, 5 had a radiological regression whereas 3 showed improved clinical outcomes.
In 1992, Lambert et al., evaluated the impact of mifepristone in 10 patients with 12 meningiomas, which were either recurrent or primarily inoperable. All the patients enrolled in this study showed a recent ophthalmological or neuroradiological recurrence. The tumor size was assessed by serial CT scans following treatment and compared with the immediate pretreatment radiological findings. They showed a growth progression of 5 meningiomas in 4 (42%) patients, a regression of 4 meningiomas in 3 (33%) patients, and a stable size in 3 (25%) patients with 3 meningiomas. Tumor regression was only transient, and after discontinuation of the treatment, the disease progressed further. Mifepristone was also shown to decrease headache and improve the general well-being in half of the patients. The exact histological type and the PR receptor status were not studied by this group.
Spitz et al., studied the role of mifepristone in 25 patients. Although this study was mainly done to monitor the long-term side effects of mifepristone, they also noted minor responses to therapy in 8 patients, as recorded by radiological or clinical parameters.
De Keizer and Smit  administered mifepristone in 2 patients with a recurrent unresectable sphenoid wing meningioma and followed them for 14 years. The initial course of mifepristone showed a good radiological and clinical outcome, with one patient experiencing visual improvement and the other having relief in the headache. However, after discontinuing the first course of mifepristone, the disease was found to progress in both the patients. Hence, a second course was started, after which the disease remained stable radiologically.
Touat et al., studied the role of mifepristone in 3 postmenopausal patients with multiple meningiomas. They observed a long lasting clinical improvement in all the patients. One patient experienced complete seizure freedom and reduction in her headache. Out of the 3 patients, 2 had radiological regression, and stabilization of the tumor size was seen in 1 patient. One patient's tumor reduced in size by as much as 72%.
Recently, a multicenteric, double-blind, phase 3 randomised controlled trial was published by Yongli ji et al. The population (n = 164) was randomly divided into the mifepristone (n = 80) and the placebo groups (n = 84). Patients were given treatment for 2 years unless the disease progressed. The population included patients having histologically confirmed primary, recurrent, or unresectable meningiomas. Twenty-four patients (30%) in the mifepristone arm and 28 patients in the placebo arm (33%) were able to complete the treatment. The median failure-free survival was calculated which failed to show the superiority of mifepristone therapy, compared to the placebo.
The most common side effect encountered during mifepristone therapy by all the authors was fatigue; it was mild in most of the cases and did not lead to discontinuation of the therapy. Nausea, anorexia, and vomiting were also reported by some authors., In very few patients, there was severe fatigue, abdominal pain, and nausea, from which the patients recovered after exogenous steroid administration., Hot flashes, gynecomastia, and decreased libido were the other side effects. Premenopausal women developed amenorrhoea, which reversed after discontinuing mifepristone therapy. Hypothyroidism was noted in 2 patients., One case of clinical hypoadrenalism was also noted. Endometrial thickening and hyperplasia was a frequent side effect, requiring hysterectomy in 1 postmenopausal patient. A case of peritoneal adenocarcinoma (extraovarian source) in a postmenopausal female patient and a case of metastatic lung cancer in a male patient also developed during the mifepristone treatment; 1 patient developed serous cystadenoma of the ovary. The relationship of appearance of these tumors to the mifepristone therapy is doubtful at best.
Meningioma cells, like breast cancer cells, have been shown to be hormone dependent in several preclinical in-vitro and in-vivo studies. The alterations in disease progression associated with pregnancy, and its termination, further implicated involvement of hormonal mechanisms. Ever since the discovery of high PR expression in meningioma cells by monoclonal antibody staining and tissue culture methods, the role of a drug targeting these hormonal receptors became an interesting topic of discussion. Mifepristone, also known as RU-486, which was used as an abortifacient initially, was later found to have other uses based on its activity against progesterone and glucocorticoid receptors.
Grunberg et al., was the first to study the role of mifepristone and found 38% favorable response in 13 patients. The same group added 14 more patients to the first study in 2006, and the combined data showed only 28% patients responding to mifepristone treatment. However, the hormone status of the patients was not reported, and the factors confounding the effect of mifepristone were not carefully studied. Similarly Lambert et al., showed a decrease in size of 4 out of 12 meningiomas (10 patients). However, there was progressive decrease in the tumoral volume in only 1 patient, whereas in the other 2, the initial regression was followed by a growth of tumor while therapy was being continued. Thus, mifepristone failed to show any consistent benefit in terms of the tumor size reduction or stability. In the same manner, Spitz et al., noted only minor responses to therapy in only 32% of the patients. However, de Keizer and Smit  achieved clinical improvement in both the patients, who deteriorated after stopping mifepristone and then stabilized after reinitiating therapy, providing some positive evidence towards the role of mifepristone. Touat et al., were also able to show volumetric reduction in the size of the tumor on CT/MRI scan in all the 3 patients studied, with 1 patient showing a promising 72% reduction in size. One reason for such a successful outcome in this case may be the disease profile of the patients included in the studies. All the patients enrolled by the authors had diffuse meningiomatosis. The difference in the biological characteristics of the tumor may have been responsible for the difference in the efficacy of the medication.
Recently, a double-blind, phase 3 randomised controlled trial  found mifepristone therapy to be similar to a placebo in terms of both failure-free survival (FFS) and overall survival, further discrediting the hypothesis that it is useful in the treatment of meningiomas. The median FFS in the placebo arm was found to be 11 months, and in the mifepristone arm, it was 10 months, with the mifepristone group having no superior advantage.
In terms of adverse events, mifepristone seems to be well tolerated in most patients with minimal side effects. Mild fatigue is the most common side effect reported by most studies. Adrenal insufficiency, possibly because of the minimal antiglucocorticoid effect, was well tolerated. It may need exogenous steroid supplementation, which is administered either after appearance of symptoms or from the outset. Endometrial hyperplasia occurred in a few female patients, which may require monitoring with frequent ultrasound examinations. Interaction with the hypothalamus-pituitary-ovarian axis due to the hormonal effect could be a possible cause. There were isolated cases of de-novo neoplasia occurrence, with one case of serous cystadenoma, one case of peritoneal adenocarcinoma, and one case of metastatic lung cancer developing in those patients receiving mifepristone. However, the data is insufficient to establish the causative role of mifepristone, and further large trials are needed to evaluate this conclusively.
In the initial studies, it was thought that the menopausal status, gender, PR expression, and histological grade might affect the response to mifepristone. Grunberg et al., observed a favorable response to mifepristone therapy in males and premenopausal females. The PR status has been found to be inversely related to the tumor grade, which was earlier considered to be a possible reason for a decreased response because most studies included patients with meningiomas that were either unresectable/refractory/malignant. However, a randomized control trial (RCT) which was published recently had 88% PR positivity in the 164 patients studied, and still failed to show a significant response. At least three different isotypes of PR have been identified. The differential roles of these isoforms to meningioma progression and the differential activity of mifepristone with respect to these isoforms may be responsible for the confusing results of various preclinical and clinical studies and RCTs. It is also observed that some of the actions of progesterone occur through the indirect mechanism of estrogen receptor downregulation. The lack of efficacy of the medication in meningiomas despite PR positivity could be because of the low estrogen receptor positivity of the tumor. Sequeria et al., in their preclinical studies observed that mifepristone had good effects in breast cancers having a higher PR isoform A (PRA) expression as compared to breast cancers having a higher PR isoform B (PRB) expression. Lack of significant action could be because of a higher PRB expression in meningioma cells; however, Verheijen et al., found that meningiomas have a higher PRA expression. Koper et al, have found that progesterone acts in-vitro by altering the cellular response to epidermal growth factor (EGF), insulin, and insulin like growth factor-1 (IGF-1) on human meningioma cells. Thus, it may be postulated that mifepristone inhibits the growth induced by EGF and also alters the IGF-1 signalling pathways.
Keeping in mind that there have been few studies reporting a good response, it is possible that there is a biological subset of meningiomas which is mifepristone responsive. This renders the use of mifepristone as a blanket therapy for all recurrent, unresectable, or multiple meningiomas or even the subset of patients with PR positivity, unadvisable. Studying the various signal transduction pathways through which mifepristone may act is required to identify the subset of patients who may respond positively to the therapy. Thus, there is a void in terms of the preclinical studies aimed at identifying the exact mechanism of action of mifepristone. Once this void is filled, it must be followed by the proper selection of cases for mifepristone therapy in the clinical studies. Majority of the clinical studies available at present have not studied even the PR status of the patients, let alone the specific isoform distribution, prior to the starting of therapy. It is also notable that most of the studies have failed to record the clinical and radiological parameters in a standard way to aid in quantification or to follow the changes over a long duration. Addressing this will not only help in identifying if there is a mifepristone sensitive subset of meningiomas but may also help in finding other agents that are more specific for meningioma cells. Thus, future discoveries regarding the downstreaming of signal transduction pathways may show promising results.
Hormonal modalities of cancer therapy have played a significant role in the treatment of breast cancer. However, preclinical and clinical studies with mifepristone as a hormonal agent for meningioma have produced mixed results. Hence, it is time to study the molecular mechanisms more clearly and search for possible mechanisms of action for a subset of mifepristone-responsive meningioma patients. It may additionally help in the search for alternate agents. Further, large multicentre randomized controlled trials with a careful patient selection based on preclinical studies, a detailed evaluation of biological characteristics of the tumor, and an objective documentation of the initial and follow-up clinical and radiological parameters are needed to give any final word on the topic.
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[Table 1], [Table 2]