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Table of Contents    
COMMENTARY
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 706-707

Antiprogesterone therapy in recurrent meningiomas: A disappointing end to four decades of research?


Department of Neurological Sciences, Section of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Ari G Chacko
Department of Neurological Sciences, Section of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263217

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How to cite this article:
Chacko SR, Chacko AG. Antiprogesterone therapy in recurrent meningiomas: A disappointing end to four decades of research?. Neurol India 2019;67:706-7

How to cite this URL:
Chacko SR, Chacko AG. Antiprogesterone therapy in recurrent meningiomas: A disappointing end to four decades of research?. Neurol India [serial online] 2019 [cited 2019 Aug 24];67:706-7. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/706/263217




In this issue of Neurology India, Sharma et al.,[1] update an earlier systematic review published by Cossu et al.,[2] in June 2015 on the role of mifepristone, a progesterone receptor (PR) antagonist, in meningioma management. Their update includes a multicenter randomized controlled trial (RCT)[3] published in November 2015. At the time of the earlier systematic review,[2] the results of the same RCT were available as an abstract presented in 2001.[4] From both the reviews, it is quite clear that mifepristone provides no benefit in the management of recurrent or progressive meningiomas but might possibly be useful in rare cases of meningiomatosis.[5]

This disappointing conclusion, after 40 years of intense investigation into PRs and the effects of their antagonists on meningioma cell cultures, animal studies, case reports, case series, and finally a Phase III clinical trial, might in part be related to our eagerness to find a magic drug to treat those unfortunate patients who harbor aggressive meningiomas. The discovery of estrogen/PRs in meningiomas,[6],[7] the higher incidence of meningiomas in women, along with the progression of these tumors during pregnancy, coupled with the success of tamoxifen in breast cancer, naturally raised our hopes regarding hormonal manipulation as a possible therapeutic strategy in recurrent meningiomas.

While the preclinical data on the effect of mifepristone on meningioma cells implanted subcutaneously into nude mice [8] seemed encouraging enough to proceed to clinical trials, a closer look at the in vitro cell culture studies done in the 1980s and 1990s would indicate that the efficacy of mifepristone was not spectacular. They showed only a modest cell growth inhibitory effect ranging from no effect [9] to 18%–36%[10] and 50%.[11] Further doubts regarding the mechanism of action of mifepristone arose when it was shown that the growth inhibitory effect on meningioma cells occurred regardless of the PR status.[11] The interest in progesterone was perpetuated by the demonstration that epidermal growth factor (EGF) and its receptor were implicated in tumor growth stimulation and that there seemed to be interactions between sex steroid hormones and cell division in response to EGF.[12] Thymidine incorporation, used as a marker of cell division, increased in response to EGF in the presence of progesterone. Mifeprestone significantly lowered thymidine incorporation but only at very high concentrations of EGF.[12]

Nevertheless, subsequent retrospective clinical studies reported from 1991 onward, using oral mifeprestone 200 mg in patients with recurrent or unresectable meningiomas showed questionable clinical and radiological responses,[13],[14] except for some benefit in three patients with meningiomatosis.[5] These studies had very few patients, none of them documented the PR status, and the assessment of clinicoradiological response was quite subjective. In view of the modest clinical success and acceptable incidence of side effects,[15] the South West Oncology Group (SWOG) conducted a Phase III multicenter RCT comparing mifeprestone with a placebo in unresectable, recurrent, or progressive meningiomas in an attempt to put the question of the efficacy of mifeprestone to rest.[3]

The RCT was done on 164 unresectable meningiomas that demonstrated progression. Only a third of patients completed their treatment in both the arms. Failure to complete therapy was attributed to tumor progression in 40% of patients in the mifepristone arm and in 50% in the placebo group, while another 10% in the mifepristone arm could not continue the drug due to adverse effects. Approximately 40% patients in both the arms had received radiation therapy (RT) 1 year prior to enrolment in the trial. We are not told whether the patients who had tumor progression had received RT prior to their enrolment. In addition, the main problem with the reporting of the histology was that we have not been provided with the complete data regarding the World Health Organization (WHO) grading, MIB-1 labeling index, or PR status. While MIB-1 index increases significantly from WHO Grade I through Grade III tumors, there seems to be a trend toward increased PR positivity in low-grade meningiomas when compared with meningiomas of higher grades.[16] We have been told that 8 of 80 (10%) patients in the mifepristone group and 9 of 84 (10.7%) patients in the placebo group had atypical meningiomas, presumably WHO Grade II, while 72 of 80 patients in the mifepristone group and 75 of 84 in the placebo group were merely classified as meningioma “not otherwise specified.” They went on to say that the PR status was positive in 88% of patients; however, a closer look at the data reveals that PR status was assessed in only 42 of 80 patients in the mifepristone group and 43 of 84 patients in the placebo group. Therefore, although 36 of 42 (85.7%) samples were PR-positive in the mifepristone group and 39 of 43 (90%) samples were PR-positive in the placebo group, the PR status in the remaining 79 (48%) patients was unknown either because it was not done or the sample was insufficient. No patient in either arm achieved a complete response and one patient in the mifepristone arm achieved a partial response, defined as a 50% reduction in radiologically assessed tumor size. And finally, there was no statistically significant difference between the two groups in terms of the primary outcome of failure-free survival and the secondary outcome of overall survival.

One often wonders why a Phase III clinical trial would fail to show the efficacy of a drug after it has gone through preclinical testing. To address this, Wilisch-Neumann et al., in 2014[17] re-evaluated several chemotherapeutic agents that had failed clinical studies, including mifepristone, on four meningioma cell lines of different grades. The other drugs tested were hydroxyurea, metformin, temozolamide, erlotinib, tamoxifen, verapamil, and losartan. Of all these drugs, only hydroxyurea demonstrated moderate cytotoxic activity at reasonable plasma concentration levels. The remaining drugs, including mifepristone and temozolamide, failed to exert significant cell growth inhibition at clinically usable plasma concentrations. It should be kept in mind that in experimental work on tumor cell lines, cells undergo senescence after three to four passages and may not be morphologically similar to the original tumor.[18]

The reason why these chemotherapeutic agents failed in clinical studies is probably due to the wide molecular heterogeneity of meningiomas. The future may lie in next-generation sequencing that has enabled some characterization of this heterogeneity with subsequent molecular subclassification of meningiomas. This strategy should pave the way to the discovery of new molecular targets that might be more successful than all our previous attempts over the past four decades.[19]



 
  References Top

1.
Sharma R, Garg K, Katiyar V, Tandon V, Agarwal D, Singh M, et al. The role of mifepristone in the management of meningiomas: A systematic review of literature. Neurol India 2019;67:698-705.  Back to cited text no. 1
  [Full text]  
2.
Cossu G, Levivier M, Daniel RT, Messerer M. The role of mifepristone in meningiomas management: A systematic review of the literature. Biomed Res Int 2015;2015:267831.  Back to cited text no. 2
    
3.
Ji Y, Rankin C, Grunberg S, Sherrod AE, Ahmadi J, Townsend JJ, et al. Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005. J Clin Oncol 2015;33:4093-8.  Back to cited text no. 3
    
4.
Grunberg SM, Rankin C, Townsend J, Ahmadi J, Feun L, Fredericks R, editors. Phase III Double-Blind Randomized Placebo-Controlled Study on Mifepristone (RU) for the Treatment of Unresectable Meningioma. Alexandria, VA: American Society of Clinical Oncology; 2001.  Back to cited text no. 4
    
5.
Touat M, Lombardi G, Farina P, Kalamarides M, Sanson M. Successful treatment of multiple intracranial meningiomas with the antiprogesterone receptor agent mifepristone (RU486). Acta Neurochir (Wien) 2014;156:1831-5.  Back to cited text no. 5
    
6.
Donnell MS, Meyer GA, Donegan WL. Estrogen-receptor protein in intracranial meningiomas. J Neurosurg 1979;50:499-502.  Back to cited text no. 6
    
7.
Yu ZY, Wrange O, Haglund B, Granholm L, Gustafsson JA. Estrogen and progestin receptors in intracranial meningiomas. J Steroid Biochem 1982;16:451-6.  Back to cited text no. 7
    
8.
Olson JJ, Beck DW, Schlechte JA, Loh PM. Effect of the antiprogesterone RU-38486 on meningioma implanted into nude mice. J Neurosurg 1987;66:584-7.  Back to cited text no. 8
    
9.
Schrell UM, Adams EF, Fahlbusch R, Greb R, Jirikowski G, Prior R, et al. Hormone dependency of cerebral meningiomas. Part 1: Female sex steroid receptors and their significance as specific markers for adjuvantmedical therapy. J Neurosurg 1990;73:743-9.  Back to cited text no. 9
    
10.
Olson JJ, Beck DW, Schlechte J, Loh PM. Hormonal manipulation of meningiomas in vitro. J Neurosurg 1986;65:99-107.  Back to cited text no. 10
    
11.
MatsudaY, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T. Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo. J Neurosurg 1994;80:527-34.  Back to cited text no. 11
    
12.
Koper JW, Foekens JA, Braakman R, Lamberts SW. Effects of progesterone on the response to epidermal growth factor and other growth factors in cultured human meningioma cells. Cancer Res 1990;50:2604-7.  Back to cited text no. 12
    
13.
Grunberg SM, Weiss MH, Spitz IM, Ahmadi J, Sadun A, Russell CA, et al. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 1991;74:861-6.  Back to cited text no. 13
    
14.
Lamberts SW, Tanghe HL, Avezaat CJ, Braakman R, Wijngaarde R, Koper JW, et al. Mifepristone (RU 486) in treatment of meningiomas. J Neurol Neurosurg Psychiatry 1992;55:486-90.  Back to cited text no. 14
    
15.
Grunberg SM, Weiss MH, Russell CA, Spitz IM, Ahmadi J, Sadun A, et al. Long-term administration of mifepristone (RU486): Clinical tolerance during extended treatment ofmeningioma. Cancer Invest 2006;24:727-33.  Back to cited text no. 15
    
16.
Wolfsberger S, Doostkam S, Boecher-Schwarz HG, Roessler K, van Trotsenburg M, Hainfellner JA, et al. Progesterone-receptor index in meningiomas: Correlation with clinico-pathological parameters and review of the literature. Neurosurg Rev 2004;27:238-45.  Back to cited text no. 16
    
17.
Wilisch-Neumann A, Pachow D, Wallesch M, Petermann A, Böhmer FD, Kirches E, et al. Re-evaluation of cytostatic therapies for meningiomas in vitro. J Cancer Res Clin Oncol 2014;140:1343-52.  Back to cited text no. 17
    
18.
Zava DT, Markwalder TM, Markwalder RV. Biological expression of steroid hormone receptors in primary meningioma cells in monolayer culture. Clin Neuropharmacol 1984;7:382-8.  Back to cited text no. 18
    
19.
Nigim F, Wakimoto H, Kasper EM, Ackermans L, Temel Y. Emerging medical treatments for meningioma in the molecular era. Biomedicines 2018;6. pii: E86. doi: 10.3390/biomedicines6030086.  Back to cited text no. 19
    




 

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