46ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:486-490

Mifepristone (RU 486) treatment ofmeningiomas

SW J Lamberts, H L J Tanghe, C J J Avezaat, R Braakman, RWijngaarde, JW Koper, FH de Jong

Erasmus University,Rotterdam, TheNetherlandsDepartment ofMedicineSW J LambertsJW KoperF H de JongDepartment ofRadiologyH L J TangheDepartment ofNeurosurgeryC J J AvezaatR BraakmanDepartment ofOphthalmologyRWijngaardeCorrespondence to:Professor Lamberts,Department of Medicine,University Hospital Dijkzigt,40 Dr Molewaterplein, 3015GD Rotterdam, TheNetherlands.Received 19 March 1991and in revised form19 March 1991.Accepted 8 August 1991

AbstractMeningiomas are common brain tumourswhich are generally benign, well circum-scribed and slow growing. In a minority ofpatients complete surgical removal is notpossible and re-growth oftumour tissue isa major clinical problem. Most meningio-mas contain progesterone receptors. Theanti-progestational drug mifepristone(RU 486) binds to these receptors. Tenpatients were treated with 12 recurrent or

primary "inoperable" meningiomas, allof whom had shown recent neuroradio-logical and/or ophthalmological evidenceof tumour growth. They received 200 mgmifepristone daily for 12 months. Mostpatients initially had complaints of nau-

sea, vomiting and/or tiredness. In fourpatients prednisone (7.5 mglday) was giv-en after which these side-effects subsided.CT scan analysis of tumour size, showedprogression of growth of five meningio-mas in four patients, stable disease inthree patients with three tumours andregression of four tumours in threepatients. A decrease in the complaints ofheadache and an improved general well

being was observed in five patients. Twopatients died during the treatment periodfrom unrelated causes. Mifepristonetreatment resulted in control of tumourgrowth (= stable disease) in six of 10patients who had shown recent evidence oftumour growth. In three of these sixpatients consistent tumour shrinkage was

observed.

Meningiomas occur more frequently in womenthan in men.' Previous clinical and epidemio-logical studies suggest that these tumours often

grow during pregnancy,2 while an associationbetween breast cancer and meningiomas hasbeen reported.3 These observations suggest a

biological role of female sex steroids in theregulation of the growth of meningiomas.Indeed, progesterone, but not oestradiol recep-

tors have been found in virtually all meningio-mas, both from female and male patients.4-9The first clinically available progesteronereceptor antagonist mifepristone (RU 486) hasbeen shown to bind to the progesteronereceptors in meningiomas.9 Both studies withcultured meningioma cells or explants andwith nude mice carrying meningioma tissuesuggest that hormonal manipulation can influ-ence growth in part of the tumours.'"'7 Ourown culture studies indicate that progesteroneincreases the sensitivity of cultured meningio-ma cells to mitogenic stimuli, while mifepris-tone counteracts these stimulating effects.18Preliminary studies of treatment of meningio-ma patients with medroxyprogesterone ace-

tate, tamoxifen, and LHRH analogs suggestthat the growth of meningiomas in a minorityof patients can be controlled.' 9-22

In this study we investigated the effect oftherapy with mifepristone (200 mg/day) for 12months on 10 meningiomas patients whoshowed neuroradiological and/or ophthalmo-logical evidence of recent progressive tumourgrowth.

Patients and methodsPatients and experimental protocolIn this study 10 patients with single or multiplemeningiomas were investigated (table). Apartfrom patient 10, all females were menopausal.In all patients there was neuroradiologicalevidence (nine patients) and/or ophthalmo-

Table Patient data

MIF Age Phenytoin Localisation meningioma, size at start (cm3), previous therapy, recent growththerapy

1 F 71 - Tuberculum sellae (right): 8-3 cm3; continuous growth since 2 years, blindness right eye2 F 53 - Inner ridge (left) and tentorium (left) of 10-2 and 5-3 cm3; slow, persistent growth since 1-5

yr; visual loss left eye3 M 63 + Inner/middle ridge (left): 67-4 cm3; previous operations 1972, 1982, 1986; rapid

progressive growth, visual loss left eye4 F 72 + Frontal: 66-5 cm': previous operations 1965, 1981; continuous growth since 6 years; slow

affect; epilepsy5 F 48 - Suprasellar: 28 cm3: previous operation 1978; tumour size unchanged since 8 years;

blindness right eye, progressive visual loss left eye6 M 54 + Parasagittal (right): 68-7 cm3; previous operation 1974; continuous growth since 2 years7 M 68 + Sphenoid (right) with infratemporal and intraorbital extension: 164 cm3; previous

operations 1973, 1986; blindness right eye and continuous growth since 2 years; proptosisright eye

8 F 64 - Parasellar (left) at apex left opticus (9-6 cm3); continuous growth since 3 years, progressivevisual loss left eye, proptosis left eye

9 F 53 - Sphenoid (left) with para-sellar, sellar and infratemporal extension: 89-5 cm'; previousoperations 1983 and 1987; rapid growth since 2 years; tumour palpable in upper jaw,hypopituitarism, treated with hydrocortisone (30 mg/day)

10 F 32 + Falx (left) and cerebellar/tentorium (right) tumours of 25-3 and 21-5 cm3; bilateralacousticus neurinomas, bilateral opticus tumours, previous operation in 1987

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logical evidence of recent progressive tumourgrowth (patients 1, 2, 3 and 5). In sevenpatients this was tumour progression or recur-

rence after previous operation(s), while threepatients had not had a previous operation. Allpatients had been selected by at least twoindependent neurosurgeons of the staff of thedepartment of neurosurgery of the UniversityHospital Rotterdam because: a) Reoperationwas not expected to completely remove thetumour; b) The localisation of the tumourcaused a high risk of severe complicationsduring/after surgery; c) The general conditionof the patient was so poor, that surgery seemedcontraindicated (patients 3 and 4). Exclusioncriteria were pregnancy, the use of oral contra-ceptives, patients with a very poor performancestatus, signs or symptoms of an elevatedintracranial pressure, coexistent psychiatricdiseases, other cancer, renal and liver insuffi-ciency.The experimental protocol had been

approved by the ethical committee of theUniversity Hospital Rotterdam. All patientssigned an informed consent form in which theseriousness of their disease and the unknowneffects of mifepristone therapy were

explained.According to the experimental protocol the

patients were treated for 12 months with 200mg mifepristone daily. If side effects or signs of(relative) adrenocortical insufficiency devel-oped, a daily dose of 7-5 mg prednisone wouldbe added to mifepristone therapy. Clinicalevaluation was done every two to three weeksduring the first three months and every twomonths during the second part of the study. Ifvisual abnormalities existed, the patients werealso followed on a regular basis by an ophthal-mologist. Side effects were carefully noted andECGs, measurement of blood pressure androutine clinical chemical determinations were

carried out at least four times during theinvestigation period.

CT scanning and analysis of tumour sizeThe size of the meningiomas was measuredrepeatedly with the same Philips Tomoscan310 apparatus. Tumour volume was calculatedby CT planimetry independently by the sameneuroradiologist (HT) and neurosurgeon (RB)under the same conditions. The thickness ofthe slices was kept constant at 3 mm. Measure-ment of the planar surface of the tumour ineach slice was calculated by computer aftercircling the outer border. All calculated sur-

faces were added to calculate the volume of thetumour. If hyperostotic bone was present at thesurface of the tumour, this was added in a

constant manner as part of the tumour. Thisalso applied to the cavernosus sinus in the fewcases were no sharp margin with the tumourcould be determined. Repeated measurementby a given neuroradiologist of the same tumouron the same CT scan had an error rate of< 5%.

Results1) Tolerancelside effectsMifepristone caused no or minimal transient

side effects in six patients: nausea and anorexiaoccurred for a period of a few days to up to twoweeks in three patients, while three patientstook the drug without side effects. The otherfour patients (2, 3, 4 and 6), however, experi-enced more severe complaints of nausea (4)and recurrent attacks of vomiting (3) startingduring the first week of therapy. In additionthese four patients felt exhausted and anor-ectic. In patient 4 prolonged vomiting stoppedon the third day of mifepristone therapy,shortly after the start of the simultaneousadministration of 7-5 mg prednisone daily. Inpatients 2, 3 and 6 these complaints persistedand concomitant prednisone therapy (7 5 mg)was started after three weeks. Thereafter thesecomplaints subsided, but prednisone therapywas continued in all four patients throughoutthe study. No changes in blood pressure(supine and/or standing) were noted duringmifepristone treatment for up to one year. AlsoECG and routine clinical chemical investiga-tions did not show changes. These included themeasurements of fasting glucose, potassium,chloride and sodium concentration in serum,renal and liver functions, as well as haemoglo-bin, haematocrit, white blood cell and throm-bocyte counts. Body weights did not changesignificantly in these 10 patients during mife-pristone treatment.

2) Changes in tumour size and tumour relatedcomplaints during treatmentMifepristone resulted in a general improve-ment of well being in four patients (1, 7, 8 and9). Especially complaints of headaches and/ortension in the jaw, skull or eye improved ordisappeared in five patients. In patient 2 thevisual acuity of the left eye improved slightly,while in patient 8 the palpable part of the softtissue mass in the upper jaw shrank con-siderably. The proptosis of one eye in patients 7and 8 did not change during mifepristonetreatment. In patient 5, however, the alreadyvery bad visual acuity of the remaining eyefurther deteriorated during therapy.Changes in tumour volume were measured

in these 10 patients by CT scanning at regularintervals during and after mifepristone therapy(figure). In four patients clear growth of fivemeningiomas was observed during therapy.Two of these patients died during this period.Fourteen months before the start of therapypatient 3 had undergone a coronary bypassoperation because of longstanding angina. Inparallel he developed progressive visual loss ofthe left eye, aphasia, headaches, paresis of theright arm, while he could no longer walkbecause of loss of equilibrium. These symp-toms were attributed to a rapidly growingmeningioma in the inner and middle ridge withintra-orbital expansion on the left side. Theinitiation of mifepristone therapy resulted inside effects (see above), which were wellcontrolled by prednisone (7-5 mg/day). Therewere no complaints of headaches. Precordialpains were controlled with beta-blockingagents. No signs or symptoms of congestiveheart failure were observed. After 4*5 monthsof mifepristone therapy he developed pulmo-nary oedema and a period of ventricular

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Figure The course oftumour size before, duringand after mifepristone (200mg/day) treatment of 10patients with inoperableprimary or recurrentmeningiomas. Top: fivetumours in four patientswhich showed growth;middle: three tumours inthree patients whichremained stable andbottom: four tumours inthree patients which showed(transient) decrease in size.(The numbers correspondto the patient numbers inthe table, on the x-axistime is expressed inmonths, before (-) andafter (+) therapy).

300

250

Mifepristone 200 mg/day

, (10~~~~~1)(4)8~~~4)1( 1 0 )~~~~~~~~(0

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-8 -6-4-2 o 2 4 6 8 10 12+2+4+~6+;810

fibrillation was treated by defibrillation. Noevidence of an acute myocardial infarction wasfound. After four months of treatment the sizeof the meningioma had further increased from67-4 to 77X4 cm3 (+ 15%). This patient diedafter 5.5 months of mifepristone treatmentfrom sudden asystole.

Patient 4 had a frontal meningioma andsevere flattened affect. Her skull was open withlocal uncontrollable inflammation after theremoval of a large piece of osteomyelitic boneat a previous operation. She often experiencedsmall epileptic fits despite therapy with pheny-toin. These attacks did not change after thestart of mifepristone therapy. The tumourprogressively increased in size from 66-5 to80-8 after three months and to 90 cm3 afternine months of treatment. After 12 months oftherapy this patient died at home from a severe

epileptic attack. In patient 1 an inner ridgemeningioma on the right side had nearlydoubled in size in the eight months before thestart ofmifepristone treatment (from 4.4 to, 8-3cm3). Thereafter, a further progressive rise intumour size to maximally 12-2 cm3 (at 12months) was observed. Patient 10 was excep-tional in that she has neurofibromatosis type 2.Apart from bilateral acoustic neurinomas andbilateral opticus tumours she had multiplemeningioma-type tumours along the falx cer-ebri and the tentorium. One tentorium menin-gioma on the right side and a falx meningiomaon the left side showed progressive furthergrowth during mifepristone therapy.The meningiomas of patients 5, 7 and 8

showed evidence for a stabilisation of tumourgrowth during and also in the period afterstopping mifepristone treatment (figure, mid-dle section). All three tumours initially stillincreased in size during the first months oftherapy, but thereafter shrinkage and/or stabil-isation of size was seen.

In patients 2, 6 and 9 (transient) decrease intumour size was observed during mifepristone

treatment (the fig. lower section). The rightparasagittal meningioma of patient 6 onlytransiently decreased in size after two monthsof treatment, while the huge sphenoid menin-gioma with considerable extension in theinfratemporal fossa and into the pituitary fossaof patient 9 also transiently decreased in size.This was accompanied by an impressive clin-ical improvement in this patient throughoutthe 12 month treatment period with dis-appearance of pain and swelling of the jaw. Inpatient 2 both a parasellar and a tentoriummeningioma decreased in size, while the visualacuity of the left eye improved.

DiscussionMeningiomas are common tumours of thearachnoidea, which account for about 20% ofintracranial tumours.2' They are generallybenign, well circumscribed, and slow growing.They can, however, be accompanied by inva-sion of the bone and/or encasement of majorblood vessels, or they may grow to massiveproportions, compromising the likelihood oftotal surgical removal. In addition multiplemeningiomas occur in 5-10% of patients. Theprimary and central role of surgery in thetreatment of meningiomas is well-establishedand the operative and long-term mortalityrates have considerably declined over the pastdecades.24 However, the likelihood of completeresection ofmeningiomas is determined in partby the tumour site.25 For example, convexitymeningiomas can be removed easily in mostinstances and have a low recurrence rate (3%after five years25), while the operative results ofparasellar and sphenoid ridge meningiomas areless impressive and show a much higherincidence of recurrence (19% and 34%,respectively25). Medical treatment whichmight slow or inhibit tumour growth would beof benefit especially in these last categories ofpatients.The discovery that a majority of human

meningiomas contain high numbers of highaffinity progesterone binding sites was the basisfor new thoughts and hypotheses concerning amedical therapy of meningiomas.4 10 Subse-quently, it was shown that the anti-progestinmifepristone has the same affinity for theprogesterone receptor of meningiomas, asdoes, for example R5020, a known progester-one analog and binder of the progesteronereceptor.926 Preliminary studies on culturedmeningioma cells indicated a certain degree ofhormonal dependency of these tumour cells,although this was not uniformly found. Stim-ulation of the growth of meningioma cells inthe presence ofphysiologically relevant proges-terone concentrations was observed in somebut not all tumour cell cultures. "'8 Inter-estingly, mifepristone caused inhibition of cellgrowth and of thymidine incorporation inseveral tumours. Our own studies indicatethat progesterone causes only minimal effectson the growth of cultured meningioma tissue(cells or explants), but that progesterone mod-ulates the stimulatory response of culturedhuman meningioma cells to epidermal growth

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factor and other growth factors, while mife-pristone blocks this enhancing effect of proges-terone.'8 This suggests that the presence ofprogesterone in the culture medium increasesthe sensitivity of meningioma cells to mito-genic stimuli, whereas mifepristone counter-acts these stimulating effects of progesterone.

In vivo studies with nude mice carryingtransplanted human meningiomas tissue indi-cated a growth inhibitory effect of mifepris-tone. 7 Such a tumour growth inhibitory effectof the drug was also observed in several otherhormone-dependent tumour models,27-30while (transient) tumour growth inhibition wasreported in a minority of breast cancerpatients.3' 32

Medical therapy of meningioma patientswith the progesterone agonist/antagonistmedroxyprogesterone, with tamoxifen or withan LHRH analog resulted in varying, but insome cases encouraging results.'9-22The results of therapy with mifepristone in

the present 10 meningioma patients were notdramatic. All patients had been selected on thebasis of recent (mostly neuroradiological) evi-dence of growth of the tumours. The previoushistories of these patients showed that theyrepresented a group of aggressively growingmeningiomas. In four patients we observed afurther growth of the meningioma duringmifepristone therapy, without evidence ofinhibition of growth by the drug. Two of thesepatients died during mifepristone treatment:one from a pre-existing cardiovascular compli-cation and one from pre-existing epilepsy. Wedo not know whether these intercurrent deathswere directly tumour-related, but we also donot have evidence that they were treatment-related. The initial complaints of nausea, tired-ness and vomiting which occurred in some ofthe patients during the first period of mifepris-tone therapy was interpreted as relative adrenalinsufficiency which was caused by the cortisolreceptor blocking activity of the drug. Exten-sive endocrine studies in these patients duringmifepristone therapy have been published in aseparately.33 The two meningiomas of patient10 showed a rapid growth both before andduring mifepristone treatment. This patienthad the rare syndrome of neurofibromatosistype 2, consisting of bilateral acoustic neu-rinomas, bilateral optic tumours and multiplemeningiomas, which is related to a geneticabnormality, involving chromosome 22.34 35 Inthe other six patients a total of seven meningio-mas showed stabilisation or slight regression oftumour growth during mifepristone treatment.In patient 5 this therapy can be considered as afailure because the already very low visualacuity of her remaining eye further deteri-orated, although no change in tumour size wasobserved during therapy. In three patients a(transient) decrease in tumour size wasobserved. Medical therapy was accompaniedby a decrease in headaches in five patients, anincrease in the feeling of general well being infour, a slight improvement in visual acuity ofone eye in one (patient 2), and a decrease inpalpable tumour size in one patient (patient 9).Stable disease and/or slight tumour shrinkage

in six of 10 patients (seven of 12 meningiomas)during mifepristone therapy was in our opinionof special value (except in patient 5 whoshowed visual loss), because all patients hadbeen selected because of recent evidence oftumour growth.Our study suffers from methodological

shortcomings which makes it only an observa-tional one. Apart from the low number ofpatients studied, the size, location and dura-tion of existence of the tumours varied con-siderably. Most importantly, there was noplacebo or control arm, which makes definiteconclusions on the beneficial effects attributedto mifepristone doubtful at present.A further shortcoming of this study is that

we do not have data on the presence and theaffinity of progesterone receptors on thesetumours. This might be of importance,because in a preliminary study involving agroup of 24 meningioma patients36 we showedthat there is an inverse relationship betweenthe number of progesterone receptors and CTscan characteristics of these tumours whichindicate regressive behaviour (for example, thepresence of necrosis, cyst formation and/orintratumoural haemorrhage). This might meanthat medical treatment ofmeningioma patientswith progesterone receptor blocking drugs isbeneficial and effective especially in thosepatients harbouring meningiomas with a rela-tively "low degree of aggression", which mightmean those tumours which do not grow veryfast.

In conclusion, preliminary evidence hasbeen presented that therapy with the proges-terone receptor blocking drug mifepristone(RU 486) results in control of tumour growthin some meningioma patients. Mifepristonecaused considerable side effects, however, andnew more specific anti-progestins (with lessglucocorticoid-receptor blocking activity)might be better tolerated and therefore moreattractive compounds to use in follow upstudies (phase 2). Also future studies should beplacebo-controlled and include patients inwhom the progesterone receptor content of themeningiomas is known.

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