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Mifepristone (RU 486) Treatment of J Neurol Neurosurg Psychiatry: First Published As 10.1136/Jnnp.55.6.486 on 1 June 1992

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Mifepristone (RU 486) Treatment of J Neurol Neurosurg Psychiatry: First Published As 10.1136/Jnnp.55.6.486 on 1 June 1992 48646ournal ofNeurology, Neurosurgery, and Psychiatry 1992;55:486-490 Mifepristone (RU 486) treatment of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from meningiomas S W J Lamberts, H L J Tanghe, C J J Avezaat, R Braakman, R Wijngaarde, J W Koper, F H de Jong Abstract grow during pregnancy,2 while an association Meningiomas are common brain tumours between breast cancer and meningiomas has which are generally benign, well circum- been reported.3 These observations suggest a scribed and slow growing. In a minority of biological role of female sex steroids in the patients complete surgical removal is not regulation of the growth of meningiomas. possible and re-growth of tumour tissue is Indeed, progesterone, but not oestradiol recep- a major clinical problem. Most meningio- tors have been found in virtually all meningio- mas contain progesterone receptors. The mas, both from female and male patients.4-9 anti-progestational drug mifepristone The first clinically available progesterone (RU 486) binds to these receptors. Ten receptor antagonist mifepristone (RU 486) has patients were treated with 12 recurrent or been shown to bind to the progesterone primary "inoperable" meningiomas, all receptors in meningiomas.9 Both studies with of whom had shown recent neuroradio- cultured meningioma cells or explants and logical and/or ophthalmological evidence with nude mice carrying meningioma tissue of tumour growth. They received 200 mg suggest that hormonal manipulation can influ- mifepristone daily for 12 months. Most ence growth in part of the tumours.'"'7 Our patients initially had complaints of nau- own culture studies indicate that progesterone sea, vomiting and/or tiredness. In four increases the sensitivity of cultured meningio- patients prednisone (7.5 mglday) was giv- ma cells to mitogenic stimuli, while mifepris- en after which these side-effects subsided. tone counteracts these stimulating effects.18 CT scan analysis of tumour size, showed Preliminary studies of treatment of meningio- progression of growth of five meningio- ma patients with medroxyprogesterone ace- mas in four patients, stable disease in tate, tamoxifen, and LHRH analogs suggest three patients with three tumours and that the growth of meningiomas in a minority regression of four tumours in three of patients can be controlled.' 9-22 patients. A decrease in the complaints of In this study we investigated the effect of headache and an improved general well therapy with mifepristone (200 mg/day) for 12 being was observed in five patients. Two months on 10 meningiomas patients who patients died during the treatment period showed neuroradiological and/or ophthalmo- from unrelated causes. Mifepristone logical evidence of recent progressive tumour treatment resulted in control of tumour growth. http://jnnp.bmj.com/ growth (= stable disease) in six of 10 patients who had shown recent evidence of tumour growth. In three of these six Patients and methods patients consistent tumour shrinkage was Patients and experimental protocol observed. In this study 10 patients with single or multiple Erasmus University, meningiomas were investigated (table). Apart Rotterdam, The Netherlands Meningiomas occur more frequently in women from patient 10, all females were menopausal. men.' Previous clinical and In all patients there was neuroradiological on September 30, 2021 by guest. Protected copyright. Department of than in epidemio- Medicine logical studies suggest that these tumours often evidence (nine patients) and/or ophthalmo- S W J Lamberts J W Koper F H de Jong Table Patient data Department of MIF Age Phenytoin Localisation meningioma, size at start (cm3), previous therapy, recent growth Radiology therapy H L J Tanghe 1 F 71 - Tuberculum sellae (right): 8-3 cm3; continuous growth since 2 years, blindness right eye Department of 2 F 53 - Inner ridge (left) and tentorium (left) of 10-2 and 5-3 cm3; slow, persistent growth since 1-5 Neurosurgery yr; visual loss left eye C J J Avezaat 3 M 63 + Inner/middle ridge (left): 67-4 cm3; previous operations 1972, 1982, 1986; rapid R Braakman progressive growth, visual loss left eye 4 F 72 + Frontal: 66-5 cm': previous operations 1965, 1981; continuous growth since 6 years; slow Department of affect; epilepsy Ophthalmology 5 F 48 - Suprasellar: 28 cm3: previous operation 1978; tumour size unchanged since 8 years; RWijngaarde blindness right eye, progressive visual loss left eye Correspondence to: 6 M 54 + Parasagittal (right): 68-7 cm3; previous operation 1974; continuous growth since 2 years Professor Lamberts, 7 M 68 + Sphenoid (right) with infratemporal and intraorbital extension: 164 cm3; previous Department of Medicine, operations 1973, 1986; blindness right eye and continuous growth since 2 years; proptosis University Hospital Dijkzigt, right eye 40 Dr Molewaterplein, 3015 8 F 64 - Parasellar (left) at apex left opticus (9-6 cm3); continuous growth since 3 years, progressive GD Rotterdam, The visual loss left eye, proptosis left eye Netherlands. 9 F 53 - Sphenoid (left) with para-sellar, sellar and infratemporal extension: 89-5 cm'; previous operations 1983 and 1987; rapid growth since 2 years; tumour palpable in upper jaw, Received 19 March 1991 hypopituitarism, treated with hydrocortisone (30 mg/day) and in revised form 10 F 32 + Falx (left) and cerebellar/tentorium (right) tumours of 25-3 and 21-5 cm3; bilateral 19 March 1991. acousticus neurinomas, bilateral opticus tumours, previous operation in 1987 Accepted 8 August 1991 Mifepristone (RU 486) treatment of meningiomas 487 logical evidence of recent progressive tumour side effects in six patients: nausea and anorexia J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.6.486 on 1 June 1992. Downloaded from growth (patients 1, 2, 3 and 5). In seven occurred for a period ofa few days to up to two patients this was tumour progression or recur- weeks in three patients, while three patients rence after previous operation(s), while three took the drug without side effects. The other patients had not had a previous operation. All four patients (2, 3, 4 and 6), however, experi- patients had been selected by at least two enced more severe complaints of nausea (4) independent neurosurgeons of the staff of the and recurrent attacks of vomiting (3) starting department of neurosurgery of the University during the first week of therapy. In addition Hospital Rotterdam because: a) Reoperation these four patients felt exhausted and anor- was not expected to completely remove the ectic. In patient 4 prolonged vomiting stopped tumour; b) The localisation of the tumour on the third day of mifepristone therapy, caused a high risk of severe complications shortly after the start of the simultaneous during/after surgery; c) The general condition administration of 7-5 mg prednisone daily. In of the patient was so poor, that surgery seemed patients 2, 3 and 6 these complaints persisted contraindicated (patients 3 and 4). Exclusion and concomitant prednisone therapy (7 5 mg) criteria were pregnancy, the use of oral contra- was started after three weeks. Thereafter these ceptives, patients with a very poor performance complaints subsided, but prednisone therapy status, signs or symptoms of an elevated was continued in all four patients throughout intracranial pressure, coexistent psychiatric the study. No changes in blood pressure diseases, other cancer, renal and liver insuffi- (supine and/or standing) were noted during ciency. mifepristone treatment for up to one year. Also The experimental protocol had been ECG and routine clinical chemical investiga- approved by the ethical committee of the tions did not show changes. These included the University Hospital Rotterdam. All patients measurements of fasting glucose, potassium, signed an informed consent form in which the chloride and sodium concentration in serum, seriousness of their disease and the unknown renal and liver functions, as well as haemoglo- effects of mifepristone therapy were bin, haematocrit, white blood cell and throm- explained. bocyte counts. Body weights did not change According to the experimental protocol the significantly in these 10 patients during mife- patients were treated for 12 months with 200 pristone treatment. mg mifepristone daily. If side effects or signs of (relative) adrenocortical insufficiency devel- 2) Changes in tumour size and tumour related oped, a daily dose of 7-5 mg prednisone would complaints during treatment be added to mifepristone therapy. Clinical Mifepristone resulted in a general improve- evaluation was done every two to three weeks ment of well being in four patients (1, 7, 8 and during the first three months and every two 9). Especially complaints of headaches and/or months during the second part of the study. If tension in the jaw, skull or eye improved or visual abnormalities existed, the patients were disappeared in five patients. In patient 2 the also followed on a regular basis by an ophthal- visual acuity of the left eye improved slightly, mologist. Side effects were carefully noted and while in patient 8 the palpable part of the soft ECGs, measurement of blood pressure and tissue mass in the upper jaw shrank con- routine clinical chemical determinations were siderably. The proptosis of one eye in patients 7 http://jnnp.bmj.com/ carried out at least four times during the and 8 did not change during mifepristone investigation period. treatment. In patient 5, however, the already very bad visual acuity of the remaining eye CT scanning and analysis of tumour size further deteriorated during therapy. The size of the meningiomas was measured Changes in tumour volume were measured repeatedly with the same Philips Tomoscan in these 10 patients by CT scanning at regular 310 apparatus. Tumour volume was calculated intervals during and after mifepristone therapy on September 30, 2021 by guest. Protected copyright. by CT planimetry independently by the same (figure). In four patients clear growth of five neuroradiologist (HT) and neurosurgeon (RB) meningiomas was observed during therapy. under the same conditions.
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