Eye (2004) 18, 954–958. doi:10.1038/sj.eye.6701370 Published online 19 March
2004

Mifepristone treatment in patients with surgically incurable sphenoid-ridge
meningioma: a long-term follow-up

http://www.nature.com/eye/journal/v18/n9/full/6701370a.html

R J W de Keizer1 and J W A Smit2



1Department of Ophthalmology, Leiden University, Medical Center, PO Box 9600, 23
00 RC Leiden, The Netherlands

2Department of Endocrinology, Leiden University, Medical Center, PO Box 9600, 23
00 RC Leiden, The Netherlands


Correspondence: RJW de Keizer, Tel: +31 71 526 2374; Fax: +31 71 524 8222;
E-mail: R.J.W.de_Keizer@...



Sir,

Sphenoid-ridge meningiomas are slow-growing benign tumours that may reach
massive proportions, invading bone and/or encasing major blood vessels. Although
the importance of surgery is well established, meningiomas often recur after
incomplete resection, 'subtotal' or even 'total' extirpation. After subtotal
resection, most frequently used in sphenoid-ridge meningioma surgery, 69% of
patients are still recurrence-free, with the probability of recurrence as high
as 91% after 15 years.1, 2 After a second resection; the probability that more
surgery will be needed is 56% after 10 years. Although the survival rate is high
after 15 years, there is a serious threat that, after one or more operations,
the patient will become functionally disabled by impaired vision, even
blindness, and suffer motor deficits having cosmetic and social implications.2

Therefore, other therapies such as gamma-knife and stereotactic radiotherapy=2
0have been developed,3 although conventional radiosurgery remains beneficial.
Recurrence and cerebral and/or visual radio-complications are frequently found
at 10-year follow-up.1 Hormone treatment is possible because most meningiomas
contain progesterone-specific receptors.4, 5 Epidemiological data (preponderance
in women, tumour growth during pregnancy, coexistence with breast cancer)
suggests that progesterone receptors may play a role. Therefore, investigating
how progesterone antagonists' function may prove advantageous. The
progesterone-receptor antagonist Mifepristone (MIF;
17--hydroxy-(4-dimenthyl-aminophenyl)-17-(1-propynyl)estra-4,9-dien-one) binds
to and blocks both this as well as cortisol receptors in meningiomas.

Several pilot studies suggest that progression of sphenoid-ridge meningiomas can
be halted using progesterone-receptor antagonists.4, 6, 7 In most cases, tumour
growth and visual functions could be stabilized. Slight improvements in visual
function, motility disturbances, and orbital symptoms were occasionally
observed, as in the prospective study with 1-year follow-up6 (see Table 1) in
Rotterdam4 and Leiden including 10 patients (five from Rotterdam, two from
Leiden) with recurrent primary inoperable sphenoid-ridge and/or cavernous-sinus
meningiomas. In Leiden, disease continued in two cases after stopping MIF
treatment by protocol; visual functions recovered after renewing treatment. As
to date, no long-term results can be found in the literature, the two Leiden
cases showing initially favourable results will receive a 14-year follow-up.


Table 1 - Unresectable meningiomas in two=2
0women treated with MIF.
Full table




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Case reports

Case 1

In 1985, a 48-year-old woman with diplopia, caused by VI nerve palsy, and
trigeminal problems and proptosis was diagnosed in our clinic with
sphenoid-ridge meningioma (Table 1). Visual acuity (VA) was 1.0 for right (RE)
and left (LE) eyes. Her menstrual cycle subsided in 1981. After craniotomy with
tumour-block excision, III nerve palsy persisted. She appeared to develop
diabetes insipidus for which DDAVP (anti-diuretic hormone) was prescribed. In
1986, LE-VA deteriorated to 0.5 with a slightly pale optic disc. Homonym
visual-field (VF) defects together with cavernous-sinus syndrome and
hypopituitarism, probably resulting from tumor progression, were diagnosed and
treated with hydrocortisone and thyroxin. In 1987, LE visual functions rapidly
decreased to hand movements with more homonym impairment and RE nasal VF loss
but improved to 1.0 and 0.6 after a second neurosurgical decompression of the
opticochiasmal system. In 1988, LE-VA decreased to light perception and her
general condition deteriorated. As surgery and radiotherapy were undesirable,
hormone therapy using 200 mg MIF was chosen with permission according to the
Rotterdam protocol. Since MIF blocks the cortisol receptor, 0.5 mg doses of
dexamethasone (DEX) were given three times daily. Tumour growth was halted and
all visual functions improved (RE-VA 1.0, LE LP and less VF defects). After 1
year, MIF therapy was stopped according to protocol. However, all signs and
symptoms showed that her co
ndition was deteriorating again (VA 1.0, VF 0, more VF defects on both sides).
Our pituitary-tumour group decided to renew MIF treatment. Visual functions
improved. In 1990, RE-VA was 1.0 while LE-VA improved to finger counting at
2 m. During the 12-year follow-up, LE vision deteriorated slowly to zero, while
RE visual functions stabilized during the next 2 years, with a normal nasal VF
and small ventral island on the temporal side. In 1993, VA and VF decreased
slightly, and MIF was increased successfully to 400 mg daily. During the next 2
years, slight improvement was followed by stabilization over the next 7 years
(Figure 1, special VF bar). Neither CT scan nor MRI showed any tumour growth
during that period: a large meningioma of the sphenoid and cavernous sinus was
found with carotid-artery encasement, extension in the sphenoidal sinus and
clivus with slight impression of the III ventricle and close relation to the
optic nerve in the apex of the orbit on both sides.


Figure 1.

(a) Humphrey visual field analyses one example of the stationary 14 years of the
RE. (b) Change analysis for Case 1 who had no significant progression of the
visual fields/visual defects in 14 years. The box plot summarize the range of
sensitivities in each test result relative to what is normal for the patient's
age. The highest and the lowest points of each box plot show the extreme values
for each test result, 45% of test points have deviations from normal falling
within the middle box.
Full figure and legend (1
53K)




Case 2

In 1987, a 52-year-old woman was referred to our clinic (Table 1) with a medical
history including headache in 1978 and amenorrhoea at the age of 41 years.
Craniotomy was performed in 1980 for a skull-based meningioma. In 1986, she
suffered from persistent headache and progressive impairment of visual
functions. CT scan showed no recurring meningioma. In our outpatient department,
CT scan revealed a large recurrent en plaque skull-based tuberculum sellae
meningioma causing LE blindness and decreased RE visual functions. Lung embolus
developed after a second craniotomy. Her visual functions improved until they
failed again severely in September 1988. Only a small island of vision remained
(RE-VA 0.16; Figure 2a). Using Lamberts et al.4 protocol with permission,
200 mg MIF was given once daily that blocked the cortisol receptor, increasing
levels of plasma cortisol and ACTH. To prevent hypocortisolism, DEX therapy
(0.5 mg, 3 daily) was initiated. All endocrinological and systemic functions
and ultrasound of the intra-abdominal sex organs were normal. After 5 months,
headache vanished and visual functions stabilized. CT scan of the skull base and
orbit showed no tumour growth. Thereafter, following some changes in visual
function together with malaise, the dosages of MIF (to 2 200 mg) and DEX (to 4
0.5 mg) were increased.


Figure 2.

VF of Case 2. upper part: VF during the first period of observation, after
surgery, and again progression. Lower part: Goldmann and Humphrey analyzer after
1
2 years (total) treatment period.
Full figure and legend (428K)




Hormone therapy was discontinued after 1 year, following treatment protocol.
However, VA decreased again (to FC 4 m) after 1 month. As only a small island
of vision remained, MIF treatment was renewed using the same treatment protocol.
After 4 months of treatment, visual functions (RE-VA 0.2, fewer VF defects)
improved to the levels found during the first year of treatment. In 1991, visual
functions stabilized, CT scan revealed no tumour growth, and DEX was reduced to
3 0.5 mg.

In 1993, after blood loss, gynaecological ultrasound examination showed an
irregular uterus and endometrial polyp. Serum levels of oestradiol, LH, and FSH
did not verify the assumption that the patient was menopausal. After
hysterectomy, pathology revealed endometrial hyperplasia. It was concluded that
the irregular cycle probably resulted from the antiprogestagenic effect of MIF.
Based on hormone studies, DEX was changed to prednisone in decreasing doses and
MIF was reduced to 200 mg. From July 1992 to May 2002, VA measured 0.2–0.3
(sometimes 0.4) with a small island of vision especially located at the nasal
side 10° field (Figure 2b). MRI demonstrated no tumour growth of the tuberculum
sellae meningioma, a large tumour process located anterior to the sella and
extending to the clivus, pineal body, with erosion of the anterior clinoid
process, sella bottom, and dorsum sellae.


Top of page
Comment

From 1988 to 1990, two women with skull-based meningiomas
containing progesterone-positive receptors were treated for 1 year with 200 mg
MIF according to protocol to stabilize both tumour and visual functions. After a
period without MIF, all VFs decreased again with increasing blindness. In an
open study (second part), hormone treatment using either 200 or 400 mg MIF was
given during 12.5 years. (The drug was not available for treating more cases
between the original study and 1998.) During the first 2-year observation
period, ophthalmic and neuro-ophthalmic screening were performed every 3 months
and CT scans were made twice. Thereafter, the eyes were examined every 3 months
and VFs measured every 6 months. Later, MRI was performed every 1 and 2 years.

Endocrinal tests, including determination of plasma ACTH, cortisol, and
progesterone levels, were run every 6 weeks during the first year of treatment.
The women were examined gynaecologically at regular intervals. After 12 years,
all visual functions were still at the level achieved after 1 year of MIF
treatment. Our second patient who deteriorated severely and had been threatened
with imminent blindness (Table 1), even showed slight improvement after
treatment. One patient underwent hysterectomy for endometrial hyperplasia.

Both the short-term studies of Haak et al6 and Grunberg et al7 as well as our
study with a long-term follow-up have shown that the initial benefits of
treatment persist. Although Grunberg et al7 only prescribed 1 mg DEX during the
first 14 days of therapy, we advise combining MIF with DEX to prevent cort
isol deficiency. Apparently, there is no sign of tachyphylaxis. Although based
on a small patient group, these results appear more favourable than those
expected after radiotherapy, an alternative treatment associated with optic
neuropathy, neurological impairment, or cerebral necrosis (3%) and death (4%).3

We conclude that MIF is an attractive option for treating patients with
inoperable recurrent sphenoid-ridge and cavernous-sinus meningiomas and for
preventing severe cranial nerve and general morbidity, even after long-term
follow-up exceeding 14 years.


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References


Black P. Mcl Meningiomas. Neurosurgery 1993; 32: 643–657. | PubMed |

Klink DF, Sampath P, Miller NR, Brem H, Long DM. Long-term visual outcome after
nonradical microsurgery in patients with parasellar and cavernous sinus
meningiomas. Neurosurgery 2000; 47: 24–32. | PubMed |

Stafford SL, Pollock BE, Foote RL, Link MJ, Gorman DA, Schomberg PJ et al.
Meningioma radiosurgery: tumor control, outcomes, and complications among 190
consecutive patients. Neurosurgery 2001; 49: 1029–1038. | PubMed |

Lamberts SWJ, Avezaat AJJ, Braakman R, Tanghe R, Wijngaarde R, Koper JW et al.
Treatment of (recurrent) meningiomas with antiprogestin RU 38486 (mifepristone).
J Neurol Neurosurg Psych 1992; 55: 491–496.

Matsuda Y, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T. Antitumor effects
of antiprogestrones on human meningioma cells in vitro and in vivo. J Neurosurg
1994; 80: 527–534. | PubMed |

Haak HR,
de Keizer RJW, Hagenouw Taal JCW, v Seters AP, Vielvoye GJ, van Dulken H.
Successful mifepristone treatment of recurrent inoperable meningioma. Lancet
1990; 336: 124–125. | PubMed |

Grunberg GM, Weiss MH, Spitz JM, Sadun A, Russell CA, Lucci L et al. Treatment
of unresectable meningiomas with the antiprogesteron agent mifepristone. J
Neurosurg 1991; 74: 861–866. | PubMed |





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Please take this Mifepristone drug report and share it with your doctors and ask
them to check out the PUBMED references and ask if they checked your tumor
tissue for progesterone receptors during the pathology report, according to Dr
Peter Black's lab in Boston about 80% of meningiomas have high levels of
progesterone receptors. I believe that may also include a subset of some
neurofibromatosis type 2, acoustic neuromas and vestibular shwannomas.   

Here are some more recently published medical reports of mifepristone for
meningioma 

Spitz IM, Grunberg SM, Chabbert-Buffet N, Lindenberg T, Gelber H & Sitruk-Ware
R. Management of patients receiving long-term treatment with mifepristone.
Fertility and Sterility 2005 84 1719–1726.[CrossRef][ISI][Medline]


Grunberg SM, Weiss MH, Russell CA, Spitz IM, Ahmadi J, Sadun A & Sitruk-Ware R.
Long-term administration of mifepristone (RU 486): clinical tolerance during
extended treatment of meningioma. Cancer Investigation 200
6 24 727–733.[CrossRef][ISI][Medline]


Selective progesterone receptor modulators 3: use in oncology, endocrinology and
psychiatry.

Benagiano G, Bastianelli C, Farris M.

Expert Opin Pharmacother. 2008 Oct;9(14):2487-96. Review.

PMID: 18778186 [PubMed - indexed for MEDLINE]

Related Articles




The fight for a life-saving drug: a personal perspective.

Lander M.

Med J Aust. 2007 Dec 3-17;187(11-12):706-8. No abstract available.

PMID: 18072931  

GBYAY Anne McGinnis Breen, a 22 year meningioma survivor who had craniotomies in
1986 and 2000 and is currently on 200 mg Mifepristone (mifeprex) daily again
since Feb 2005, I also took it for three years from 1996-1999 in Dr Steven
Grunberg's Phase 3 SWOG 9005 clinical trial and I believe it has saved my life
and my mind. Most people are not being offered this drug to stabilize their
meningioma condition because of the national politics of its use as an abortion
agent. Please read Mary Lander's personal perspective with the same drug use
issue in Australia,  





See my ponytail bouncing and my smiley face winking at you? &;>)

My new personal bt blog with my list of 28 questions to ask your doctor about
brain tumor treatments is http://gbyay.blogspot.com
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
"Hope has two daughters--anger and courage: anger at the way things are and the
courage to work to make things other than they are." -- Saint Augustine
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
Keep you faith, cherish your reason, treasure your mind and hold to your own
good purpose...be not afraid!


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