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Uwe M. H. Schrell, M.D., Michael G. Rittig, M.D., Marc Anders, Uwe H. Koch, Ph.D., Rolf Marschalek, Ph.D., Franklin Kiesewetter, M.D., and Rudolf Fahlbusch, M.D.
Departments of Neurosurgery, Anatomy, Dermatology, and Genetics, University of Erlangen-Nürnberg, Erlangen, Germany
In this paper the authors present the first evidence that meningiomas respond to treatment with hydroxyurea. Hydroxyurea was administered as an adjunct chemotherapeutic treatment in patients with recurrent and unresectable meningiomas. Hydroxyurea was used because experimental data demonstrated that it inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis. The authors therefore treated four selected patients with hydroxyurea. All patients had undergone multiple gross resections and all except one received radiotherapy. Three patients with recurrent Grade I meningiomas assessed according to World Health Organization (WHO) guidelines received hydroxyurea because of an increased tumor growth rate, documented by magnetic resonance (MR) imaging, within a 6- or 12-month interval. A fourth patient with a malignant meningioma (WHO Grade III) began a course of treatment with hydroxyurea immediately after his sixth palliative operation without waiting for another relapse to be demonstrated on MR imaging. Because of their location and invasive growth behavior none of the meningiomas could have been removed completely by surgical intervention.
All patients received hydroxyurea at a dosage level of 1000 to 1500 mg/day (approximately 20 mg/kg/day). In a man with a large sphenoid wing meningioma invading the right cavernous sinus and the temporal base, the intracranial tumor mass was reduced by 60% during 6 months of treatment. A woman with a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus exhibited a 74% decrease of the initial tumor volume in 10 months of treatment with oral hydroxyurea. Serial MR images obtained monthly revealed that the process of size reduction was continuous and proportionate. The shrinkage of the tumor was accompanied by a complete remission of symptomatic trigeminal neuralgia after 2 months and by improved abducent paresis after 5 months. The third patient had a slowly growing meningioma that exhibited a 15% reduction in mass when reassessed after 5 months of hydroxyurea treatment. The fourth patient with the malignant meningioma in the left cerebellopontine angle has had no recurrence for 24 months. Long-term treatment with hydroxyurea may result in full remission of tumors in meningioma patients.
The preliminary data indicate that hydroxyurea provides true medical treatment in patients with unresectable and recurrent meningiomas, replacing palliative surgery and radiotherapy in the management of this disease.
Key Words * hydroxyurea * chemotherapy * meningioma * nonglial brain tumor * adjunct therapy * growth inhibition * apoptosis
Meningiomas are solid tumors of mesodermal origin that appear as intracranial and intraspinal tumors. According to the World Health Organization (WHO) grading system[35] most meningiomas are Grade I (benign), whereas Grades II and III (malignant) meningiomas account for about 7%[23] of cases. Although the primary treatment is surgical, complete resection is often impossible because of the extent of osseous tumor invasion or the tumor penetration into the connective tissue of the cavernous sinus, which causes functional deficits by compression of and infiltration into the optic and motor nerves and the wall of the internal carotid artery.[7,19,21] Permanent cranial nerve dysfunction may be a consequence of total and radical tumor resection in this region.
The surgical concept of total removal of cavernous sinus meningiomas has lost favor because of high morbidity combined with a high recurrence rate.[3,10,15,18,33] Therefore the current treatment strategy is less aggressive, aiming at decompression[15,18] and radiotherapy in progressive tumors.[22,26] Although radiotherapy only rarely achieves a true tumor mass reduction, it can arrest growth in malignant as well as benign meningiomas for some years.[2,4,9,12,14,24,27]
The concept of an adjunct medical treatment using glucocorticoids and their antagonists for unresectable meningiomas has been explored since the late 1970s.[6,11,2830] However, none of these drugs, including the progesterone antagonist RU-486, was efficient in controlling tumor proliferation in meningioma patients, although initial minor responses in tumor regression have been reported.[16,20]
The use of systemic chemotherapy for treatment of malignant meningiomas has been reported recently.[8] This treatment regimen (adjuvant radiotherapy followed by cycles of cyclophosphamide, adriamycin, and vincristine) did not produce better results than adjuvant radiotherapy alone. Because of their toxicity, these chemotherapeutic agents can be applied only once, in therapeutic cycles lasting a few weeks.
In contrast, our concept is based on long-term (over years) chemotherapeutic treatment taking into account that meningiomas are slowly growing tumors with a low mitotic index. Therefore, we tested the effects of various low morbiditycausing chemotherapeutic drugs on human meningioma cell growth in vitro. The selected agent was hydroxyurea. This chemotherapeutic drug drastically inhibits the growth of human meningioma cells and meningioma transplants in nude mice by triggering the apoptotic cascade.[31,32]
This is the first report of a successful use of hydroxyurea in the medical treatment of unresectable and recurrent benign as well as malignant meningiomas.
CLINICAL MATERIAL AND METHODS
Patient Eligibility Criteria
This study was designed to evaluate the efficacy and side effects of hydroxyurea as an adjunct therapy in meningioma patients. Patients with recurrent and unresectable intracranial meningiomas were eligible for this study. In all cases with remnants of solid meningioma, the tumor had either grown into the cavernous sinus or originated from that site. Patients who had received prior cranial radiation treatment were also eligible if the tumor had shown radiologically documented progression following irradiation. Because hydroxyurea decreases hematological values, adequate hematological reserves (white blood cell count > 3000/µl [normal value 400010,000/µl], platelet count > 100,000/µl), hepatic reserves (bilirubin < 2 mg%), and renal reserves (creatinine < 2 mg%) were required. Patients were deemed ineligible if there was evidence of a second active neoplasm requiring cytotoxic chemotherapy, a serious intercurrent illness, or a history of thrombophlebitis.
Patient Characteristics
Four patients, two women and two men, ranging in age from 44 to 56 years (mean 48 years) were included in this study (Table 1 and 1A). Both women were postmenopausal. All patients were ambulatory adults with a Karnofsky Performance Scale rating of greater than 70%.
In each case the diagnosis of meningioma was based on histological evaluation. The tumor histology was meningotheliomatous, WHO Grade I in three patients, with an angiomatous component in two cases and a fibrous component in one. One male patient had a malignant meningioma (WHO Grade III). All patients had undergone surgical procedures previously; two had undergone multiple attempted complete resections of recurrent meningiomas over a period of 4 and 9 years, respectively, the latter with progression from a Grade I meningotheliomatous meningioma to a Grade III malignant meningioma. Because of the enhanced proliferative activity, a recurrent tumor had been documented by magnetic resonance (MR) imaging within 3 months of follow up, after his fourth and fifth operations. Three patients had previously received radiotherapy. Two patients had symptomatic trigeminal neuralgia, and one of them had abducent nerve paresis.
Treatment Protocol and Follow-Up Period
Patients received a daily oral dosage of 1000 or 1500 mg of hydroxyurea supplied as 500-mg tablets, equal to 20 mg/kg/day, throughout the course of the study. The dosage was estimated not to lower the white blood cell count below 3000/µl. Hematological monitoring was performed by a general practitioner twice a week during the 1st month and once a week thereafter. Full blood counts and a selection of serum chemistry tests were obtained once a month. A complete physical and neurological examination was performed every 3 months and included evaluation for subjective side effects and improvement or worsening of clinical symptoms caused by the meningioma. Tumor measurement was assessed by MR imaging before treatment and every 3 months therafter. In one patient MR images were obtained monthly. None of the patients received supplements of dexamethasone or other glucocorticoids.
RESULTS
Responses to Therapy
In this group of patients daily hydroxyurea therapy has been administered for periods ranging from 5 to 24 months and will be continued for a minimum of 2 years (Table 1 and 1A).
Before treatment all patients exhibited tumor progression within 1 year, as documented on MR imaging. During the course of treatment none of the patients has shown further growth of the tumor. The patient with the right-sided large sphenoid wing meningioma infiltrating the cavernous sinus and the temporal base (Case 1) showed drastic tumor regression (60%) after 6 months of hydroxyurea treatment (Fig. 1).
Fig. 1. Case 1. Coronal T1-weighted gadolinium-enhanced MR images. Note the infundibulum at the bottom of the third ventricle in all three panels revealing identical slice positions. Left: Pretreatment MR image revealing a large meningioma of the right sphenoid wing invading the cavernous sinus and the right temporal base. Center: An MR image obtained 3 months after initiation of hydroxyurea treatment revealing the meningioma in place and unchanged in size, but with a huge clearly demarcated hypointense area indicating a significantly reduced gadolinium uptake. Right: An MR image obtained 6 months after initiation of hydroxyurea treatment revealing a small tumor rim in the base of the right temporal fossa. The right temporal horn, which had been compressed by the tumor mass, is now unfolded. The intracranial tumor mass was reduced by 60%.
The patient with the extensive right-sided sphenoid wing meningioma infiltrating the cavernous sinus and causing abducent nerve paresis and symptomatic trigeminal neuralgia (Case 2) also achieved a dramatic decrease in tumor mass (74%) after 10 months of treatment. This tumor regression was documented monthly on serial MR images (Figs. 2 and 3).
Fig. 2. Case 2. Coronal T1-weighted gadolinium-enhanced MR images. Note the pituitary stalk at the bottom of the third ventricle in all panels, revealing identical slice positions. Left: Pretreatment MR image revealing a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus. Center: An MR image obtained 5 months after initiation of hydroxyurea treatment, revealing the meningioma in place but reduced in size by 53%. Note that even the small tumor satellite was reduced in size. Right: An MR image obtained 10 months after initiation of hydroxyurea treatment, revealing the meningioma in place but reduced in size by 74%. Note the similar configuration seen in left and right panels. The tumor mass was reduced proportionally as documented monthly by means of serial MR imaging (see Fig. 3).
The shrinkage of the tumor was accompanied by a complete remission of the trigeminal neuralgia after 2 months and by improved extraocular muscle function after 5 months of treatment. Another patient with a slowly growing left-sided cavernous sinus meningioma (Case 3) and symptomatic trigeminal neuralgia achieved a minor decrease in tumor size (15%) and remission of her neuralgia after 5 months of treatment. The patient with the malignant Grade III meningioma in the left posterior fossa (cerebellopontine angle, Case 4), who was treated with hydroxyurea immediately after his sixth palliative operation without awaiting his next relapse, has not experienced recurrence during the 24-month course of hydroxyurea therapy.
Fig. 3. Case 2. Graphs based on serial T1-weighted gadolinium-enhanced cortical MR images. The patient was examined before and at monthly intervals during hydroxyurea (HU) treatment. The graphs clearly demonstrate a continuous proportional reduction in tumor size. The arrowhead marks the initiation of HU treatment. Left: Graph showing growth rate of the meningioma before treatment. Tumor volume was calculated as 14.3 cm3 (100%) at the beginning of HU treatment. Right: Graph showing growth rate during HU treatment. Tumor volume after 5 months of treatment was 6.7 cm3 (47%), corresponding to a 53% reduction in size; after 10 months it was 3.7 cm3 (26%), corresponding to a 74% reduction in size.
Toxicity and Side Effects
None of the patients had any problematic side effects. The maximum dose did not exceed 20 mg/kg/day, and was well tolerated. With respect to hematological toxicity, none of the patients experienced significant bone marrow suppression. If the white blood cell count fell below 3000/µl the dose was reduced for a few days. The most common nonhematological side effects were mild fatigue in two, bleeding of the gums in three, and constipation in two patients.
DISCUSSION
It has been demonstrated in this pilot study that hydroxyurea can reduce the size of intracranial meningiomas within 6 months. A chemotherapeutic regimen for intracranial meningiomas associated with such a dramatic cytoreductive effect has not been reported previously. As expected, hydroxyurea acts more efficiently as a chemotherapeutic drug in rapidly than in slowly proliferating meningiomas. The therapeutic application for this agent ranges from benign (WHO Grades I and II) to malignant (WHO Grade III) meningiomas.
Radical surgical treatment of meningiomas causes high morbidity rates, which is evident in cavernous sinus meningiomas. Even totally resectable tumors such as convexity meningiomas have a median recurrence rate as high as 10% after 5 years, 20% after 10 years, and 50% after 20 years.[1,23,25,34] Recurrent meningiomas increase the morbidity and mortality rates of the patients. The likelihood of premature death in patients with Grade I and II lesions who undergo subtotal tumor removal is 4.2 times higher than in those who undergo total tumor removal and is comparable to patients with Grade III meningiomas (4.6 times higher).[17] Even adjunct radiotherapy only delayed regrowth or recurrence for a few years.[4,27]
The risks and limitations of surgery and fractionated radiotherapy are well known and despite years of investigation, cytotoxic and hormonal chemotherapy have not proven particularly beneficial.[5,8,16,20] The high rates of morbidity and mortality necessitate a more effective therapy and justify chemotherapeutic treatment of unresectable and recurrent meningiomas. Because most meningiomas are benign tumors bearing no biological features in common with carcinomas,[35] we considered chemotherapeutic drugs adapted to the biology of meningiomas. We selected hydroxyurea, which is used for long-term treatment of chronic myelogenous leukemia and is actually prescribed for permanent treatment of sickle cell anemia.[13] The decision to introduce hydroxyurea in the treatment of unresectable and recurrent meningiomas was ultimately based on our experimental findings in cell cultures and in tumor cell transplants in nude mice, which demonstrated that hydroxyurea stopped cell growth by triggering the apoptotic cascade.[31,32]
Hydroxyurea has never been used in the treatment of meningiomas and response rates of up to 70% within 1 year of initiation of oral administration reflect extraordinary success in the treatment of this solid tumor. By analogy with our experimental data,[31,32] we suggest that induction of apoptosis is also the cause of tumor regression in our patients. The activation of this mechanism gives hope that long-term treatment with hydroxyurea can lead to a true remission.
The preliminary clinical data presented in this report correlate in a fascinating way with our experimental data on meningioma biology and response to hydroxyurea, and justifies further study in a larger group of patients.
Acknowledgments
We thank Mrs. Annemarie Gundler, Mr. Klaus-Jürgen Wolff, and all of the others who participated in this first trial study. We thank Dr. J. Wickboldt for referring the first patient. We appreciate the generous support of Dr. G. Moissl who performed the monthly MR imaging.
References
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Manuscript received October 14, 1996.
Accepted in final form February 7, 1997.
Dr. Schrell is supported by a Career Development Award from the Ria Freifrau von Fritsch Stiftung.
Address reprint requests to: Uwe M. H. Schrell, M.D., Neurochirurgische Klinik der Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
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