Progressive Meningioma Research Articles

A phase II trial of PTK787/ZK 222584 (PTK787) in recurrent high-grade meningioma.

2046 Background: Systemic treatment options are limited for patients with recurrent meningioma. VEGF and PDGF promote angiogenesis and cellular proliferation. PTK-787 is an oral inhibitor of VEGF and PDGF receptors. The primary endpoint was to determine overall response rate. Secondary endpoints were 6-month progression-free survival (PFS-6) and overall survival. Methods: Patients (pts) with histologically confirmed recurrent WHO Grade 2 or 3 meningioma were eligible. Pts had no limit on prior therapies though must have included surgery and radiotherapy, a KPS ≥60, and were not taking enzyme inducing anticonvulsants. PTK-787 administration began at 250 mg BID and increased by 250 mg/day weekly to a dose of 500 mg BID. Clinical examinations were performed after each 4-week cycle and imaging every 8 weeks. Responses were graded using modified Macdonald criteria. Results: 21 pts were treated: 14 grade 2 and 7 grade 3 meningiomas (11 men; 10 women). Median age was 59 (29-88) years. Median KPS was 80 (60-100). Median number of cycles was 2 (range < 1-14) with one patient remaining on treatment. Main toxicities were transaminase elevation grade 4 (n=1) and 3 (n=3), fatigue grade 3 (n=4) and rash grade 3 (n=2). 3 pts were withdrawn early due to toxicity and were not evaluable for response. Best response in the remaining 17 pts was PR (n=1; 5.8%), SD (n= 12; 70.6%) and PD (n = 5; 29.4%). Overall PFS-6 and 12 was 37.5% and 12.5%; median time to progression was 3.7 m grade 2 and 3.6 m grade 3 months among the 21 pts (intent to treat). Median overall survival was 22.9 m for grade 2 and 19.6 m for grade 3. Conclusions: The combination VEGF/PDGF inhibition in pts with recurrent or progressive high-grade meningiomas can lead to disease stabilization. Targeted therapy may have a better role than cytotoxic therapies given the limited activity of available agents and suggest further studies with VEGF signaling pathway inhibition are warranted.

Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma

The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 μg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992-1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and ≥18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.

Treatment of unresectable skull base meningiomas with somatostatin analogs

The standard surgical treatment for meningiomas is total resection, but the complete removal of skull base meningiomas can be difficult for several reasons. Thus, the management of certain meningiomas of the skull base--for example, those involving basal vessels and cranial nerves--remains a challenge. In recent reports it has been suggested that somatostatin (SST) administration can cause growth inhibition of unresectable and recurrent meningiomas. The application of SST and its analogs is not routinely integrated into standard treatment strategies for meningiomas, and clinical studies proving growth-inhibiting effects do not exist. The authors report on their experience using octreotide in patients with recurrent or unresectable meningiomas of the skull base. Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Postoperative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months. Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range 48-180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption. Although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful.

Fractionated stereotactic conformal radiotherapy for large benign skull base meningiomas

Purposeto assess the safety and efficacy of fractionated stereotactic radiotherapy (FSRT) for large skull base meningiomas.Methods and MaterialsFifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cm3 (range 24.1-94.9 cm3), and the median PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively.ResultsAt a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits.ConclusionFSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity.

2010 Society for Neuro-Oncology Annual Meeting: a report of selected studies

A number of important studies were presented at the Society for Neuro-Oncology annual meeting in Montréal, Canada, on 18–21 November 2010. Cediranib as monotherapy or in combination with lomustine did not show increased efficacy when compared with lomustine alone in patients with recurrent glioblastoma (GBM). Addition of temozolomide (TMZ) or irinotecan (CPT) to bevacizumab (BEV) in patients with recurrent GBM was well tolerated, with similar efficacy to BEV alone. The addition of BEV to radiation and TMZ in newly diagnosed GBM improved progression-free survival but did not improve overall survival. TMZ alone may be a reasonable approach in elderly GBM patients with poor performance status. Two Phase II trials with suntinib and vatalanib showed a hint of activity in patients with recurrent or progressive meningiomas.

Primary radiotherapy in progressive optic nerve sheath meningiomas: a long-term follow-up study

Background/aimsTo report the outcome of primary radiotherapy in patients with progressive optic nerve sheath meningioma (ONSM).MethodsThe clinical records of all patients were reviewed in a retrospective, observational, multicentre study.ResultsThirty-four consecutive...

Imaging of Meningioma Progression by Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry

Often considered benign, meningiomas represent 32% of intracranial tumors with three grades of malignancy defined by the World Health Organization (WHO) histology based classification. Malignant meningiomas are associated with less than 2 years median survival. The inability to predict recurrence and progression of meningiomas induces significant anxiety for patients and limits physicians in implementing prophylactic treatment approaches. This report presents an analytical approach to tissue characterization based on matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry imaging (MSI) which is introduced in an attempt to develop a reference database for predictive classification of brain tumors. This pilot study was designed to evaluate the potential of such an approach and to begin to address limitations of the current methodology. Five recurrent and progressive meningiomas for which surgical specimens were available from the original and progressed grades were selected and tested against nonprogressive high-grade meningiomas, high-grade gliomas, and nontumor brain specimens. The common profiling approach of data acquisition was compared to imaging and revealed significant benefits in spatially resolved acquisition for improved spectral definition. A preliminary classifier based on the support vector machine showed the ability to distinguish meningioma image spectra from the nontumor brain and from gliomas, a different type of brain tumor, and to enable class imaging of surgical tissue. Although the development of classifiers was shown to be sensitive to data preparation parameters such as recalibration and peak picking criteria, it also suggested the potential for maturing into a predictive algorithm if provided with a larger series of well-defined cases.

A menigothelial meningioma (WHO grade I) with malignant progression and cutaneous, pulmonary and bone metastases: a case report

We present the case report of a 50-year-old man suffering from a frontal meningothelial meningioma (WHO grade I) with malignant transition and metastases in the lung, scalp, skin and bone. Fractionated radiation, though a fundamental part of therapy in progressive and malignant meningiomas, did not prevent tumour progression in our case. In our case, the tumour progressed under the application of Sandostatin® and salvage therapy with Avastin® and Campto®. Therapeutic strategies are reviewed and discussed.

Primary optic nerve tumours

Advances have been made in the treatment of primary optic nerve tumours. With a focus on the last few years' publications, recommendations for clinical management are being developed. In low-grade optic nerve glioma, two divergent developments are observed: an increasing reluctance in treating such tumours because of reports about treatment toxicity (secondary tumours, moyamoya syndrome) and a steady and marked improvement both in radiotherapy and chemotherapy. Many reports on beneficial effects of radiotherapy on optic nerve meningioma have been published. Radiotherapy does not only preserve but in many cases even improves or restores visual function and has, therefore, become the therapy of choice in this tumour. Establishing a treatment plan in cases of optic nerve glioma is difficult and must be made on an individual basis. Although both chemotherapy and radiotherapy can stabilize and sometimes improve vision in progressive tumours, chemotherapy is the preferred modality in children younger than 9 years and in patients with neurofibromatosis 1. In functionally progressive optic nerve meningioma with useful visual function, multifractioned stereotactic conformal radiotherapy is the treatment of choice.

A phase II trial of PTK-787 (PTK/ZK) in recurrent or progressive meningiomas

2060 Background: Treatment options are limited for patients (pts) with recurrent meningiomas. VEGF and PDGF promote angiogenesis and cellular proliferation. PTK-787 is an orally active inhibitor of VEGF and PDGF receptors. The primary endpoint of this trial was to determine the efficacy of PTK-787 in pts with recurrent or progressive meningiomas as noted by radiographic response. Main secondary endpoints were 6-month progression-free survival (PFS-6) and overall survival. Methods: Adult patients with histologically proven meningiomas (grade I, II, or III) or hemangiopericytomas were eligible. Pts must have a history of progressive disease, KPS ≥60, and not be on enzyme inducing anti-convulsants. No limit on number of prior therapies was placed. PTK-787 administration began at 250 mg BID and increased by 250 mg/day weekly to a dose of 500 mg BID. Exams were done after each 4-week treatment cycle; imaging was done every 8 weeks. Treatment continued for 12 months or until disease progression. Evaluation of VEGF, EGFR, PDGF, HER2, and ET 1 and 2 in tissue is planned. Results: 13 of planned 25 pts have enrolled: 6 grade II and 6 grade III meningiomas, 1 hemangiopericytoma (7 men; 6 women). Median age was 60 years (range 30–89). Median number of cycles to date is 4 (range 1.5–9.4) with 4 pts still on treatment. No grade 4 toxicity was observed. All pts experienced fatigue, which reached grade 3 in 3 pts. Other grade 3 toxicities: jaw pain, elevated transaminases, anorexia, rash, and hypertension. Due to intolerability, original dose escalation to 750 mg BID was reduced to 500 mg BID. Two pts were withdrawn due to rash prior to imaging and were not evaluable for response. Best response in the remaining 11 evaluable pts was partial response in 1 (8%), stable disease in 9 (69%), and progression in 1. Overall PFS-6 was 46% and median time to progression was 15.7 weeks (range 7.6–32) among the 7 evaluable pts who progressed. Conclusions: This is the first trial to use a combination VEGF/PDGF inhibitor in pts with recurrent or progressive meningiomas. PTK-787 is better tolerated at a total dose of 1,000 mg. Although data is accumulating, disease stabilization and minor responses were seen, suggesting this targeted approach may be useful in meningiomas. Updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis

Brain-sparing total meningeal radiation for a patient with widespread progressive meningiomas using helical intensity modulated radiation

Multiple meningioma is a rare but difficult clinical entity. We describe the case of a patient with widespread progressive meningiomas who could not safely have surgery or radiosurgery. We have previously treated these patients with whole brain radiation, despite the risks of neuropsychological side effects. In this case, we treated with a novel use of helical intensity modulated radiation therapy: brain-sparing total meningeal radiation. The brain-sparing technique allowed us to treat the patient's meninges with higher doses than would have been possible with whole brain radiation and with the goal of achieving long-term disease control.

Targeted drug therapy for meningiomas

✓ Although advances in surgery, radiation therapy, and stereotactic radiosurgery have significantly improved the treatment of meningiomas, there remains an important subset of patients whose tumors are refractory to conventional therapy. Treatment with traditional chemotherapeutic agents has provided minimal benefit. In this review, the role of targeted molecular therapies for recurrent or progressive meningiomas is discussed.

Targeted drug therapy for meningiomas

Although advances in surgery, radiation therapy, and stereotactic radiosurgery have significantly improved the treatment of meningiomas, there remains an important subset of patients whose tumors are refractory to conventional therapy. Treatment with traditional chemotherapeutic agents has provided minimal benefit. In this review, the role of targeted molecular therapies for recurrent or progressive meningiomas is discussed.

Prolonged Oral Hydroxyurea and Concurrent 3d-Conformal Radiation in Patients with Progressive or Recurrent Meningioma: Results of a Pilot Study

Treatment of recurrent and progressive meningiomas remains a challenge in clinical neurooncology. This study was designed to evaluate the efficacy of the simultaneous application of 3d-conformal radiotherapy and chemotherapy with hydroxyurea (HU). Twenty-one patients with recurrent or progressive meningiomas (13 benign, 4 atypical and malignant, 4 with unproven histology) received treatment by fractionated 3d-conformal radiation (55.8-59.4 Gy) and concurrent HU, administered for a median time of three months with a daily dosage of 20 mg/kg. Response was evaluated using clinical and neuro-imaging data. Disease stabilization was achieved in 14/21 patients (pts). Three pts had significant improvement of tumor associated neurological symptoms with imaging criteria of minor response. Progression free survival rates 1 year and 2 years after the initiation of radio-chemotherapy were 84% and 77%, respectively. At the time of analysis a total of 6/21 pts presented with progressive disease with a median time to progression of 59 weeks. Documented radio- and chemotherapy associated toxicity was minimal; only one patient discontinued HU treatment due to gastrointestinal symptoms such as anorexia and weight loss. Results obtained in this study indicate that treatment with HU and simultaneous radiotherapy is safe and effective with disease stabilization in the majority of patients. Randomized trials comparing radiosurgery versus radiochemotherapy versus fractionated radiotherapy are warranted.

Traitement des méningiomes par hydroxyurée

Management of unresectable progressive meningioma remains controversial and constitutes a major challenge since therapeutic options including chemotherapy and hormone modulation are limited. Recent data have suggested that hydroxyurea treatment may have an antitumoral effect. The purpose of this prospective phase II study was to evaluate the efficacy of hydroxyurea treatment for unresectable progressive meningioma. From 1997 to 1999, consecutive patients presenting unresectable meningioma with clinically and/or neuroradiologically documented progression were considered for entry into this protocol. Previous radiotherapy was not a mandatory inclusion criteria. Treatment consisted of continuous oral administration of hydroxyurea at a dose of 20 mg/kg per day. Follow-up assessment included physical examination, computed tomography (CT), and magnetic resonance imaging (MRI) performed every three months, as well as regular blood testing. The primary endpoint was documentation of objective response by MRI or CT. The intent-to-treat population was 43 patients with at least 18 months follow-up. Median age was 60.4 years. Twenty-eight patients had undergone surgery following initial diagnosis. The meningioma was located in the skull base in 67% of patients. Histology was benign in 18 and atypical in 10. The eligible population included 36 patients with documented progressive disease at the time of inclusion; with progression documented clinically in 29 (67.5%) and/or radiologically in 20 (46%). In 7 patients, clinical or radiological progression could not be confirmed. The intent-to-treat analysis at median 26 months follow-up revealed objective response to hydroxyurea in only 3 patients (7%) including one on the basis of improvement in visual symptoms and two on MRI analysis. Progressive disease was observed clinically or radiologically in 26 patients (60.5%). Of the eligible population (n=36), 2 achieved an objective response and 13 (36%) exhibited stabilization under hydroxyurea therapy, while 21 (58%) progressed under treatment. Overall tolerance was good but anemia (grade I-II) and asthenia (grade I-II) were observed in 28% and 23.5% respectively. Treatment was discontinued in 3 patients because of chronic skin toxicity in one and anemia and asthenia in two. Hydroxyurea treatment is of marginal efficacy for meningioma and must not be considered as an alternative if radiotherapy or surgery is feasible. New efficient medical treatments are still required for progressive meningiomas.

Microvessel density in progressive meningiomas and its influence on time to tumour recurrence

1563 Background: Meningiomas constitute circumscribed intracranial tumours of limited resectability. Adjuvant therapy is applied for growth control of incompletely resected tumours. However, radiotherapy is limited for tumours in certain locations due to the presence of adjacent radiosensitive neural structures. In such cases, chemotherapy is mandatory for tumour control, but hitherto used chemotherapy protocols showed unsatisfactory therapeutic effects. Methods: In order to develop new approaches based upon angiogenetic properties, we analysed systematically tumour vascularization in a set of 26 recurrent or inoperable meningiomas of 13 patients using the endothelial cell marker anti-CD34 for immunostaining. We determined microvessel density (MVD) within the tumour area with the highest vessel density by counting all anti-CD34 immunostained vessels at a magnification of x 200 within an examination area of 0.25 mm2 using an eye grid. Further, we analysed expression of vascular endothelial growth factor (VEGF) at the messenger RNA and protein levels. Results: MVD ranged from 22 to 149 vessels/standard area with a median of 50.5. Focal or widespread expression of VEGF messenger RNA was detectable in 17/19 analysed samples and VEGF protein expression was observed in all tumour samples. Clinically, the time to recurrence of tumours with high ( ≥ 50.5) MVD ( 28.4 months) was significantly shorter as compared to tumours with low MVD ( 72.1 months; p = 0.0136). Conclusions: Our data indicate that MVD may influence the progression of meningiomas. Due to the expression of VEGF messenger RNA and/or VEGF protein in all tumour samples, anti-VEGF strategies may exert a beneficial therapeutic effect in progressive meningiomas. No significant financial relationships to disclose.

Microvessel density in progressive meningiomas and its influence on time to tumour recurrence

1563 Background: Meningiomas constitute circumscribed intracranial tumours of limited resectability. Adjuvant therapy is applied for growth control of incompletely resected tumours. However, radiotherapy is limited for tumours in certain locations due to the presence of adjacent radiosensitive neural structures. In such cases, chemotherapy is mandatory for tumour control, but hitherto used chemotherapy protocols showed unsatisfactory therapeutic effects. Methods: In order to develop new approaches based upon angiogenetic properties, we analysed systematically tumour vascularization in a set of 26 recurrent or inoperable meningiomas of 13 patients using the endothelial cell marker anti-CD34 for immunostaining. We determined microvessel density (MVD) within the tumour area with the highest vessel density by counting all anti-CD34 immunostained vessels at a magnification of x 200 within an examination area of 0.25 mm2 using an eye grid. Further, we analysed expression of vascular endothelial growth factor (VEGF) at the messenger RNA and protein levels. Results: MVD ranged from 22 to 149 vessels/standard area with a median of 50.5. Focal or widespread expression of VEGF messenger RNA was detectable in 17/19 analysed samples and VEGF protein expression was observed in all tumour samples. Clinically, the time to recurrence of tumours with high ( ≥ 50.5) MVD ( 28.4 months) was significantly shorter as compared to tumours with low MVD ( 72.1 months; p = 0.0136). Conclusions: Our data indicate that MVD may influence the progression of meningiomas. Due to the expression of VEGF messenger RNA and/or VEGF protein in all tumour samples, anti-VEGF strategies may exert a beneficial therapeutic effect in progressive meningiomas. No significant financial relationships to disclose.

Treatment of high risk or recurrent meningiomas with hydroxyurea

Recurrent, irresectable meningioma constitutes an uncommon but significant problem. Many systemic therapies have been tested without clear evidence of efficacy. More recently, two reports have suggested that hydroxyurea has activity in this context. This study examined the efficacy and toxicity of hydroxyurea in the treatment of 15 patients with high risk meningioma, residual meningioma post resection and progressive meningioma. Hydroxyurea was well tolerated although two patients ceased therapy because of skin rashes. There were no objective responses. Eleven patients achieved stable disease including eight patients who had documented progression prior to commencing hydroxyurea. These results are consistent with previous reports. In conclusion, hydroxyurea may provide some clinical benefit in patients with progressive meningioma by delaying progression of disease.

Visual Loss Caused by Rapidly Progressive Intracranial Meningiomas During Pregnancy

Three cases of intracranial meningiomas occurring in young pregnant women are presented. The typical growth pattern of these tumors is slow, producing insidious and chronic visual disturbances. In contrast, during pregnancy meningiomas may follow a rapidly progressive course, producing dramatic and relatively acute visual loss. This accelerated growth pattern is probably mediated by hormone receptors in these tumors. Nausea, vomiting, and other symptoms caused by the tumor may be attributed to pregnancy, delaying the diagnosis. Symptoms may abate spontaneously after delivery only to recur with greater rapidity and severity during subsequent pregnancies. Hormone-responsive intracranial meningiomas must be considered in the differential diagnosis of visual disturbances during pregnancy. Close cooperation between the ophthalmologist, neurosurgeon, obstetrician, and neonatologist is essential for an optimal outcome. Although surgical excision remains the treatment of choice, hormonal therapy may be valuable in treating unresectable or partially resectable meningiomas.