Observation or Radiation Therapy in Treating Patients With Grade I, Grade II, or Grade III Meningioma

Study Overview
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Brief Summary
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RATIONALE: Sometimes a tumor may not need treatment until it progresses. In this case, observation may be sufficient. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor, such as 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy, may kill more tumor cells and cause less damage to normal tissue. It is not yet known whether observation is more effective than radiation therapy in treating patients with meningioma. PURPOSE: This phase II trial is studying observation to see how well it works compared with radiation therapy in treating patients with grade I, grade II, or grade III meningioma.

Detailed Description
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OBJECTIVES: Primary To estimate the rates of progression-free survival at 3 years in patients with low-risk meningioma undergoing observation and in patients with intermediate- or high-risk meningioma undergoing radiotherapy. Secondary To study the concordance, or lack thereof, between central and parent institution histopathologic diagnosis, grading, and subtyping. To estimate the rates of overall survival at 3 years in these patients. To estimate the incidence rates of acute and late adverse events ≥ grade 2 in patients with intermediate- or high-risk meningioma undergoing radiotherapy. To evaluate MRI imaging predictors by central neuroradiology review at diagnosis, at any failure, and at 3 years. To evaluate adherence to protocol-specific target and normal tissue radiotherapy parameters. This is a multicenter study. Patients are assigned to 1 of 3 groups according to risk. After completion of study treatment, patients are followed up every 3-6 months for 3 years and then annually for 10 years.

Official Title
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Phase II Trial of Observation for Low-Risk Meningiomas and of Radiotherapy for Intermediate- and High-Risk Meningiomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Radiation: 54 Gy radiotherapy
* Radiation: 60 Gy radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A histologically documented World Health Organization (WHO) grade I, II, or III meningioma, newly diagnosed or recurrent, and of any resection extent, confirmed by central pathology review. Patients are partitioned according to three groupings: Group I (low risk), Group II (intermediate risk), and Group III (high risk) as defined below: Group I (low risk): Patients with a newly diagnosed WHO grade I meningioma that has been gross totally resected (Simpson's grade I, II, or III resections, with no residual nodular enhancement on postoperative imaging) or subtotally resected (residual nodular enhancement or Simpson grade IV or V excision). The extent of resection will be based upon the neurosurgeons' assessment and postoperative MR imaging. Group II (intermediate risk): Patients with a newly diagnosed gross totally resected WHO grade II meningioma or patients with a recurrent WHO grade I meningioma irrespective of the resection extent. Resection extent will be recorded on the same basis described above for the low-risk group. Group III (high risk): Patients with a newly diagnosed or a recurrent WHO grade III meningioma of any resection extent; patients with a recurrent WHO grade II meningioma of any resection extent; or patients with a newly diagnosed subtotally resected WHO grade II meningioma. In the setting of a newly diagnosed meningioma, the histologic diagnosis must have been reached within 6 months of Step 2 registration. Resection extent will be recorded on the same basis described above for the low-risk group. 1.1 In the setting of a newly diagnosed meningioma, the histologic diagnosis must have been reached within 24 weeks prior to Step 2 registration. In the setting of a recurrent meningioma, there are no such time constraints. Additional resection or biopsy is encouraged for patients with recurrence but is not requisite. If further biopsy or resection is performed at recurrence, these specimens must be submitted; submission of the original pathology specimens is encouraged but not required. The diagnosis of recurrence solely on the basis of imaging findings is permitted, but if no additional resection is performed, specimens from prior resection must be submitted. 1.2 In cases of newly diagnosed or surgically treated recurrent meningioma, the operating neurosurgeon must provide a Simpson grade for the degree of resection. History/physical examination, including neurologic examination, within 8 weeks prior to Step 2 registration Zubrod Performance Status 0-1 Age ≥ 18 All patients must have a magnetic resonance imaging (MRI) scan within 12 weeks prior to Step 2 registration. Both preoperative and postoperative MRIs are required for all newly diagnosed patients in groups I, II, or III. In the setting of group II or III patients with recurrent/progressive meningioma and without recent surgery, a pre-operative study may not apply, although MRI documentation of recurrence or progression is required. MRIs must include precontrast T1, T2, and flair images and multiplanar (axial, sagittal, and coronal) postcontrast T1. The postoperative study must be completed within 12 weeks of surgery. 5.1 Group I: All group I patients will have surgery. Preoperative and postoperative MRIs are thus required in order to assess resection extent. 5.2 Group II: Surgery will be undertaken for the subgroup with a gross totally resected WHO grade II meningioma. For these patients preoperative and postoperative MRIs are necessitated. For the other subgroup with recurrent WHO grade I meningioma, preoperative and postoperative MRIs are required if surgery is undertaken for the recurrent/progressive tumor. However, only the follow-up imaging documenting recurrence or progression will apply if further surgery is not completed. 5.3 Group III: Surgery will be undertaken for the subgroup with a newly diagnosed WHO grade III meningioma. For these patients preoperative and postoperative MRIs are obligatory. For the subgroups with recurrent WHO grade II or III meningioma, preoperative and postoperative MRIs are required if surgery is undertaken for the recurrent/progressive tumor. However, only the follow-up imaging documenting recurrence or progression will apply if further surgery is not completed. For woman of childbearing potential who are intermediate or high risk: 6.1 Negative serum pregnancy test within 14 days prior to Step 2 registration 6.2 The patient must agree to practice adequate contraception from the time of the negative serum pregnancy test throughout the entire course of EBRT. Patient must sign study-specific informed consent prior to study entry Exclusion Criteria: Extracranial meningioma Multiple meningiomas Hemangiopericytoma Major medical illnesses or psychiatric impairments which, in the investigators opinion, will prevent administration or completion of the protocol therapy or preclude informed consent Previous radiation therapy to the scalp, cranium, brain, or skull base Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) Patients with severe, active comorbidity including, but not restricted to: 7.1 Unstable angina and/or congestive heart failure requiring hospitalization at the time of Step 2 registration 7.2 Transmural myocardial infarction within the last 6 months 7.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of Step 2 registration 7.4 Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of Step 2 registration 7.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. Note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. 7.6 Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. 7.7 Active connective tissue disorders such as lupus or scleroderma if the patient is intermediate or high risk Inability to receive gadolinium

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Low Risk<br>No treatment given. | |
| Experimental: Intermediate Risk<br>54 Gy radiotherapy | Radiation: 54 Gy radiotherapy<br>* External beam radiation therapy (EBRT) to a total dose of 54 Gy (RBE) in 30 fractions. 1.8 Gy (RBE) daily, 5 fractions per week, excluding weekends. 3D-CRT or IMRT or Proton allowed.<br>* Other names: Intensity-modulated radiation therapy (IMRT);|
| Experimental: High Risk<br>60 Gy radiotherapy | Radiation: 60 Gy radiotherapy<br>* External beam radiation therapy using intensity-modulated radiation therapy (IMRT) to a total dose of 60 Gy in 30 fractions. 2.0 Gy daily, 5 fractions per week, excluding weekends.<br>* Other names: Intensity-modulated radiation therapy (IMRT);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate at 3 Years | Progression was determined by central review of magnetic resonance imaging (MRI) exams and is defined as an increase in measurable tumor of greater than 20% in any diameter, or as new nodular enhancement in patients with no measurable tumor on initial postoperative imaging. In the absence of neurologic progression (NP), suspected imaging progression of less than 5 mm (maximum diameter) must be confirmed on two successive follow-up MRI studies, a minimum of 3 months apart. NP is defined as a new or progressive neurologic deficit attributed to the meningioma, with or without measurable meningioma growth. Progression-free survival (PFS) rates are estimated using the binomial method. | From registration to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grades 2-5 Acute Adverse Events in the Following Categories Individually and Combined: Neurology, Ocular/Visual, Dermatologic/Skin [Excluding Alopecia] | Grades 2-5 neurology, ocular/visual, dermatologic/skin [excluding alopecia] categories, individually and combined for acute adverse events as assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0 where the attribution is related to treatment as definite, probable, possible, or unknown. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From start of radiation to 90 days. | 
| Number of Patients With Grades 2-5 Late Adverse Events in the Following Categories Individually and Combined: Neurology, Ocular/Visual, Dermatologic/Skin [Excluding Alopecia] | Grades 2-5 neurology, ocular/visual, dermatologic/skin [excluding alopecia] categories, individually and combined for acute adverse events as assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0 where the attribution is related to treatment as definite, probable, possible, or unknown. Late adverse events are those occurring more than 90 days from start of radiation therapy. | Ninety-one days from start of radiation therapy to last follow-up. Maximum follow-up at time of analysis was 6.3 years. | 
| Overall Survival Rate at 3 Years | Overall survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From registration to 3 years | 
| Progression-free Survival Rate at 3 Years (Kaplan-Meier Method) | Progression was determined by central review of MRI exams and is defined as an increase in measurable tumor of greater than 20% in any diameter, or as new nodular enhancement in patients with no measurable tumor on initial postoperative imaging. In the absence of neurologic progression (NP), suspected imaging progression of less than 5 mm (maximum diameter) must be confirmed on two successive follow-up MRI studies, a minimum of 3 months apart. NP is defined as a new or progressive neurologic deficit attributed to the meningioma, with or without measurable meningioma growth. Progression-free survival time is defined as time from registration to the date of progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. | From registration to 3 years | 
| Number of Participants Determined to Have MRI Imaging Features as Assessed by Central Neuroradiology Review at Diagnosis, at Progression, and at 3 Years | MRI's were centrally reviewed by the study neuroradiology co-chairs for presence of edema, homogeneous enhancement, calcification, hyperostosis, and brain invasion. Data is presented for all risk groups combined, with time points presented in each column. Neither risk groups nor time points are compared. | Baseline, at time of first progression, and at 3 years | 
| Greatest Single Dimension From MRI as Assessed by Central Neuroradiology Review at Diagnosis, at Progression, and at 3 Years | MRI's were centrally reviewed by the study neuroradiology co-chairs. Data is presented for all risk groups combined, with time points presented in each column. Neither risk groups nor time points are compared. | Baseline, at time of first progression, and at 3 years | 
| Adherence to Protocol-specific Target and Normal Tissue Radiotherapy Parameters | The principle investigator performed a radiotherapy quality assurance (QA) review. | After treatment delivery | 
| Concordance Between Central and Parent Institution Histopathologic Grading/Subtyping | A pathology review was conducted both by the institution and centrally, with three possible choices for grade / subtype: World Health Organization (WHO) Grade I / benign; WHO grade II / atypical; WHO grade III / anaplastic. Data is presented for all risk groups combined. | Baseline | 
| Molecular Correlative Studies |  | From registration to 3 years | 
| Histopathologic Correlates of PFS Including Light Microscopy, Immunohistochemical Analysis, and Microarray Analysis |  | From registration to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult grade I meningioma, adult grade II meningioma, adult grade III meningioma, adult anaplastic meningioma, adult papillary meningioma, recurrent adult brain tumor