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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00895622
• Other study ID #: RTOG-0539
• Secondary ID: CDR0000641815
• Status: Completed
• Phase: Phase 2
• Start date: June 2009
• Est. completion date: August 15, 2023

Study information

• Verified date: August 2023
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 244
• Est. completion date: August 15, 2023
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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.

2. History/physical examination, including neurologic examination, within 8 weeks prior to Step 2 registration

3. Zubrod Performance Status 0-1

4. Age = 18

5. 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.

6. 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.

7. Patient must sign study-specific informed consent prior to study entry

Exclusion Criteria:

1. Extracranial meningioma

2. Multiple meningiomas

3. Hemangiopericytoma

4. Major medical illnesses or psychiatric impairments which, in the investigators opinion, will prevent administration or completion of the protocol therapy or preclude informed consent

5. Previous radiation therapy to the scalp, cranium, brain, or skull base

6. 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)

7. 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

8. Inability to receive gadolinium

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Meningioma
• Nervous System Neoplasms

Intervention

Radiation:
• 54 Gy radiotherapy
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.
• 60 Gy radiotherapy
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.

Locations

Country	Name	City	State
Canada	Cross Cancer Institute at University of Alberta	Edmonton	Alberta
Canada	Hopital Notre-Dame du CHUM	Montreal	Quebec
Canada	McGill Cancer Centre at McGill University	Montreal	Quebec
Canada	Ottawa Hospital Regional Cancer Centre - General Campus	Ottawa	Ontario
United States	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio
United States	Emory Crawford Long Hospital	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland
United States	Barberton Citizens Hospital	Barberton	Ohio
United States	Mary Bird Perkins Cancer Center - Baton Rouge	Baton Rouge	Louisiana
United States	Billings Clinic - Downtown	Billings	Montana
United States	Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center	Boise	Idaho
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois
United States	Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Grant Medical Center Cancer Care	Columbus	Ohio
United States	Riverside Methodist Hospital Cancer Care	Columbus	Ohio
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	University of Texas Medical Branch	Galveston	Texas
United States	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	M. D. Anderson Cancer Center at University of Texas	Houston	Texas
United States	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kansas City Cancer Centers - North	Kansas City	Missouri
United States	Kansas City Cancer Centers - South	Kansas City	Missouri
United States	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas
United States	Sparrow Regional Cancer Center	Lansing	Michigan
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Norton Suburban Hospital	Louisville	Kentucky
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin
United States	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin
United States	Lake/University Ireland Cancer Center	Mentor	Ohio
United States	Baptist-South Miami Regional Cancer Program	Miami	Florida
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah
United States	Yale Cancer Center	New Haven	Connecticut
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Regional Cancer Center at Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	Nebraska Medical Center	Omaha	Nebraska
United States	Kansas City Cancer Centers - Southwest	Overland Park	Kansas
United States	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania
United States	Arizona Oncology Services Foundation	Phoenix	Arizona
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	St. Joseph Mercy Oakland	Pontiac	Michigan
United States	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan
United States	CCOP - Kansas City	Prairie Village	Kansas
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	Highland Hospital of Rochester	Rochester	New York
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan
United States	Dixie Regional Medical Center - East Campus	Saint George	Utah
United States	Norris Cotton Cancer Center - North	Saint Johnsbury	Vermont
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	Regions Hospital Cancer Care Center	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Center for Cancer Medicine and Blood Disorders - Scarborough	Scarborough	Maine
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	University Cancer Center at University of Washington Medical Center	Seattle	Washington
United States	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center	Spartanburg	South Carolina
United States	Baystate Regional Cancer Program at D'Amour Center for Cancer Care	Springfield	Massachusetts
United States	Door County Cancer Center at Door County Memorial Hospital	Sturgeon Bay	Wisconsin
United States	St. John Macomb Hospital	Warren	Michigan
United States	Waukesha Memorial Hospital Regional Cancer Center	Waukesha	Wisconsin

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Rogers CL, Perry A, Pugh S, Vogelbaum MA, Brachman D, McMillan W, Jenrette J, Barani I, Shrieve D, Sloan A, Bovi J, Kwok Y, Burri SH, Chao ST, Spalding AC, Anscher MS, Bloom B, Mehta M. Pathology concordance levels for meningioma classification and gradin — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Adherence to Protocol-specific Target and Normal Tissue Radiotherapy Parameters	The principle investigator performed a radiotherapy quality assurance (QA) review.	After treatment delivery
Secondary	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
Secondary	Molecular Correlative Studies		From registration to 3 years
Secondary	Histopathologic Correlates of PFS Including Light Microscopy, Immunohistochemical Analysis, and Microarray Analysis		From registration to 3 years