RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different
ways. Some find cancer cells and help kill them or carry cancer-killing substances to them.
Others interfere with the ability of cancer cells to grow and spread. Drugs used in
chemotherapy, such as methotrexate, vincristine sulfate, procarbazine hydrochloride, and
cytarabine, work in different ways to stop the growth of cancer cells, either by killing the
cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill
cancer cells. It is not yet know whether rituximab and combination chemotherapy are more
effective when given with or without radiation therapy in treating patients with primary
central nervous system lymphoma.
PURPOSE: This randomized phase II trial studies how well giving rituximab and combination
chemotherapy with or without radiation therapy works in treating patients with primary
central nervous system lymphoma.
- To determine median progression-free survival (PFS) in both arms on an intent-to-treat
- To determine overall survival (OS) defined as the interval from randomization to death
- To determine treatment-related neurotoxicity rates and disease-related cognitive
deterioration in each arm, through the following methods: prospective formal
neuropsychological evaluation, utilizing competing-risk methodology to account for
death as a competing risk to neurotoxicity or cognitive deterioration from relapsed
tumor burden/salvage treatment and incidence of clinically defined neurotoxicity as per
investigator's assessment.
- To determine if there exists differences between the two treatment arms in terms of
- To determine response (partial response (PR) and complete response (CR)) rate after
methotrexate-based chemotherapy and after consolidation whole-brain radiotherapy
(WBRT).
- To determine chemotherapy-related toxicity, measured by Common Toxicity Criteria for
Adverse Effects (CTCAE), v. 4.0.
OUTLINE: This is a multicenter study. Patients are stratified according to Memorial
Sloan-Kettering Cancer Center recursive-partitioning analysis (RPA) classification for
primary central nervous system lymphoma on age and Karnofsky performance status (KPS) (Class
1: age ≤ 50 years vs Class 2: age > 50 years and KPS ≥ 70% vs Class 3: age > 50 years and
KPS < 70%). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive rituximab IV over 5 hours or per institutional guidelines on
days 1 and 15, methotrexate IV over 2 hours on days 2 and 16, vincristine sulfate IV on
days 2 and 16 (courses 1 and 2 only), and procarbazine hydrochloride orally (PO) on
days 2-8. Treatment repeats every 28 days for 4 courses in the absence of disease
progression or unacceptable toxicity. Patients then receive consolidation therapy
comprising cytarabine IV over 3 hours on days 1-2. Treatment repeats every 28 days for
2 courses in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive rituximab, methotrexate, vincristine sulfate, and procarbazine
hydrochloride as in arm I. After completing chemotherapy (2-5 weeks later), patients
without progressive disease undergo low-dose whole-brain radiotherapy once daily, 5
days a week, for approximately 2. 5 weeks (13 fractions total). Patients then receive
consolidation cytarabine as in arm I.
Patients may undergo blood and buccal sample collection for future correlative studies.
Paraffin-embedded tissue block of primary tumor or a core tumor tissue punched from the
tissue block, and cerebrospinal fluid may also be collected.
Patients may also complete the Hopkins Verbal Learning Test-Revised (HVLT-R), the Trail
Making Test Part A and Part B, the Controlled Oral Word Association Test (COWAT), and the
Quality of Life (QOL) questionnaires at baseline and periodically during study.
After completion of study therapy, patients are followed up every 2 months for 2 years and
then every 6 months for 3 years.
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
DISEASE CHARACTERISTICS:
- B-cell non-Hodgkin lymphoma (NHL) involving the brain, as demonstrated by contrasted
MRI and histologic confirmation by one of the following within 6 weeks prior to
registration:
- A positive cerebral spinal fluid (CSF) cytology for lymphoma or a monoclonal
lymphocyte population as defined by cell surface markers
- A biopsy of the vitreous or uvea demonstrating NHL
- Brain biopsy
- Patients in whom the type of lymphoma could not be determined or is unknown
(e. g., not enough tissue for further analysis) are assumed to have a B-cell
lymphoma and are eligible
- Patient must agree to submit tissue (i. e., the original H/E-stained slides and
immunohistochemistry studies) for central pathology review post-registration
- No evidence of systemic NHL as demonstrated by a CT scan of the chest, abdomen, and
pelvis within 6 weeks prior to registration
- Bone marrow biopsy is not required for registration but must be obtained prior
to start of treatment
PATIENT CHARACTERISTICS:
- History and physical examination within 6 weeks of registration
- Karnofsky performance status (KPS) equal to 50% or higher, with the following
exception:
- KPS 30% to 50% are eligible if the reason for the poor performance status is
neurologic deficit from primary central nervous system (CNS) lymphoma
- Patients with KPS 30% to 50% due to reasons other than primary CNS lymphoma
are ineligible
- Patients with KPS under 30% for any reason are ineligible
- Absolute neutrophil count (ANC) ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Hemoglobin (Hgb) ≥ 8. 0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8. 0
g/dL is acceptable)
- Bilirubin < 2. 0 mg/dL
- Aspartate aminotransferase (AST) < 2. 5 times upper limit of normal
- Serum creatinine < 1. 5 mg/dL
- Calculated creatinine clearance (CrCl) > 50 cc/min (CrCl from a 24-hour urine
collection may also be used)
- Women of childbearing potential and male participants must agree to practice adequate
contraception during therapy
- Patient must be able to swallow pills
- Patient must have documentation of negative HIV-1 testing within 6 weeks prior to
study registration
- No 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)
- No severe, active co-morbidity, defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days before
registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
- Laboratory tests for liver function and coagulation parameters are not
required for entry into this protocol
- Known pre-existing immunodeficiency as seen in organ transplant recipient
- No prior allergic reaction to any of the study drugs involved in this protocol
PRIOR CONCURRENT THERAPY:
- No prior treatment with chemotherapy or radiotherapy for lymphoma or chronic
lymphocytic leukemia
- Prior chemotherapy for a different cancer is allowable
- No prior cranial irradiation
- No concurrent intensity-modulated radiotherapy
Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel; Active, not recruiting
The Kirklin Clinic at Acton Road, Birmingham, Alabama 35243, United States; Active, not recruiting
University of Alabama at Birmingham, Birmingham, Alabama 35294, United States; Active, not recruiting
Arizona Oncology-Deer Valley Center, Phoenix, Arizona 85027, United States; Active, not recruiting
Arizona Oncology Services Foundation, Scottsdale, Arizona 85260, United States; Recruiting
David G. Brachman, Phone: 800-360-6371
David G. Brachman, Principal Investigator
Kaiser Permanente-Rancho Cordova Cancer Center, Rancho Cardova, California 95670, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
Rohnert Park Cancer Center, Rohnert Park, California 94928, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
The Permanente Medical Group-Roseville Radiation Oncology, Roseville, California 95678, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
South Sacramento Cancer Center, Sacramento, California 95823, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
Kaiser Permanente Medical Center - Santa Clara, Santa Clara, California 95051, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
Kaiser Permanente Cancer Treatment Center, South San Francisco, California 94080, United States; Recruiting
Samantha A. Seaward, Phone: 626-564-3455
Samantha A. Seaward, Principal Investigator
Penrose-Saint Francis Healthcare, Colorado Springs, Colorado 80907, United States; Recruiting
Alan T. Monroe, Phone: 888-785-6789
Alan T. Monroe, Principal Investigator
Cancer Specialists of North Florida-Beaches, Jacksonville Beach, Florida 32250, United States; Withdrawn
Cancer Specialists of North Florida-Southside, Jacksonville, Florida 32207, United States; Withdrawn
Edna Williams Cancer Center at the Baptist Cancer Institute, Jacksonville, Florida 32207, United States; Withdrawn
Cancer Specialists of North Florida-Baptist South, Jascksonville, Florida 32258, United States; Withdrawn
Cancer Specialists of North Florida-Orange Park, Orange Park, Florida 32073, United States; Withdrawn
Cancer Specialists of North Florida-Putnam, Palatka, Florida 32177, United States; Withdrawn
Cancer Specialists of North Florida-Saint Augustine, Saint Augustine, Florida 32086, United States; Withdrawn
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States; Recruiting
Peter A. Forsyth, Phone: 800-456-7121, Email: canceranswers@moffitt.org
Peter A. Forsyth, Principal Investigator
Saint Alphonsus Regional Medical Center, Boise, Idaho 83706, United States; Recruiting
Samir Narayan, Phone: 734-712-4673
Samir Narayan, Principal Investigator
Northwestern University, Chicago, Illinois 60611, United States; Recruiting
Jeffrey J. Raizer, Phone: 312-695-1301, Email: cancer@northwestern.edu
Jeffrey J. Raizer, Principal Investigator
Rush University Medical Center, Chicago, Illinois 60612, United States; Recruiting
Reem Karmali, Phone: 312-942-5498, Email: clinical_trials@rush.edu
Reem Karmali, Principal Investigator
Loyola University Medical Center, Maywood, Illinois 60153, United States; Terminated
Cadence Cancer Center in Warrenville, Warrenville, Illinois 60555, United States; Recruiting
Vinai Gondi, Phone: 630-352-5300
Vinai Gondi, Principal Investigator
Maine Medical Center-Bramhall Campus, Portland, Maine 04102, United States; Recruiting
Ian J. Bristol, Phone: 207-396-8090, Email: wrighd@mmc.org
Ian J. Bristol, Principal Investigator
Maine Medical Center- Scarborough Campus, Scarborough, Maine 04074, United States; Recruiting
Ian J. Bristol, Phone: 207-396-8090, Email: wrighd@mmc.org
Ian J. Bristol, Principal Investigator
University of Maryland/Greenebaum Cancer Center, Baltimore, Maryland 21201, United States; Recruiting
Navesh K. Sharma, Phone: 800-888-8823
Navesh K. Sharma, Principal Investigator
Saint Joseph Mercy Hospital, Ann Arbor, Michigan 48106-0995, United States; Recruiting
Samir Narayan, Phone: 734-712-4673
Samir Narayan, Principal Investigator
West Michigan Cancer Center, Kalamazoo, Michigan 49007, United States; Recruiting
Raymond S. Lord, Phone: 269-373-7458
Raymond S. Lord, Principal Investigator
Nevada Cancer Research Foundation CCOP, Las Vegas, Nevada 89106, United States; Recruiting
John A. Ellerton, Phone: 702-384-0013
John A. Ellerton, Principal Investigator
Memorial Sloan Kettering Cancer Center at Basking Ridge, Basking Ridge, New Jersey 07920, United States; Active, not recruiting
Memorial Sloan Kettering Cancer Center Commack, Commack, New York 11725, United States; Active, not recruiting
Columbia University Medical Center, New York, New York 10032, United States; Active, not recruiting
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Recruiting
Antonio M. Omuro, Phone: 212-639-7202
Antonio M. Omuro, Principal Investigator
University of Rochester, Rochester, New York 14642, United States; Recruiting
Yuhchyau Chen, Phone: 585-275-5830
Yuhchyau Chen, Principal Investigator
University of Cincinnati, Cincinnati, Ohio 45267, United States; Recruiting
Kevin P. Redmond, Phone: 513-558-4553, Email: uchealthnews@uc.edu
Kevin P. Redmond, Principal Investigator
Case Western Reserve University, Cleveland, Ohio 44106, United States; Recruiting
Erin S. Murphy, Phone: 866-223-8100
Erin S. Murphy, Principal Investigator
Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States; Recruiting
Erin S. Murphy, Phone: 866-223-8100
Erin S. Murphy, Principal Investigator
University Pointe, West Chester, Ohio 45069, United States; Recruiting
Kevin P. Redmond, Phone: 513-558-4553, Email: uchealthnews@uc.edu
Kevin P. Redmond, Principal Investigator
Natalie Warren Bryant Cancer Center at Saint Francis, Tulsa, Oklahoma 74136, United States; Withdrawn
Geisinger Medical Center, Danville, Pennsylvania 17822-2001, United States; Recruiting
Thomas J. Gergel, Phone: 570-271-5251
Thomas J. Gergel, Principal Investigator
American College of Radiology Imaging Network, Philadelphia, Pennsylvania 19103, United States; Recruiting
Antonio M. Omuro, Phone: 212-639-7523, Email: omuroa@mskcc.org
Antonio M. Omuro, Principal Investigator
Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, United States; Recruiting
Jon Glass, Phone: 215-955-6084
Jon Glass, Principal Investigator
Geisinger Wyoming Valley, Wilkes-Barre, Pennsylvania 18711, United States; Recruiting
Thomas J. Gergel, Phone: 570-271-5251
Thomas J. Gergel, Principal Investigator
M D Anderson Cancer Center, Houston, Texas 77030, United States; Active, not recruiting
M D Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Ivo W. Tremont, Phone: 504-340-6976
Ivo W. Tremont, Principal Investigator
University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States; Recruiting
Chul S. Ha, Phone: 210-567-0653, Email: che@uthscsa.edu
Chul S. Ha, Principal Investigator
Community Memorial Hospital, Menomonee Falls, Wisconsin 53051, United States; Recruiting
Joseph A. Bovi, Phone: 414-805-4380
Joseph A. Bovi, Principal Investigator
Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States; Recruiting
Joseph A. Bovi, Phone: 414-805-4380
Joseph A. Bovi, Principal Investigator
Waukesha Memorial Hospital - ProHealth Care, Waukesha, Wisconsin 53188, United States; Recruiting
Wingate F. Clapper, Phone: 262-928-7632
Wingate F. Clapper, Principal Investigator