Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01399372
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 91
• Locations: 45
• Arms: 2
• Duration (Months): 128.6
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chemotherapeutic Agent Toxicity; Cognitive/Functional Effects; Lymphoma; Neurotoxicity; Radiation Toxicity	Biological: Rituximab; Drug: Cytarabine; Drug: Methotrexate; Drug: Procarbazine; Drug: Vincristine; Radiation: low-dose whole-brain radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine median progression-free survival (PFS) in both arms on an intent-to-treat basis.

Secondary

• To determine overall survival (OS) defined as the interval from randomization to death due to any cause.

• 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 health-related quality-of-life and symptoms over time.

• 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Study of Rituximab, Methotrexate, Procarbazine, Vincristine, and Cytarabine With and Without Low-Dose Whole-Brain Radiotherapy for Primary Central Nervous System Lymphoma
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Mar 19, 2020
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Chemotherapy Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Biological: Rituximab; One 28-day cycle = 500 mg/m^2 intravenously on day 1 and day 5.; Drug: Cytarabine; One 28-day cycle = 3 g/m^2 intravenously on day 1 and day 2.; Drug: Methotrexate; One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.; Other Names: MTX ; Drug: Procarbazine; One 28-day cycle = 100 mg/m^2 orally on days 2-8.; Drug: Vincristine; One 28-day cycle = 1.4 mg/m^2 intravenously, dose capped at 2.4mg, on day 2 and day 16.
Experimental: Chemotherapy + Low-Dose WBRT Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.	Biological: Rituximab; One 28-day cycle = 500 mg/m^2 intravenously on day 1 and day 5.; Drug: Cytarabine; One 28-day cycle = 3 g/m^2 intravenously on day 1 and day 2.; Drug: Methotrexate; One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.; Other Names: MTX ; Drug: Procarbazine; One 28-day cycle = 100 mg/m^2 orally on days 2-8.; Drug: Vincristine; One 28-day cycle = 1.4 mg/m^2 intravenously, dose capped at 2.4mg, on day 2 and day 16.; Radiation: low-dose whole-brain radiation therapy; Total dose of 2340 cGy administered as 13 daily fractions of 180 cGy over 3 weeks. Participants with progressive disease on magnetic resonance imaging (MRI) do not receive WBRT.; Other Names: WBRT

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.]

   Progression is defined as any of the following: more than 25% increase in the contrast-enhancing lesion seen on magnetic resonance imaging (MRI) compared with baseline or best response; new site of disease (central nervous system or systemic); recurrent or new ocular disease; recurrent or positive cerebrospinal fluid (CSF) cytology. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.

Secondary Outcome Measures

1. Overall Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.]

   Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.

2. Percentage of Participants Experiencing Partial Response or Complete Response [After 4th cycle of chemotherapy, approximately 4 months after randomization.]

   Response was evaluated using the international criteria proposed by the International Primary Central Nervous System Lymphoma (PCNSL) Study Group criteria. Complete Response was defined as no contrast brain enhancement on magnetic resonance imaging (MRI), no corticosteroid use for at least 2 weeks, a normal eye exam, and negative CSF cytology. Partial response was defined as at least 50% decrease in enhancing tumor on MRI compared with baseline imaging, no or minor retinal pigment epithelium (RPE) abnormality, and negative CSF cytology.

3. Quality of Life Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core/Brain Cancer Module (QLQ-C30/BCM20) [From start of treatment to five years.]

4. Neurocognitive Function Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part A, Trail Making Test Part B, Controlled Oral Word Association Test (COWAT) [From start of treatment to five years.]

5. Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment [At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 7.3 years.]

   Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events reported as definitely, probably, or possibly related to protocol treatment are considered to be related to treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. B-cell non-Hodgkin's lymphoma(NHL) involving the brain, as demonstrated by contrast-enhanced Magnetic resonance imaging (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 non-Hodgkin's lymphoma

• Brain biopsy

Note: Patients in whom the type of lymphoma could not be determined or is unknown (eg, not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible.

1. The patient must agree to submit tissue (i.e., the original H/E stained slides and immunohistochemistry studies) for central pathology review post-registration.

2. No evidence of systemic non-Hodgkin lymphoma as demonstrated by a computed tomography (CT) scan of the chest, abdomen and pelvis within 6 weeks prior to registration (Note: Bone marrow biopsy is not required for registration but must be obtained prior to start of treatment.)

3. Age ≥ 18

4. History and physical examination within 6 weeks of registration

5. Karnofsky performance status (KPS) equal to 50 or higher, with the following exception

• Patients with 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)

1. Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study registration (Separate counseling and consent as per institutional guidelines)

2. Complete blood count (CBC)/differential obtained within 2 weeks prior to study registration, with adequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

• Platelets ≥ 100,000 cells/mm3;

• Hemoglobin (Hgb) ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.);

1. Adequate liver function within 2 weeks prior to study registration, defined as follows:

• Bilirubin < 2.0 mg/dl

• Aspartate aminotransferase (AST) <2.5 times upper limit of normal

1. Adequate renal function within 2 weeks prior to study registration, defined as follows

• Serum creatinine < 1.5 mg/dl

• Calculated creatinine clearance (CrCl) > 50cc/min/1.73m2, using the

Cockcroft-Gault equation, as follows:

Male: CrCl (ml/min) = (140-age) X (Actual weight in kg) / 72 x serum Creatinine (mg/dl).

Female: CrCl (ml/min) = (140-age) X (Actual weight in kg) X 0.85 / 72 x serum Creatinine (mg/dl).

Note: A measured CrCl from a 24 hour urine collection may also be used.

1. Women of childbearing potential and male participants must agree to practice adequate contraception during therapy

2. Patient must provide study-specific informed consent prior to study registration

3. Patient must be able to swallow pills.

Exclusion Criteria:

1. 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)

2. Prior treatment with chemotherapy or radiotherapy for lymphoma or chronic lymphocytic leukemia; note that prior chemotherapy for a different cancer is allowable; see section 1

3. Prior cranial irradiation

4. 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; note, however, that 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.

1. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

2. Prior allergic reaction to any of the study drugs involved in this protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	The Kirklin Clinic at Acton Road	Birmingham	Alabama	United States	35243
3	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
4	Arizona Oncology-Deer Valley Center	Phoenix	Arizona	United States	85027
5	Arizona Oncology Services Foundation	Scottsdale	Arizona	United States	85260
6	Fresno Cancer Center	Fresno	California	United States	93720
7	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California	United States	95670
8	Rohnert Park Cancer Center	Rohnert Park	California	United States	94928
9	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California	United States	95678
10	South Sacramento Cancer Center	Sacramento	California	United States	95823
11	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California	United States	95051
12	Kaiser Permanente Cancer Treatment Center	South San Francisco	California	United States	94080
13	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
14	Moffitt Cancer Center	Tampa	Florida	United States	33612
15	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
16	Northwestern University	Chicago	Illinois	United States	60611
17	Rush University Medical Center	Chicago	Illinois	United States	60612
18	Loyola University Medical Center	Maywood	Illinois	United States	60153
19	Cadence Cancer Center in Warrenville	Warrenville	Illinois	United States	60555
20	Maine Medical Center-Bramhall Campus	Portland	Maine	United States	04102
21	Maine Medical Center- Scarborough Campus	Scarborough	Maine	United States	04074
22	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
23	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
24	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
25	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
26	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
27	Memorial Sloan Kettering Cancer Center at Basking Ridge	Basking Ridge	New Jersey	United States	07920
28	Memorial Sloan Kettering Cancer Center Commack	Commack	New York	United States	11725
29	Columbia University Medical Center	New York	New York	United States	10032
30	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
31	University of Rochester	Rochester	New York	United States	14642
32	University of Cincinnati	Cincinnati	Ohio	United States	45267
33	Case Western Reserve University	Cleveland	Ohio	United States	44106
34	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
35	University Pointe	West Chester	Ohio	United States	45069
36	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
37	American College of Radiology Imaging Network	Philadelphia	Pennsylvania	United States	19103
38	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
39	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
40	M D Anderson Cancer Center CCOP Research Base	Houston	Texas	United States	77030
41	M D Anderson Cancer Center	Houston	Texas	United States	77030
42	Community Memorial Hospital	Menomonee Falls	Wisconsin	United States	53051
43	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
44	Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
45	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Antonio Omuro, MD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 19, 2019
• Informed Consent Form - Sep 19, 2019

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01399372
• Other Study ID Numbers: RTOG 1114; CDR0000703682; NCI-2011-02678
• First Posted: Jul 21, 2011
• Last Update Posted: Jun 21, 2022
• Last Verified: May 1, 2022

• Keywords provided by Radiation Therapy Oncology Group: neurotoxicity; chemotherapeutic agent toxicity; radiation toxicity; cognitive/functional effects; primary central nervous system non-Hodgkin lymphoma
• Additional relevant MeSH terms: Lymphoma; Neurotoxicity Syndromes; Cytarabine; Rituximab; Methotrexate; Vincristine; Procarbazine

Study Results

Participant Flow

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Period Title: Overall Study
STARTED	47	44
Eligible	44	43
Eligible and Started Protocol Treatment	43	43
COMPLETED	44	43
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT	Total
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.	Total of all reporting groups
Overall Participants	44	43	87
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	59.5	66	63
Sex: Female, Male (Count of Participants)
Female	22 50%	20 46.5%	42 48.3%
Male	22 50%	23 53.5%	45 51.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.3%	1 2.3%	2 2.3%
Not Hispanic or Latino	38 86.4%	37 86%	75 86.2%
Unknown or Not Reported	5 11.4%	5 11.6%	10 11.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 13.6%	2 4.7%	8 9.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	33 75%	37 86%	70 80.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	5 11.4%	4 9.3%	9 10.3%
Karnofsky Performance Status (KPS) (Count of Participants)
30-50	5 11.4%	6 14%	11 12.6%
60-80	23 52.3%	22 51.2%	45 51.7%
90-100	16 36.4%	15 34.9%	31 35.6%
Neurologic Symptoms (Count of Participants)
None	8 18.2%	7 16.3%	15 17.2%
Minor	15 34.1%	16 37.2%	31 35.6%
Moderate	18 40.9%	14 32.6%	32 36.8%
Severe	3 6.8%	6 14%	9 10.3%
Memorial Sloan-Kettering Cancer Center (MSKCC) Recursive Partitioning analysis (RPA) Class (Count of Participants)
Class 1	7 15.9%	6 14%	13 14.9%
Class 2	26 59.1%	25 58.1%	51 58.6%
Class 3	11 25%	12 27.9%	23 26.4%
Ocular Involvement (Count of Participants)
Count of Participants [Participants]	3 6.8%	0 0%	3 3.4%
Cerebrospinal fluid (CSF) Involvement (Count of Participants)
Count of Participants [Participants]	5 11.4%	6 14%	11 12.6%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression is defined as any of the following: more than 25% increase in the contrast-enhancing lesion seen on magnetic resonance imaging (MRI) compared with baseline or best response; new site of disease (central nervous system or systemic); recurrent or new ocular disease; recurrent or positive cerebrospinal fluid (CSF) cytology. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Measure Participants	44	43
Median (95% Confidence Interval) [years]	2.1	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chemotherapy, Chemotherapy + Low-Dose WBRT
	Comments	Sample size of 89 provided 80% power to detect a hazard ratio of 0.63 at a one-sided alpha level of 0.15.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	One-sided significance level = 0.15
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference arm = Chemotherapy

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Measure Participants	44	43
Median (95% Confidence Interval) [years]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chemotherapy, Chemotherapy + Low-Dose WBRT
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments	Two-sided significance level = 0.05
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference arm = Chemotherapy

3. Secondary Outcome

Title	Percentage of Participants Experiencing Partial Response or Complete Response
Description	Response was evaluated using the international criteria proposed by the International Primary Central Nervous System Lymphoma (PCNSL) Study Group criteria. Complete Response was defined as no contrast brain enhancement on magnetic resonance imaging (MRI), no corticosteroid use for at least 2 weeks, a normal eye exam, and negative CSF cytology. Partial response was defined as at least 50% decrease in enhancing tumor on MRI compared with baseline imaging, no or minor retinal pigment epithelium (RPE) abnormality, and negative CSF cytology.
Time Frame	After 4th cycle of chemotherapy, approximately 4 months after randomization.

Outcome Measure Data

Analysis Population Description

Eligible participants with Cycle 4 disease assessment data

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Measure Participants	30	31
Number (95% Confidence Interval) [percentage of participants]	83.3 189.3%	80.6 187.4%

4. Secondary Outcome

Title	Quality of Life Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core/Brain Cancer Module (QLQ-C30/BCM20)
Time Frame	From start of treatment to five years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Neurocognitive Function Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part A, Trail Making Test Part B, Controlled Oral Word Association Test (COWAT)
Time Frame	From start of treatment to five years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment
Description	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events reported as definitely, probably, or possibly related to protocol treatment are considered to be related to treatment.
Time Frame	At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 7.3 years.

Outcome Measure Data

Analysis Population Description

Eligible participants who started protocol treatment

Arm/Group Title	Chemotherapy	Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Measure Participants	43	43
None	2 4.5%	3 7%
Grade 1	3 6.8%	6 14%
Grade 2	4 9.1%	5 11.6%
Grade 3	20 45.5%	15 34.9%
Grade 4	14 31.8%	13 30.2%
Grade 5	0 0%	1 2.3%

Adverse Events

Time Frame	At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years. Maximum follow-up at time of analysis was 7.3 years.
Adverse Event Reporting Description	All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Arm/Group Title	Chemotherapy		Chemotherapy + Low-Dose WBRT
Arm/Group Description	Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.		Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
All Cause Mortality
	Chemotherapy		Chemotherapy + Low-Dose WBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/44 (6.8%)		1/43 (2.3%)
Serious Adverse Events
	Chemotherapy		Chemotherapy + Low-Dose WBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/43 (51.2%)		21/43 (48.8%)
Blood and lymphatic system disorders
Anemia	6/43 (14%)		5/43 (11.6%)
Blood and lymphatic system disorders - Other	0/43 (0%)		1/43 (2.3%)
Febrile neutropenia	3/43 (7%)		1/43 (2.3%)
Cardiac disorders
Heart failure	1/43 (2.3%)		0/43 (0%)
Sinus tachycardia	0/43 (0%)		1/43 (2.3%)
Gastrointestinal disorders
Diarrhea	1/43 (2.3%)		0/43 (0%)
Gastric ulcer	1/43 (2.3%)		0/43 (0%)
Ileus	1/43 (2.3%)		0/43 (0%)
Mucositis oral	1/43 (2.3%)		0/43 (0%)
Nausea	1/43 (2.3%)		1/43 (2.3%)
Rectal hemorrhage	1/43 (2.3%)		0/43 (0%)
Retroperitoneal hemorrhage	1/43 (2.3%)		0/43 (0%)
Small intestinal obstruction	1/43 (2.3%)		0/43 (0%)
Upper gastrointestinal hemorrhage	1/43 (2.3%)		0/43 (0%)
Vomiting	1/43 (2.3%)		0/43 (0%)
General disorders
Death NOS	0/43 (0%)		1/43 (2.3%)
Fatigue	1/43 (2.3%)		0/43 (0%)
Fever	1/43 (2.3%)		2/43 (4.7%)
Hypothermia	0/43 (0%)		1/43 (2.3%)
Non-cardiac chest pain	1/43 (2.3%)		0/43 (0%)
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/43 (2.3%)		0/43 (0%)
Infections and infestations
Appendicitis perforated	1/43 (2.3%)		0/43 (0%)
Catheter related infection	0/43 (0%)		1/43 (2.3%)
Infections and infestations - Other	1/43 (2.3%)		1/43 (2.3%)
Lung infection	5/43 (11.6%)		1/43 (2.3%)
Sepsis	3/43 (7%)		1/43 (2.3%)
Skin infection	1/43 (2.3%)		0/43 (0%)
Urinary tract infection	2/43 (4.7%)		1/43 (2.3%)
Injury, poisoning and procedural complications
Fall	1/43 (2.3%)		0/43 (0%)
Fracture	1/43 (2.3%)		0/43 (0%)
Injury, poisoning and procedural complications - Other	1/43 (2.3%)		0/43 (0%)
Spinal fracture	0/43 (0%)		1/43 (2.3%)
Investigations
Alanine aminotransferase increased	3/43 (7%)		0/43 (0%)
Aspartate aminotransferase increased	1/43 (2.3%)		0/43 (0%)
Blood bilirubin increased	1/43 (2.3%)		0/43 (0%)
Creatinine increased	0/43 (0%)		2/43 (4.7%)
Investigations - Other	1/43 (2.3%)		1/43 (2.3%)
Lymphocyte count decreased	2/43 (4.7%)		1/43 (2.3%)
Neutrophil count decreased	3/43 (7%)		5/43 (11.6%)
Platelet count decreased	5/43 (11.6%)		1/43 (2.3%)
White blood cell decreased	4/43 (9.3%)		1/43 (2.3%)
Metabolism and nutrition disorders
Anorexia	1/43 (2.3%)		1/43 (2.3%)
Dehydration	1/43 (2.3%)		1/43 (2.3%)
Hypoglycemia	1/43 (2.3%)		0/43 (0%)
Hypokalemia	0/43 (0%)		1/43 (2.3%)
Hyponatremia	1/43 (2.3%)		1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	2/43 (4.7%)		0/43 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	2/43 (4.7%)		0/43 (0%)
Nervous system disorders
Depressed level of consciousness	1/43 (2.3%)		2/43 (4.7%)
Dizziness	1/43 (2.3%)		0/43 (0%)
Edema cerebral	0/43 (0%)		1/43 (2.3%)
Headache	1/43 (2.3%)		0/43 (0%)
Hydrocephalus	1/43 (2.3%)		0/43 (0%)
Nervous system disorders - Other	0/43 (0%)		1/43 (2.3%)
Peripheral sensory neuropathy	1/43 (2.3%)		0/43 (0%)
Seizure	1/43 (2.3%)		0/43 (0%)
Stroke	0/43 (0%)		1/43 (2.3%)
Syncope	1/43 (2.3%)		0/43 (0%)
Psychiatric disorders
Anxiety	0/43 (0%)		1/43 (2.3%)
Confusion	0/43 (0%)		2/43 (4.7%)
Renal and urinary disorders
Acute kidney injury	1/43 (2.3%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/43 (2.3%)		0/43 (0%)
Dyspnea	1/43 (2.3%)		0/43 (0%)
Hypoxia	2/43 (4.7%)		1/43 (2.3%)
Pleural effusion	1/43 (2.3%)		0/43 (0%)
Pneumonitis	0/43 (0%)		1/43 (2.3%)
Productive cough	1/43 (2.3%)		0/43 (0%)
Pulmonary edema	1/43 (2.3%)		1/43 (2.3%)
Respiratory failure	2/43 (4.7%)		0/43 (0%)
Vascular disorders
Hypotension	3/43 (7%)		0/43 (0%)
Thromboembolic event	2/43 (4.7%)		5/43 (11.6%)
Other (Not Including Serious) Adverse Events
	Chemotherapy		Chemotherapy + Low-Dose WBRT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/43 (97.7%)		43/43 (100%)
Blood and lymphatic system disorders
Anemia	34/43 (79.1%)		30/43 (69.8%)
Blood and lymphatic system disorders - Other	3/43 (7%)		3/43 (7%)
Leukocytosis	0/43 (0%)		3/43 (7%)
Cardiac disorders
Sinus tachycardia	3/43 (7%)		2/43 (4.7%)
Ear and labyrinth disorders
Hearing impaired	1/43 (2.3%)		4/43 (9.3%)
Eye disorders
Blurred vision	7/43 (16.3%)		5/43 (11.6%)
Eye disorders - Other	6/43 (14%)		4/43 (9.3%)
Gastrointestinal disorders
Abdominal pain	3/43 (7%)		3/43 (7%)
Constipation	21/43 (48.8%)		21/43 (48.8%)
Diarrhea	8/43 (18.6%)		9/43 (20.9%)
Dyspepsia	3/43 (7%)		2/43 (4.7%)
Gastrointestinal disorders - Other	3/43 (7%)		3/43 (7%)
Mucositis oral	7/43 (16.3%)		4/43 (9.3%)
Nausea	23/43 (53.5%)		15/43 (34.9%)
Vomiting	8/43 (18.6%)		6/43 (14%)
General disorders
Chills	4/43 (9.3%)		0/43 (0%)
Edema limbs	12/43 (27.9%)		5/43 (11.6%)
Fatigue	31/43 (72.1%)		38/43 (88.4%)
Fever	7/43 (16.3%)		5/43 (11.6%)
Gait disturbance	3/43 (7%)		5/43 (11.6%)
Infusion related reaction	4/43 (9.3%)		0/43 (0%)
Pain	10/43 (23.3%)		7/43 (16.3%)
Infections and infestations
Infections and infestations - Other	1/43 (2.3%)		4/43 (9.3%)
Mucosal infection	3/43 (7%)		4/43 (9.3%)
Skin infection	2/43 (4.7%)		4/43 (9.3%)
Upper respiratory infection	3/43 (7%)		0/43 (0%)
Urinary tract infection	4/43 (9.3%)		9/43 (20.9%)
Injury, poisoning and procedural complications
Bruising	1/43 (2.3%)		3/43 (7%)
Fall	1/43 (2.3%)		5/43 (11.6%)
Investigations
Activated partial thromboplastin time prolonged	1/43 (2.3%)		4/43 (9.3%)
Alanine aminotransferase increased	28/43 (65.1%)		25/43 (58.1%)
Alkaline phosphatase increased	16/43 (37.2%)		20/43 (46.5%)
Aspartate aminotransferase increased	25/43 (58.1%)		22/43 (51.2%)
Blood bilirubin increased	6/43 (14%)		6/43 (14%)
Creatinine increased	6/43 (14%)		15/43 (34.9%)
Investigations - Other	6/43 (14%)		6/43 (14%)
Lymphocyte count decreased	20/43 (46.5%)		22/43 (51.2%)
Neutrophil count decreased	19/43 (44.2%)		20/43 (46.5%)
Platelet count decreased	27/43 (62.8%)		26/43 (60.5%)
Weight gain	4/43 (9.3%)		5/43 (11.6%)
Weight loss	4/43 (9.3%)		6/43 (14%)
White blood cell decreased	22/43 (51.2%)		22/43 (51.2%)
Metabolism and nutrition disorders
Anorexia	12/43 (27.9%)		9/43 (20.9%)
Hypercalcemia	6/43 (14%)		4/43 (9.3%)
Hyperglycemia	19/43 (44.2%)		15/43 (34.9%)
Hyperkalemia	3/43 (7%)		7/43 (16.3%)
Hypermagnesemia	2/43 (4.7%)		3/43 (7%)
Hypernatremia	7/43 (16.3%)		8/43 (18.6%)
Hypoalbuminemia	19/43 (44.2%)		19/43 (44.2%)
Hypocalcemia	14/43 (32.6%)		19/43 (44.2%)
Hypoglycemia	5/43 (11.6%)		7/43 (16.3%)
Hypokalemia	20/43 (46.5%)		13/43 (30.2%)
Hypomagnesemia	3/43 (7%)		2/43 (4.7%)
Hyponatremia	11/43 (25.6%)		6/43 (14%)
Hypophosphatemia	3/43 (7%)		4/43 (9.3%)
Metabolism and nutrition disorders - Other	3/43 (7%)		5/43 (11.6%)
Musculoskeletal and connective tissue disorders
Back pain	5/43 (11.6%)		5/43 (11.6%)
Bone pain	5/43 (11.6%)		4/43 (9.3%)
Generalized muscle weakness	5/43 (11.6%)		7/43 (16.3%)
Muscle weakness left-sided	3/43 (7%)		5/43 (11.6%)
Muscle weakness lower limb	5/43 (11.6%)		2/43 (4.7%)
Musculoskeletal and connective tissue disorder - Other	2/43 (4.7%)		5/43 (11.6%)
Myalgia	4/43 (9.3%)		0/43 (0%)
Pain in extremity	4/43 (9.3%)		8/43 (18.6%)
Nervous system disorders
Ataxia	4/43 (9.3%)		2/43 (4.7%)
Cognitive disturbance	4/43 (9.3%)		5/43 (11.6%)
Dizziness	8/43 (18.6%)		4/43 (9.3%)
Dysarthria	2/43 (4.7%)		3/43 (7%)
Dysgeusia	3/43 (7%)		1/43 (2.3%)
Headache	16/43 (37.2%)		19/43 (44.2%)
Lethargy	0/43 (0%)		3/43 (7%)
Memory impairment	5/43 (11.6%)		9/43 (20.9%)
Paresthesia	7/43 (16.3%)		4/43 (9.3%)
Peripheral motor neuropathy	4/43 (9.3%)		8/43 (18.6%)
Peripheral sensory neuropathy	17/43 (39.5%)		13/43 (30.2%)
Seizure	3/43 (7%)		5/43 (11.6%)
Psychiatric disorders
Agitation	5/43 (11.6%)		2/43 (4.7%)
Anxiety	11/43 (25.6%)		11/43 (25.6%)
Confusion	4/43 (9.3%)		5/43 (11.6%)
Depression	8/43 (18.6%)		4/43 (9.3%)
Insomnia	13/43 (30.2%)		10/43 (23.3%)
Renal and urinary disorders
Acute kidney injury	3/43 (7%)		4/43 (9.3%)
Hematuria	3/43 (7%)		1/43 (2.3%)
Proteinuria	2/43 (4.7%)		4/43 (9.3%)
Renal and urinary disorders - Other	0/43 (0%)		3/43 (7%)
Urinary frequency	7/43 (16.3%)		2/43 (4.7%)
Urinary incontinence	3/43 (7%)		4/43 (9.3%)
Urinary retention	4/43 (9.3%)		4/43 (9.3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/43 (0%)		3/43 (7%)
Cough	9/43 (20.9%)		9/43 (20.9%)
Dyspnea	7/43 (16.3%)		7/43 (16.3%)
Epistaxis	5/43 (11.6%)		2/43 (4.7%)
Hoarseness	2/43 (4.7%)		3/43 (7%)
Hypoxia	4/43 (9.3%)		2/43 (4.7%)
Respiratory, thoracic and mediastinal disorders - Other	1/43 (2.3%)		4/43 (9.3%)
Sore throat	2/43 (4.7%)		3/43 (7%)
Skin and subcutaneous tissue disorders
Alopecia	6/43 (14%)		10/43 (23.3%)
Dry skin	3/43 (7%)		5/43 (11.6%)
Pruritus	4/43 (9.3%)		3/43 (7%)
Rash acneiform	3/43 (7%)		1/43 (2.3%)
Rash maculo-papular	4/43 (9.3%)		5/43 (11.6%)
Skin and subcutaneous tissue disorders - Other	1/43 (2.3%)		3/43 (7%)
Vascular disorders
Hypertension	7/43 (16.3%)		4/43 (9.3%)
Hypotension	3/43 (7%)		1/43 (2.3%)
Thromboembolic event	7/43 (16.3%)		2/43 (4.7%)

Limitations/Caveats

A planned interim efficacy analysis was performed after 42 events (death or progression). The final analysis was planned to occur after 67 events. The Data Monitoring Committee (DMC) recommended releasing the interim results for early reporting and these results are considered the final study results.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.