Clinical trial NCT01399372
Conditions: Chemotherapeutic Agent Toxicity Cognitive/Functional Effects Lymphoma Neurotoxicity Radiation Toxicity
Keywords: neurotoxicity chemotherapeutic agent toxicity radiation toxicity cognitive/functional effects primary central nervous system non-Hodgkin lymphoma
Sponsor: Radiation Therapy Oncology Group
Start date: 2011-09-01; Completion date: 2022-05-20
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Rituximab intervention 2: Cytarabine intervention 3: Methotrexate intervention 4: Procarbazine intervention 5: Vincristine intervention 6: low-dose whole-brain radiation therapy
Intervention descriptions: intervention 1: One 28-day cycle = 500 mg/m\^2 intravenously on day 1 and day 5. intervention 2: One 28-day cycle = 3 g/m\^2 intravenously on day 1 and day 2. intervention 3: One 28-day cycle = 3.5 g/m\^2 intravenously (standard hydration/leucovorin support) on day 2. intervention 4: One 28-day cycle = 100 mg/m\^2 orally on days 2-8. intervention 5: One 28-day cycle = 1.4 mg/m\^2 intravenously, dose capped at 2.4mg, on day 2 and day 16. intervention 6: 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.

Protocol documents:
Prot_SAP_000.pdf: 
NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 1114 
 
(ClinicalTrials.gov NCT #: 01399372) 
 
 
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 
 
 
 
Amendment 10:  September 19, 2019 


1 
RTOG 1114: version date September 19, 2019 
NRG ONCOLOGY GROUP 
 
RTOG 1114 
 
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 Chairs (23-AUG-2019) 
Principal Investigator/Medical Oncology Co-Chair  
Antonio Omuro, MD 
Yale Cancer Center 
15 York Street, LLCI 920 
New Haven, CT 06510 
203-797-7084/FAX 203-737-2591 
Antonio.omuro@yale.edu 
 
Co-Principal Investigator/Medical Oncology Co-Chair 
Lisa M. DeAngelis, MD 
Memorial Sloan Kettering Cancer Center 
Department of Neurology  
1275 York Avenue 
New York, NY 10065 
212-639-7997/FAX 212-717-3296 
deangell@mskcc.org  
 
Radiation Oncology Co-Chair 
Joseph A. Bovi, MD 
Department of Radiation Oncology 
Froedtert Memorial Lutheran Hospital 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53222 
414-805-4477/FAX 414-805-4369 
JBovi@mcw.edu 
 
Pathology Co-Chair 
Marc Rosenblum, MD 
Memorial Sloan Kettering Cancer Center 
Department of Pathology  
1275 York Avenue 
New York, NY 10065 
212-639-3844/FAX 646-422-2070 
rosenbl1@mskcc.org 
 
 
Quality of Life Co-Chair  
Benjamin Corn, MD 
Sha'are Zedek Medical Center 
12 Shmuel Bait Street 
Jerusalem, Israel 91031-02 
011-972-52-426-6533/FAX 011-972-4-657-7520 
bencorn@szmc.org.il  
 
Neurocognitive Function Co-Chair 
Denise Correa, PhD 
Memorial Sloan-Kettering Cancer Center  
Department of Neurology  
1275 York Avenue 
New York, NY 10065 
646-888-3177/646-888-3175 
corread@mskcc.org 
 
Jeffrey S. Wefel, PhD 
U.T. M.D. Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX  77030 
713-563-0514/FAX 713-794-4999 
jwefel@mdanderson.org 
 
Neuro-imaging Co-Chair 
Sanjay Aneja, MD 
Yale School of Medicine 
Department of Therapeutic Radiology 
15 York Street 
Hunter Building, HRT 135 
New Haven, CT 06510 
303-200-2100/ FAX 203-737-1467 
Sanjay.Aneja@yale.edu 
 
Senior Statistician 
Theodore Karrison, PhD  
University of Chicago and NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19013 
773-702-9326 
karrisont@nrgoncology.org 
 
 
 
 
 
 
(Continued from previous page) 


2 
RTOG 1114: version date September 19, 2019 
 
RTOG 1114 
 
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  
 
Protocol Agent (1/31/13) 
Agent 
Supply 
NSC # 
IND # 
Rituximab 
Commercial 
N/A 
Exempt 
Methotrexate (MTX) 
Commercial 
N/A 
Exempt 
Vincristine 
Commercial 
N/A 
Exempt 
Procarbazine 
Commercial 
N/A 
Exempt 
Cytarabine 
Commercial 
N/A 
Exempt 
 
Participating Sites(1/31/13)  
 
(NOTE: This study is not open to Canadian sites, due to rituximab distribution.) 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 10 
September 19, 2019 
NA 
Amendment 9 
August 23, 2019 
N/A 
Amendment 8 
August 7, 2018 
N/A 
Closure 
N/A 
January 15, 2016 
Amendment 7 
August 25, 2015 
September 14, 2015 
Amendment 6 
January 27, 2015 
February 10, 2015 
Amendment 5 
April 17, 2014 
April 29, 2014 
Amendment 4 
October 28, 2013 
November 12, 2013 
Amendment 3 
January 31, 2013 
February 12, 2013 
Update 
May 15, 2012 
May 15, 2012 
Amendment 2 
April 23, 2012 
May 15, 2012 
Amendment 1 
March 30, 2012 
April 2, 2012 
Update 
September 30, 2011 
September 30, 2011 
Update 
September 7, 2011 
September 7, 2011 
Activation 
N/A 
September 7, 2011 
Current version 
August 15, 2011 
September 7, 2011 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 


3 
RTOG 1114: version date September 19, 2019 
Table of Contents 
 
SCHEMA ....................................................................................................................................................... 5 
ELIGIBILITY CHECKLIST ............................................................................................................................. 6 
 
1.0 
INTRODUCTION ............................................................................................................................... 9 
1.1 
Health-Related Quality of Life and Neurocognitive Function ............................................................. 10 
 
2.0 
OBJECTIVES .................................................................................................................................. 12 
2.1 
Primary............................................................................................................................................... 12 
2.2 
Secondary .......................................................................................................................................... 12 
 
3.0 
PATIENT SELECTION .................................................................................................................... 12 
3.1 
Conditions for Patient Eligibility ......................................................................................................... 12 
3.2 
Conditions for Patient Ineligibility ....................................................................................................... 13 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT ..................................................................... 14 
4.1 
Required Evaluations/Management .................................................................................................. 14 
4.2 
Highly Recommended Evaluations/Management ............................................................................. 14 
 
5.0 
REGISTRATION PROCEDURES ..................................................................................................... 14 
5.1 
Regulatory Pre-Registration Requirements ....................................................................................... 15 
5.2 
Pre-Registration Requirements for Neurocognitive Function Testing Certification ........................... 16 
5.3 
Registration ........................................................................................................................................ 16 
 
6.0 
RADIATION THERAPY................................................................................................................... 17 
6.1 
Dose Specifications ........................................................................................................................... 17 
6.2 
Technical Factors .............................................................................................................................. 18 
6.3 
Localization, Simulation, and Immobilization ..................................................................................... 18 
6.4 
Treatment Planning/Target Volumes ................................................................................................. 18 
6.5 
Documentation Requirements ........................................................................................................... 21 
6.6 
Compliance Criteria ........................................................................................................................... 21 
6.7 
R.T. Quality Assurance Reviews ....................................................................................................... 21 
6.8 
Radiation Therapy Adverse Events ................................................................................................... 21 
6.9 
Radiation Therapy Adverse Event Reporting .................................................................................... 21 
 
7.0 
DRUG THERAPY ............................................................................................................................ 21 
7.1 
Treatment Arms ................................................................................................................................. 21 
7.2 
Agents ................................................................................................................................................ 23 
7.3 
Rituximab Agent Information ............................................................................................................. 24 
7.4 
Methotrexate (MTX) Agent Information ............................................................................................. 25 
7.5 
Procarbazine Agent Information ........................................................................................................ 25 
7.6 
Vincristine Agent Information ............................................................................................................. 26 
7.7 
Cytarabine Agent Information ............................................................................................................ 26 
7.8 
Dose Modifications ............................................................................................................................ 27 
7.9 
Modality Review ................................................................................................................................. 29 
7.10 Adverse Events .................................................................................................................................. 30 
7.11 CTEP-AERS  Expedited Reporting Requirements ............................................................................ 31 
 
8.0 
SURGERY ...................................................................................................................................... 32 
 
9.0 
OTHER THERAPY .......................................................................................................................... 33 
9.1 
Permitted Supportive Therapy ........................................................................................................... 33 
9.2 
Non-permitted Supportive Therapy ................................................................................................... 33 
 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 34 
10.1 Tissue/Specimen Submission ........................................................................................................... 34 
10.2 Specimen Collection for Central Review ........................................................................................... 34 


4 
RTOG 1114: version date September 19, 2019 
10.3 Specimen Collection for Tissue Banking and Translational Research .............................................. 34 
10.4 Submit materials for Tissue Banking and Translational Research as follows: .................................. 36 
10.6 Confidentiality/Storage....................................................................................................................... 36 
10.7 Translational Research Description ................................................................................................... 37 
 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 38 
11.1 Study Parameters. ............................................................................................................................. 38 
11.2 Neurocognitive Function (NCF) Assessment .................................................................................... 39 
11.3 Quality of Life (QOL) Assessment ..................................................................................................... 39 
11.4 Measurement of Response ............................................................................................................... 40 
11.5 Criteria for Discontinuation of Protocol Treatment ............................................................................ 42 
 
12.0 
DATA COLLECTION ....................................................................................................................... 42 
12.1 Summary of Data Submission  .......................................................................................................... 42 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 44 
13.1 Study Endpoints ................................................................................................................................. 44 
13.2 Sample Size and Power Justification ................................................................................................ 44 
13.3 Patient Accrual ................................................................................................................................... 44 
13.4 Stratification and Randomization ....................................................................................................... 44 
13.5 Analyses Plans .................................................................................................................................. 44 
13.6 Gender and Minorities ....................................................................................................................... 47 
 
REFERENCES ............................................................................................................................................ 49 
APPENDIX I ................................................................................................................................................ 51 
APPENDIX II ............................................................................................................................................... 53 
APPENDIX III .............................................................................................................................................. 54 
APPENDIX IV  ............................................................................................................................................. 61 
APPENDIX V ............................................................................................................................................... 67 
APPENDIX VI .............................................................................................................................................. 68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5 
RTOG 1114: version date September 19, 2019 
NRG ONCOLOGY 
 
 
RTOG 1114 
 
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  
 
 
SCHEMA 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
RPA 
Class 
 
Class 1: 
age ≤ 50 
 
Class 2: 
age > 50 
and KPS 
≥ 70 
 
Class 3: 
age >50 
and KPS 
< 70 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
Arm A  
(chemo 
only) 
R-
MPV 
Cycle 
1 
R-
MPV 
Cycle 
2 
R-MP 
Cycle 3 
(no 
vincristine) 
R-MP 
Cycle 4 
(no 
vincristine) 
 
Ara-
C 
Cycle 
1 
Ara-
C 
Cycle 
2 
 
Arm B  
(chemo + 
low-dose 
WBRT) 
 
R-
MPV 
Cycle 
1 
 
R-
MPV 
Cycle 
2 
 
R-MP 
Cycle 3 
(no 
vincristine) 
 
R-MP 
Cycle 4 
(no 
vincristine) 
 
Low-
Dose 
WBRT 
(13 fx) 
 
Ara-
C 
Cycle 
1 
 
Ara-
C 
Cycle 
2 
 
1 cycle = 28 days 
(8 MTX doses total) 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
 
B-cell non-Hodgkin's lymphoma involving the brain, as demonstrated by contrasted MRI and histologic 
confirmation by one of the following within 6 weeks prior to registration:  
o 
A positive CSF cytology for lymphoma or a monoclonal lymphocyte population as defined by cell 
surface markers 
o 
A biopsy of the vitreous or uvea demonstrating non-Hodgkin's lymphoma 
o 
Brain biopsy  
 
 
 
 
 
 
Required Sample Size: 89 patients 
  


6 
RTOG 1114: version date September 19, 2019 
ELIGIBILITY CHECKLIST (4/17/14) 
(page 1 of 3) 
NRG Oncology Institution #   
 
RTOG 1114 
 
 
 
 
Case #  
 
 
 
 
 
______(Y) 
1.  Does the patient have B-cell non-Hodgkin's lymphoma involving the brain, as demonstrated 
by contrast-enhance MRI and histologic confirmation by one of the following within 6 weeks 
prior to registration?  
____(Y/N) 
A positive CSF cytology for lymphoma or a monoclonal lymphocyte population as defined 
by cell surface markers 
____(Y/N) 
 
A biopsy of the vitreous or uvea demonstrating non-Hodgkin's lymphoma 
____(Y/N) 
 
Brain biopsy  
 
_______ (Y) 
2. Did the patient agree to submit tissue (ie, the original or duplicate cut H/E stained slides and 
immunohistochemistry studies) for central pathology review post-registration? 
 
_______ (Y) 
3. Did the patient show no evidence of systemic non-Hodgkin lymphoma as demonstrated by a 
CT scan of the chest, abdomen and pelvis within 6 weeks prior to registration? 
 
_______ (Y) 
4. Is the patient’s age ≥ 18? 
 
_______ (Y) 
5. Did the patient have a history and physical examination within 6 weeks prior to registration? 
 
_______ (Y/N) 6. Is the patient’s Karnofsky performance status ≥ 50? 
_______ (Y)  
If no, is the patient’s Karnofsky performance status ≥ 30.   
_______ (Y) 
Is the reason for the poor performance status due to neurologic deficit from primary CNS 
lymphoma? Note that if the reason is other than primary CNS lymphoma, the patient 
is not eligible.  
 
_______ (Y) 
7. Is there documentation of negative HIV-1 testing within 6 weeks prior to study registration? 
 
_______ (Y) 
8. Was a CBC/differential obtained within 2 weeks prior to study registration, with adequate 
bone marrow function per Section 3.1.8? 
 
_______ (Y) 
9. Does the patient have adequate liver function within 2 weeks prior to study registration per 
Section 3.1.9? 
 
_______ (Y) 
10. Does the patient have adequate renal function within 2 weeks prior to study registration per 
Section 3.1.10? 
 
_______ (Y) 
11. If the patient is a woman of childbearing potential or a male, has the patient agreed to 
practice adequate contraception during therapy? 
 
_______ (Y) 
12. Has the patient provided study-specific informed consent prior to study registration? 
 
_______ (Y/N) 13. Did the patient have prior invasive malignancy per Section 3.2.1? 
 
_______ (Y) 
If yes, is patient disease free for a minimum of 3 years? 
 
_______ (N) 
14. Did the patient have prior treatment with chemotherapy or radiotherapy for  lymphoma or 
chronic lymphocytic leukemia? Note: prior chemotherapy for a different cancer is allowable. 


7 
RTOG 1114: version date September 19, 2019 
 
NRG Oncology Institution #   
 
RTOG 1114 
 
 
 
ELIGIBILITY CHECKLIST (4/17/14) 
Case #  
 
 
 
     (page 2 of 3)  
 
_______ (N) 
15. Did the patient have prior cranial irradiation? 
 
_______ (N) 
16. Does the patient have a severe, active co-morbidity as defined in Section 3.2.4? 
 
_______ (N) 
17. Did the patient have a prior allergic reaction to any of the study drugs involved in this 
protocol? 
_______ (Y) 
18.  Is the patient able to swallow pills? 
 
 
 
The following questions will be asked at Study Registration:  
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
(≤50/>50) 
18. 
Age 
 
(≥70/˂70)  
19. 
Karnofsky performance status 
 
 
         
20. 
Medical oncologist’s name  
 
 
 


8 
RTOG 1114: version date September 19, 2019 
NRG Oncology Institution #   
 
RTOG 1114 
 
 
 
ELIGIBILITY CHECKLIST (4/17/14) 
Case #  
 
 
 
     (page 3 of 3)  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her bone marrow/eye biopsy to be kept 
for use in research to learn about, prevent, treat, or cure cancer? 
 
              (Y/N) 
23. 
Have you obtained the patient's consent for his or her cerebrospinal fluid to be kept for 
use in research to learn about, prevent, treat, or cure cancer? 
 
              (Y/N) 24.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 25. 
Have you obtained the patient's consent for his or her buccal cells to be kept for use in 
research to learn about, prevent, treat, or cure cancer? 
 
              (Y/N) 26. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, Alzheimer's 
disease, and heart disease)?   
 
              (Y/N) 27. 
Have you obtained the patient's consent for his or her bone marrow/eye biopsy to be kept 
for use in research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)? 
 
              (Y/N) 28. 
Have you obtained the patient's consent for his or her cerebrospinal fluid to be kept for 
use in research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)? 
 
              (Y/N) 29. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's disease, or 
heart disease).  
 
              (Y/N) 30. 
Have you obtained the patient's consent for his or her buccal cells to be kept for use in 
research about other health problems (for example: causes of diabetes, Alzheimer's 
disease, and heart disease)? 
 
              (Y/N) 31. 
Have you obtained the patient's consent to allow someone from this institution to contact 
him or her in the future to take part in more research?  
  
              (Y/N) 32. 
Did the patient agree to participate in the neurocognitive function/quality of life 
component? 
 
 
         
 
If no, please provide: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other: specify_________________ 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and 
dated checklist used at study entry must be retained in the patient’s study file and will be evaluated during an 
institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 


9 
RTOG 1114: version date September 19, 2019 
1.0 INTRODUCTION 
The optimal treatment for primary central nervous system lymphoma (PCNSL) remains controversial. 
Historically, WBRT and corticosteroids were considered a mainstay of treatment, achieving a median 
survival of 15-18 months and a 3% to 4% 5-year survival. In the 1990s, however, evidence emerged from 
retrospective studies that the addition of high-dose MTX improved survival in PCNSL. RTOG 93-10 
played a pivotal role in testing that hypothesis, as the first prospective study demonstrating the value of 
adding MTX to WBRT (DeAngelis 2002). That study, enrolling 102 patients, achieved a median 
progression-free survival (PFS) of 24 months and overall survival (OS) of 36.9 months. However, 
radiotherapy-related neurotoxicity emerged as a major complication of treatment in that and other studies 
of chemoradiation, affecting 16% to 24% of patients (Abrey 2000; Omuro 2005). Such patients develop a 
progressive frontal-subcortical dementia that eventually leads to death. Elderly patients are at particular 
risk, with neurotoxicity rates affecting up to 100% of those patients achieving long-term survival.  
Because of the risk of neurotoxicity, several studies tried to investigate the role of chemotherapy-only 
approaches in PCNSL. In a clinical trial of high-dose MTX (8g/m2) given as single agent without WBRT, a 
shorter PFS was observed (median PFS: 13 months), but the OS did not seem to be compromised 
(median: 55 m) (Batchelor 2003). However, it was unclear whether such short PFS was related to 
deferring WBRT or to the use of a single-agent regimen rather than a combination of drugs, which may be 
more effective. In another study of chemotherapy-only treatment for newly diagnosed PCNSL utilizing 
MTX 5 g/m2 and 5 other drugs, the PFS was substantially longer, particularly in young patients (median 
PFS: 20 months for the entire population and not reached in patients under age 60) (Pels 2003). 
However, the follow-up was relatively short (32 months), and when the same regimen was given without 
intrathecal (IT) chemotherapy in a second study by the same group, the median PFS was only 8 months 
(Pels 2009). Although it is possible that IT chemotherapy was important to improve disease control, it is 
unlikely that it would account for such a striking difference in outcomes. Therefore, results of the first 
study remain to be reproduced to confirm that an intensive chemotherapy-only regimen can replace 
WBRT in terms of disease control. In a retrospective study of 64 PCNSL patients younger than 60, 
patients who achieved a CR after induction chemotherapy were selected to receive maintenance therapy 
and no consolidation WBRT (Omuro 2010). The median PFS in those patients was 22 months, 
significantly below the expected for that population, but the 3-year OS was 69%, again suggesting that 
aggressive salvage therapy (in that study WBRT and/or high-dose chemotherapy with stem-cell rescue) 
was effective. Because approximately half of the patients required WBRT, neurotoxicity rates were 
reduced, but not eliminated. 
More recently, a large randomized study conducted in Germany has been reported (Thiel 2010). The 
study was initially designed to evaluate the role of consolidation WBRT following chemotherapy with MTX 
(4 g/m2). The protocol was then amended and ifosfamide was added.  A total of 551 patients were 
enrolled, but due to high dropout rates, 318 were analyzed. The study found no statistically significant 
differences in PFS or OS. The median PFS in the chemotherapy only arm was 12 months versus 18 
months in the WBRT arm (p=0.13); the OS was 37 versus 32 months (p=0.80). While remarkable for its 
size, this study is unfortunately limited by the high dropout rates, relatively inefficient and variable 
chemotherapy, underpowered non-inferiority design, and insufficient neurotoxicity evaluation. Regardless, 
findings seem to support the concept that omitting WBRT results in decreased PFS but not OS in PCNSL. 
It remains, however, unknown whether the potential reduction in WBRT-related neurotoxicity rates 
justifies the reduction in PFS and on the number of patients cured upfront. No prospective study has 
investigated the potentially negative impact of early relapses and salvage therapies on the cognitive 
function of long-term survivors and how that compares to the gains in decreased neurotoxicity rates. 
Nevertheless, chemotherapy-only treatments have become the preferred treatment strategy in the 
community.  
As an alternative approach, a study lead by MSKCC investigated the use of reduced-dose WBRT in 
newly diagnosed PCNSL (Shah 2007). In that phase II trial, patients received 5-7 cycles of R-MPV 
(rituximab, MTX, vincristine, procarbazine). Patients achieving a CR after chemotherapy received dose-
reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose 
cytarabine were administered after WBRT. The initial cohort of 30 patients has been published (Shah 
2007). Among the 21 patients achieving a CR, 19 received the planned 23.4 Gy WBRT. With a median 
follow-up of 37 months, the 2-year OS and PFS was 67% and 57%, respectively, and no treatment-
related neurotoxicity was observed (Correa 2009). Since then, the study has been amended to expand 
the sample size to 52 patients. Accrual has been completed, and a preliminary analysis (personal data) of 


10 
RTOG 1114: version date September 19, 2019 
the first 45 patients seems to confirm results of the pilot study. Thirty-one of the 45 patients have received 
a reduced-dose of 23.4 Gy WBRT. For the entire population, the median PFS has been 40 months and 
the median OS has not been reached after a median follow-up of 46 months. These results suggest that 
reduced-dose WBRT achieves disease control that is comparable to full-dose WBRT and likely superior 
to chemotherapy-only approaches, and that neurotoxicity rates were substantially decreased. However, 
because the R-MPV-A regimen has not been tested without radiotherapy, it is unclear whether the 
excellent results are due to a better drug combination or to the addition of reduced-dose WBRT. 
Therefore, to further evaluate this regimen, we are proposing a randomized phase II study in newly 
diagnosed PCNSL. The experimental arm will consist of R-MPV followed by reduced-dose radiotherapy, 
followed by consolidation cytarabine. The control arm will consist of a chemotherapy-only approach, with 
R-MPV followed by cytarabine, without WBRT. At progression, in both arms, patients will be treated at 
investigator’s discretion. However, to characterize the impact of both RT-related neurotoxicity and 
disease burden from relapses on cognitive function, all patients will undergo neuropsychological 
evaluation for 5 years, regardless of progression status.  
This study will therefore test the following hypotheses: 
 
We hypothesize that the addition of low-dose WBRT to R-MPV-A chemotherapy improves 
progression-free survival (PFS) in newly diagnosed primary central nervous system lymphoma in 
comparison to R-MPV-A alone. The primary endpoint will be median PFS.  
 
We hypothesize that the use of low-dose WBRT will result in improved long-term cognitive 
function outcomes in comparison to full-dose WBRT by decreasing radiation therapy–related 
neurotoxicity rates. All consenting patients will undergo neuropsychological evaluation throughout 
the study and results will be compared to historical controls. 
 
We hypothesize that the addition of low-dose WBRT to R-MPV-A will result in improved long-term 
cognitive function outcomes in comparison to R-MPV alone by decreasing the cognitive 
deterioration resulting from early disease recurrence and multiple salvage therapies associated 
with chemotherapy-only approaches. To capture the cognitive dysfunction associated with 
disease burden from relapses and salvage treatments, we will perform neuropsychological follow-
up in both arms for 5 years, regardless of disease status (including in patients with disease 
progression), and analyze results utilizing competing-risk methodology accounting for death.   
 
We hypothesize that the improved neurocognitive outcomes associated with R-MPV-A followed 
by low-dose WBRT will be achieved without compromising overall survival (OS). We will analyze 
OS in both arms and compare to historical RTOG data. 
 
1.1 
Health-Related Quality of Life and Neurocognitive Function 
The literature on formal evaluation of cognitive function, neurotoxicity and QOL in PCNSL is 
limited. The term “neurotoxicity” has been used to characterize treatment related cognitive 
dysfunction, but studies reporting on different clinical trials have used subjective definitions of 
“neurotoxicity”, ranging from noticeable cognitive changes found on a routine neurologic exam, to 
severe and fatal dementia. 
 
The recognition of neurotoxicity as a severe complication of combined chemo-radiotherapy in 
PCNSL arose from studies conducted in the 90’s (Abrey 2000, Deangelis 2002). None of these 
studies included formal measurements of cognitive function or quality of life. In these studies, 
which utilized full doses of WBRT, neurotoxicity was defined clinically as per investigator’s 
assessment. Typically, neurotoxicity was defined as progressively severe cognitive dysfunction 
with frontal-subcortical type of dementia, with associated urinary incontinence and gait ataxia. 
These symptoms resembled disease recurrence, but imaging only showed leukoencephalopathy. 
Most patients developing these symptoms died from neurotoxicity in the absence of disease 
recurrence. These studies utilizing qualitative definitions of neurotoxicity reported cumulative 
rates of 15-30%, with elderly (>60 yo) at the highest risk (up to 80-100% of long-term survivors). 
However, there is no information on milder cognitive dysfunction and corresponding impact on 
quality of life. Moreover, length of followup and absence of competing-risk methodology further 
limits the interpretation and comparison of such results. In spite of the lack of accurate 
characterization in these trials, neurotoxicity rates were considered alarming enough to warrant 


11 
RTOG 1114: version date September 19, 2019 
abandoning WBRT, at the expense of a decrease in PFS and in the number of patients cured 
upfront. 
 
In an effort to characterize the impact of WBRT in cognitive function and QOL in PCNSL patients, 
Correa et al (manuscript under review) has retrospectively investigated 50 PCNSL survivors in a 
cross-sectional study. In that study, the 24 patients who received WBRT at some point throughout 
their disease course were compared to 26 patients who never received WBRT. Patients treated 
with WBRT had statistically significantly lower scores on tests of selective attention and memory, 
in addition to impairment in other domains that did not reach statistical significance. QOL was 
measured with the FACT-BR and showed significantly higher scores (21.2 vs 29.1; p<0.003) in 
patients who received WBRT. It must be noted that patients who received WBRT as salvage 
therapy were included in the WBRT group. 
 
A smaller, cross-sectional, study in long-term young (<60y) PCNSL survivors treated with WBRT 
(Harder 2004) is available. That study evaluated neuropsychological assessment in addition to 
QOL as measured by the EORTC QLQ-C30 and BCM30 module, in comparison to a matched 
control group with hematologic malignancies treated with chemotherapy. Cognitive impairment 
was found in 63% of PCNSL, and only 47% of patients reported excellent QOL (score >5); 
moreover, several of the QOL subscores were significantly lower than the control population.  
 
Taken together, these two cross-sectional studies depict the cognitive and QOL consequences of 
radiotherapy in PCNSL survivors, but because of their inherent selection bias and retrospective 
nature, they do not provide adequate historical controls for evaluation of cognitive function and 
QOL for future trials.                    
                 
Conversely, the study conducted at MSKCC utilizing reduced-dose WBRT detailed above (Shah 
2007, Correa 2009) is the single prospective report on cognitive function and quality of life. In that 
study, Correa demonstrated that the reduced doses of radiotherapy did not result in significant 
cognitive impairment. Among the patients who completed the 2y follow-up, there was a 
continuous improvement in most of the domains tested, particularly the executive domain 
(p<0.05), although a minor, non-significant decline in verbal memory domain was observed. QOL 
was evaluated with the FACT-BR, which showed significant improvement in comparison to 
baseline, and stability over the 2y period, with no late decline. A limitation of this study is that 
manifestations of radiotherapy-related neurotoxicity are cumulative over time, and longer followup 
would be necessary for full characterization of treatment-related effects. 
 
As detailed above, evaluation of quality of life and neurocognitive function are important aspects 
of  this present study, as they may be affected by tumor burden, both at initial presentation and at 
relapse, as well by initial and salvage treatments with chemotherapy and radiotherapy (Omuro 
2005). Therefore, this study will incorporate comprehensive evaluation of these aspects, with all 
patients followed for 5 consecutive years regardless of tumor status.   
 
NRG Oncology has been successfully incorporating quality of life and neurocognitive function 
evaluation in the multicenter setting. This is exemplified by RTOG 0825, examining the role of 
bevacizumab in addition to chemoradiotherapy in glioblastomas. Given the high rates of 
compliance and quality of data being acquired in that study, we will utilize a similar battery of 
tests, consisting of the following: 
 
EORTC 
Quality 
of 
Life 
Questionnaire-Core 
30/Brain 
Cancer 
Module-20 
(EORTCQLQ30/BCM20) 
 
Neuropsychological evaluation:  
o 
- Memory:  Hopkins Verbal Learning Test-Revised (HVLT-R) 
o 
- Cognitive Processing Speed : Trail Making Test, Part A 
o 
- Executive Function: Trail Making Test, Part B 
o 
- Verbal fluency: Controlled Oral Word Association Test (COWAT) 
 
The EORTC core Quality of Life Questionnaire (QLQ-C30) and a Brain Cancer Module (BCM20) 
were developed and validated for use in this patient population (Osoba 1996). Extensive health-
related quality of life data were obtained during 1 randomized phase II study comparing 
temozolomide with procarbazine in patients with recurrent glioblastoma (Yung 2000). This study, 


12 
RTOG 1114: version date September 19, 2019 
which used the EORTC QLC-C30/BCM20, demonstrated an improvement in most domains 
tested. In addition to the randomized phase II trial described above, the EORTC QLQ-
C30/BCM20 has become the standard and has been used in many large cooperative group trials.  
 
 
The neuropsychological evaluation used in this study consists of a battery of standard, largely 
validated neurocognitive tests, which have been successfully applied in brain tumor clinical trials 
(Groves 1999, Levin 2002). This battery has been demonstrated to be practical in terms of cost 
and burden to the patient, with good compliance in multicenter trials (Meyers 2004). This battery 
also shares most of the tests with an internationally recognized battery to be utilized in primary 
CNS lymphoma (Correa 2009). Each institution will undergo a training and certification process, 
which is already being used for RTOG 0825.  
 
 
2.0 OBJECTIVES 
2.1 
Primary 
 
To determine median progression-free survival (PFS) in both arms on an intent-to-treat basis. 
PFS will be defined as the interval from randomization to progression or death, whichever occurs 
first. 
 
 
2.2 
Secondary  
2.2.1 
To determine overall survival (OS) defined as the interval from randomization to death due to 
any cause. 
2.2.2 
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. 
- Incidence of clinically defined neurotoxicity as per investigator’s assessment.  2.2.3 
To determine if 
there exists differences between the two treatment arms in terms of health-related quality of life 
and symptoms over time.   
2.2.4 
To determine response (partial response [PR] and complete response [CR]) rate after MTX-
based chemotherapy and after consolidation WBRT. 
2.2.5 
To determine chemotherapy-related toxicity, measured by CTCAE, v.4.0. 
 
 
3.0 PATIENT SELECTION 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
3.1 
Conditions for Patient Eligibility (10/28/13) 
For questions concerning eligibility, please contact the study data manager. 
 
3.1.1 
B-cell non-Hodgkin's lymphoma involving the brain, as demonstrated by contrast-enhanced 
MRI and histologic confirmation by one of the following within 6 weeks prior to registration:  
• 
A positive 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.  
3.1.2 
The patient must agree to submit tissue (ie, the original H/E stained slides and 
immunohistochemistry studies) for central pathology review post-registration (See Section 10 
for details). 
3.1.3 
No evidence of systemic non-Hodgkin lymphoma as demonstrated by a 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; see section 4.1) 


13 
RTOG 1114: version date September 19, 2019 
3.1.4 
Age ≥ 18 
3.1.5 
History and physical examination within 6 weeks of registration  
3.1.6 
Karnofsky performance status 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 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) 
3.1.7 
Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study 
registration (Separate counseling and consent as per institutional guidelines)  
3.1.8 
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 ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb 
≥ 8.0 g/dl is acceptable.); 
3.1.9 
Adequate liver function within 2 weeks prior to study registration, defined as follows: 
• 
 
Bilirubin < 2.0 mg/dl 
• 
 
AST <2.5 times upper limit of normal 
3.1.10 
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. 
3.1.11 
Women of childbearing potential and male participants must agree to practice adequate 
contraception during therapy  
3.1.12 
Patient must provide study-specific informed consent prior to study registration 
3.1.13      Patient must be able to swallow pills. 
 
3.2 
Conditions for Patient Ineligibility (10/28/13) 
3.2.1 
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) 
3.2.2 
Prior treatment with chemotherapy or radiotherapy for lymphoma or chronic lymphocytic 
leukemia; note that prior chemotherapy for a different cancer is allowable; see section 3.2.1 
3.2.3 
Prior cranial irradiation 
3.2.4 
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. 
3.2.5 
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.  
3.2.6 
Prior allergic reaction to any of the study drugs involved in this protocol. 
 
 


14 
RTOG 1114: version date September 19, 2019 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility. 
 
4.1 
Required Evaluations/Management (1/27/15) 
See Section 11.1; note that failure to perform one or more of these tests may result in 
assessment of a protocol violation.  
4.1.1 
Bloods: CBC with white cell differential, creatinine, calculated creatinine clearance, BUN, 
electrolytes, LFTs (ALT, AST, bilirubin), and LDH within 2 weeks of start of treatment.  
4.1.2 
Routine urinalysis within 2 weeks of start of treatment.  
4.1.3 
Radiographic studies: Chest X-ray (PA and lateral), MR scan of brain with gadolinium  within 2 
weeks of starting chemotherapy.    
4.1.4 
A complete history and physical, including neurologic exam within 2 weeks of start of treatment  
• 
History and physical must consist of full history, including history of present illness, review 
of systems, past medical history, family history, medication, complete physical and 
neurological examinations, KPS performance status, height/weight, BSA, corticosteroid use 
4.1.5 
Lumbar puncture should be performed within 6 weeks of start of treatment in all patients unless 
contraindicated on the basis of the patient’s neurological condition.  CSF should be analyzed 
for cytology, glucose, protein, cell count, and in some patients’ oligoclonal bands and 
lymphocyte markers. (Note: A sample of CSF may be stored for research purposes, per Section 
10, if the patient consents.)  
4.1.6 
Complete ophthalmologic exam including slit lamp within 2 weeks of start of treatment.  
4.1.7 
Bone marrow biopsy should be performed within 6 weeks of start of treatment and should be 
sent for routine lab studies. Patients must have the bone marrow biopsy performed prior to start 
of treatment, but may start treatment while results are awaited. Results should be submitted to 
NRG Oncology within 1 month of start of treatment. If results indicate presence of lymphoma in 
the bone marrow, the patient will be removed from study and additional treatment will be left at 
discretion of treating physician (see Section 11.5 for criteria for study removal). [Note: A bone 
marrow sample (can be residual) may be stored for research purposes, per Section 10, if the 
patient consents.] 
 
4.2 
Highly Recommended Evaluations/Management (1/31/13) 
4.2.1 
Hepatitis B Reactivation Prophylaxis  
Chemotherapies, particularly rituximab, may result in reactivation of hepatitis B. Screening for 
hepatitis B is strongly recommended within 6 weeks pre-treatment and should follow 
institutional guidelines. Results are not needed for patient to start treatment. In patients at risk 
for hepatitis B reactivation, hepatitis B prophylaxis (e.g. entecavir) should be strongly 
considered. For reference, MSKCC guideline is as follows: 
- Obtain HB surface antigen and HB core antibody. If both are negative, no further action is 
needed. If either test is positive, obtain HBV PCR and start entecavir 0.5 mg PO daily 
throughout treatment and for at least 6 months after completion; consider consulting a GI 
specialist for guidance. 
 
5.0 
REGISTRATION PROCEDURES (23-AUG-2019) 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).   
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 


15 
RTOG 1114: version date September 19, 2019 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications (e.g., 
Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs must list all 
clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
 
 
 
5.1 
Regulatory Pre-Registration Requirements  (19-SEP-2019) 
 
NOTE: This study is not open to Canadian sites, due to rituximab distribution. 
 
5.1.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Sites must submit their approval to the CTSU Regulatory Office using the Regulatory Submission Portal 
located in the Regulatory section of the CTSU website. Acceptable documentation of local IRB/REB 
approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 


16 
RTOG 1114: version date September 19, 2019 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB approval) 
must meet the following criteria to complete processing of the IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval and on at least one participating roster; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR profile; 
and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Requirements for RTOG 1114 site registration: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
• 
IRB/REB approved consent (International sites only: English Version and native language 
versions) 
*Note: Institutions must provide certification/verification of IRB/REB consent translation to 
NRG Oncology (described below).  
• 
CTSU RT Facilities Inventory Form (if applicable) 
• 
NOTE:  Per NCI policy all institutions that participate on protocols with a radiation therapy 
component must participate in the Imaging and Radiation Oncology Core (IROC) monitoring 
program.  If this form has been previously submitted to CTSU it does not need to be 
resubmitted unless updates have occurred at the RT facility 
 
Non-English Speaking Non-North American Institutions: 
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REB approved consent, must be provided in English and 
in the native language. Certification of the translation is optimal but due to the prohibitive costs 
involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation 
consists of the actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational/letterhead stationery that includes the professional title, 
credentials, and signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
 
. 
 
5.2 
Pre-Registration Requirements for Neurocognitive Function Testing Certification 
NOTE: Sites must offer English-speaking participants the opportunity to participate in the 
neurocognitive function component of this study  
 
Institutions with patients participating in the quality of life/neurocognitive function components of 
this study must meet certification requirements for administering neurocognitive assessments.  
Upon review and successful completion of the Neurocognitive Certification, Dr. Denise Correa will 
notify both the certified examiner and CTSU that the examiner has successfully completed this 
requirement. 
 
See Appendix IV for certification requirements.  
 
5.3 
Registration (8/25/15) 
5.3.1 
OPEN Registration Instructions 


17 
RTOG 1114: version date September 19, 2019 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria 
have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have 
signed and dated all applicable consents and authorization forms.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
< 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. All site staff will use OPEN to enroll patients to this study. It is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or 
from the OPEN tab 
on the CTSU members’ web site 
https://www.ctsu.org 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
• 
All patients have signed an appropriate consent form and HIPPA authorization form (if 
applicable).  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' web site OPEN tab or 
within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-
5923 or ctsucontact@westat.com.  
 
 
In the event that the OPEN system is not accessible, participating sites can contact web 
support for assistance with web registration: websupport@acr.org or call the Registration Desk 
at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the 
site to fax in the eligibility checklist and will need the registering individual’s e-mail address 
and/or return fax number. This information is required to assure that mechanisms usually 
triggered by the OPEN web registration system (e.g. drug shipment and confirmation of 
registration) will occur. 
 
6.0 RADIATION THERAPY 
Note: Intensity Modulated RT (IMRT) Is Not Allowed 
 
Protocol chemotherapy treatment must begin within 6 weeks following histologic diagnosis. (See 
Section 7)  
The radiotherapy must start no earlier than 2 weeks and no later than 5 weeks following the end of 
R-MPV. 
 
6.1 
Dose Specifications  
Following chemotherapy with R-MPV, all patients in arm B will receive cranial irradiation to a total 
dose of 2340 cGy (180 cGy per fraction X 13 administered daily over a period of 3 weeks).  
 
The opposed lateral radiation fields will include the whole brain down to the level of C2 (“German 
helmet” shape) and will exclude the anterior two thirds of the orbit. Treatment will be delivered 
once daily, 5 fractions per week, over 2.5 weeks. Breaks in treatment should be minimized. 
 
Patients in arm B with ocular involvement will be irradiated without orbital shielding to the full 
dose of 2340 cGy. If no ocular involvement is evident on initial exam then only the posterior one 
third of the orbit is to be included in the treatment portal (see 6.4 for details).  
 
Doses are specified as the target dose that will be representative of the dose in the center of the 
target volume. For 2 opposed coaxial equally weighted beams, the target dose will be specified 
on the central ray at mid-separation of beams. 


18 
RTOG 1114: version date September 19, 2019 
 
 
6.2 
Technical Factors  
Treatment shall be delivered with megavoltage machines. Photon beams with energies of 
between 6 and 10 mV are to be used. Source to skin distances must be at least 80 cm. 
 
6.3 
Localization, Simulation, and Immobilization 
The patient shall be treated in the supine position. Head immobilization with a thermoplastic mask 
or other appropriate device is encouraged. A radio opaque marker should be placed on the right 
and left soft tissue canthus. Simulation may include a dedicated radiotherapy simulator or a 
virtual simulation using a treatment planning CT. 
 
6.4 
Treatment Planning/Target Volumes 
A left and right lateral equally weighted, opposed field arrangement is to be used. Custom blocks 
or a multi-leaf collimator are to be used to shape the fields such that the meninges are included. 
Care should be taken in shaping the fields at the skull base to avoid inadvertent shielding of the 
meninges in the region of the anterior temporal lobes and the cribiform plate. If no ocular 
involvement is evident on initial exam then only the posterior one third of the orbit is to be 
included in the treatment portal. (See Fig 1 below) If ocular involvement is evident on initial slit 
lamp exam the entirety of both eyes will be included in the treatment volume. (See Fig 2 below) 
The anterior field edge is to be made coplanar via a gantry rotation so as to avoid contralateral 
ocular divergence. The anterior, posterior, and superior field borders shall include 1-2 cm of “fall 
off”. The inferior border is the C2-3 inter-space. 


19 
RTOG 1114: version date September 19, 2019 
Figure 1 
 
 


20 
RTOG 1114: version date September 19, 2019 
Figure 2 
 
 
 


21 
RTOG 1114: version date September 19, 2019 
 
6.5 
Documentation Requirements 
For patients accrued to the protocol, treatment verification and documentation should be carried 
out, at least for the first treatment fraction, and more frequently, based on institutional policy; 
weekly verification is common. We suggest orthogonal images for documenting isocenter setup 
accuracy for the first fraction. These orthogonal images can be obtained with film or EPID. 
 
6.6 
Compliance Criteria 
Radiotherapy will be continued without interruption if at all possible. If the sum total of 
radiotherapy interruptions exceeds 2 normally scheduled treatment days, the treatment will be 
considered an unacceptable deviation from the protocol and the patient will be considered 
inevaluable on final data analysis. 
 
6.7 
R.T. Quality Assurance Reviews 
The Radiation Oncology Co-Chair, Joseph A. Bovi, MD, will perform an RT Quality Assurance 
Review only in the event that an adverse event warrants the collection of the RT data for review. 
 
6.8 
Radiation Therapy Adverse Events 
6.8.1 
Acute Reactions 
All patients are likely to develop alopecia, erythema, and dry desquamation of the scalp within 
the treatment portal. Some patients may experience a headache, anorexia and or nausea. 
Middle ear congestion is commonly experienced following whole brain RT. Patients requiring 
treatment to the entire eye are likely to experience conjunctival irritation and may note dry eyes. 
All of the described acute effects are likely to be reversible with the exception of alopecia.  
6.8.2 
Late Reactions (> 90 days from RT start) 
All patients are likely to have permanent partial or total alopecia corresponding to the treatment 
portal. Rarely, persistent middle ear effusion(s) requires myringotomy tube placement. There is 
a low risk of sensory neural hearing loss. All patients are at high risk of developing cataracts, 
which may or may not require treatment. The probability of cataract formation increases with 
post treatment survival time. The risk of cataract is greatest for patients who require treatment 
to the entire eye. All patients are at risk for developing neurocognitive dysfunction; the greatest 
risk is for patients > 60 years of age. There is a low risk of developing radiation necrosis of the 
brain, which may require surgery and/or extended use of steroids.  
 
6.9 
Radiation Therapy Adverse Event Reporting  
 
See Sections 7.9 and 7.10 
 
 
7.0 DRUG THERAPY 
 
Protocol chemotherapy treatment must begin within 6 weeks following histologic diagnosis.  
The radiotherapy must start no earlier than 2 weeks and no later than 5 weeks following the end of 
R-MPV (See Section 6.0). 
 
7.1 
Treatment Arms (10/28/13) 
7.1.1 
Arm 
A 
(Chemotherapy-Only): 
Chemotherapy 
With 
Rituximab, 
Methotrexate 
(MTX), 
Procarbazine, Vincristine And Consolidation Cytarabine (R-MPV-A) Without WBRT 
 
4 cycles of R-MPV (1 cycle = 28 days; vincristine not given during cycles 3 and 4), as 
follows: 
 
 
 
Day 
Agent 
Dose 
Day 1 
Rituximab 
500 mg/m2 
 
Day 2 
MTX 
3.5 g/m2 (standard hydration/leucovorin support) 
 
Vincristine 
1.4 mg/m2, dose capped at 2.4mg. Vincristine is given during 
cycles 1 and 2 only. 
 


22 
RTOG 1114: version date September 19, 2019 
Days 2-8 
Procarbazine 
100 mg/m2/day 
 
Days 
10-
14 
Filgrastim* 
(Neupogen) 
5 mcg/kg/ day SC (the use of filgrastim is mandatory) 
Day 15 
Rituximab 
500 mg/m2 
 
Day 16 
MTX 
3.5 g/m2 (standard hydration/leucovorin support) 
 
Vincristine 
1.4 mg/m2, dose capped at 2.4 mg. Vincristine dose is given during 
cycles 1 and 2 only.   
Days 
18-
22 
Filgrastim* 
(Neupogen) 
5 mcg/kg/ day SC (the use of filgrastim is mandatory) 
* Filgrastim should be discontinued if leucocytes > 20,000/mm3, then re-started in the 
following cycle as planned. (See Section 9.1).  
 
4 weeks (+/- 1 week) following cycle 4 day 28 of R-MP, 2 cycles of consolidation 
chemotherapy will be given as follows (1 cycle = 28 days):  
 
Day 
Agent 
Dose 
Days 1 and 2 of each 
cycle 
Cytarabine 
3 g/m2/day  
Day 4  
Pegfilgrastim 
(Neulasta)** 
6 mg SC 
**The use of G-CSF is mandatory. Pegfilgrastim may be substituted for Filgrastim (5 
mcg/kg/ day for 14 days); in this case, if leucocytes >20,000 mm3, then Filgrastim should 
be discontinued (See Section 9.1). 
 
7.1.2 
Arm B: Chemotherapy Followed by Low-Dose WBRT Arm: Same Chemotherapy Regimen, 
With Low-Dose WBRT Given After R-MPV and Prior to Consolidation Cytarabine 
4 cycles of R-MPV (1 cycle = 28 days; vincristine not given during cycles 3 and 4), as follows: 
 
Day 
Agent 
Dose 
Day 1 
Rituximab 
500 mg/m2 
 
Day 2 
MTX 
3.5 g/m2 (standard hydration/leucovorin support) 
 
Vincristine 
1.4 mg/m2, dose capped at 2.4mg. Vincristine is given during 
cycles 1 and 2 only. 
Days 2-8 
Procarbazine 
100 mg/m2/d 
 
Days 
10-
14 
Filgrastim* 
(Neupogen) 
5 mcg/kg/ day SC (the use of filgrastim is mandatory) 
Day 15 
Rituximab 
500 mg/m2 
 
Day 16 
MTX 
3.5 g/m2 (standard hydration/leucovorin support) 
 
Vincristine 
1.4 mg/m2, dose capped at 2.4mg. Vincristine is given during 
cycles 1 and 2 only. 
Days 
18-
22 
Filgrastim* 
(Neupogen) 
5 mcg/kg/ day SC (the use of filgrastim is mandatory) 
* Filgrastim should be discontinued if leucocytes > 20,000/mm3, then re-started in the 
following cycle as planned. (See Section 9.1). In case of delayed MTX elimination, at the 
discretion of the treating physician, initiation of filgrastim may be delayed for up to 2 days in 
order to avoid administration of filgrastim in the setting of high methotrexate levels. 
 
Following the 4 cycles of R-MPV, all patients will receive low-dose WBRT (see Section 6), 
except those with progressive disease on MRI. 
 
4 weeks (+/- 1 week) after the end of WBRT, patients will receive 2 cycles (1 cycle = 28 
days) of consolidation chemotherapy as follows: 
 


23 
RTOG 1114: version date September 19, 2019 
 
Day 
Agent 
Dose 
Days 1 and 2 of each 
cycle 
Cytarabine 
3 g/m2/day  
Day 4  
Pegfilgrastim 
(Neulasta)** 
6 mg SC 
 
 
**The use of G-CSF is mandatory. Pegfilgrastim may be substituted for Filgrastim (5 
mcg/kg/ day for 14 days); in this case, if leucocytes >20,000 mm3, then Filgrastim should 
be discontinued (See Section 9.1). 
 
7.2 
Agents (10/28/13) 
7.2.1 
Rituximab 
Rituximab 500 mg/m2 will be given intravenously on the days specified in Section 7.1. Prior to 
rituximab infusion, patients will be premedicated as per institutional guidelines 
(recommended: lorazepam 0.5-1 mg intravenously, diphenhydramine l 25-50 mg 
intravenously or orally, acetaminophen  650 mg orally). meperidine  25-50 mg will be given to 
the patient prn rigors. Rituximab will be infused over approximately 5 hours or per institutional 
guidelines.  
7.2.2 
Methotrexate (MTX) 
Methotrexate, 3.5 g/m2, diluted in 500 cc D5W containing 50 mEq NaHCO3* will be infused 
intravenously over approximately 2 hours on the days specified on Section 7.1. 
 
* In the event of national shortages of NaHCO3, methotrexate will be diluted in 500cc D5W 
and administered as above, with no NaHCO3 or substitutes added. In that event, the urine 
alkalinization protocol (see below) should be adjusted to compensate for the suppression of 
the 50 mEq NaHCO3 originally added to the methotrexate. 
 
Standard pretreatment hydration and alkalinization of urine will be done per 
institutional guidelines or using the outlined standard pretreatment below. In the event 
of national shortages of NaHCO3, the use of substitutes considered suitable by the 
investigator (eg, sodium acetate, sodium citrate, etc) is allowed, but such substitutes 
should not be mixed together in the same IV bag with the methotrexate as stated 
above.  
 
Example: Infuse 1 liter D5W + 100 mEq sodium bicarbonate over 4 hours and urine output 
should be > 150 ml/hour and urine pH > 7.5 prior to the start of the high-dose MTX). Prior to 
MTX administration, 1 mEq/kg of NaHCO3 in 50 cc D5W will be given. Oral NaHCO3 (2 
tablets orally every 6 hours) will be given for the 3 days following MTX infusion to maintain 
urine pH > 7.0. If a patient is unable to take NaHCO3 by mouth or if adequate alkalinization of 
the urine is not accomplished, intravenous NaHCO3 will be started. 15 mEq NaHCO3 in 50 
cc D5W are administered intravenously over 15 minutes every 6 hours; the frequency can be 
increased to every 4 hours if the urine pH remains < 7.0.  
 
Leucovorin, 25 mg orally every 6 hours for 12 doses, (if a patient is unable to take oral 
leucovorin, it will be administered intravenously at 20 mg every 6 hours) will begin 
approximately 24 hours after MTX infusion and continue for 72 hours or until the MTX level is 
< 1 X 10-7.  
 
MTX levels, CBC and electrolytes (including BUN/Cr) will be obtained daily for 3 days 
following MTX administration until MTX is cleared. If MTX levels are toxic at 48 hours (>10-6 
M), leucovorin will be increased to 40 mg orally or intravenously every 4 hours and total fluid 
intake will increase to 3000 cc/m2. MTX levels > 1 X 10-7 M at 72 hours will dictate continuing 
leucovorin (40 mg orally/intravenously q 6 hours), hydration at 3000 cc/m2/day and NaHCO3 
(or per institutional guidelines) until MTX level is 1 X 10-7 M or less. Institutional guidelines for 
standard IV hydration and alkalinization post HDMTX will be used.  
Note: Blood concentration levels of MTX must be reported in micromol/L on the treatment 
form (TF form) at the time of web data submission. 


24 
RTOG 1114: version date September 19, 2019 
 
All patients will be instructed to maintain vigorous oral hydration throughout the MTX infusion 
and for 72 hours thereafter. For the first 24 hours after the MTX administration, total fluid 
intake should be at least 1500-1800 cc/m2 and increased to 2000 cc/m2 for the following 48 
hours. Patients will be instructed to refrain from eating citrus fruit, drinking citrus fruit juices or 
taking vitamin C supplements during MTX administration and for the following 72 hours.  
 
In case of significant delays in MTX elimination (see Section 7.8.1), the use of glucarpidase 
(carboxypeptidase G2) is permitted; in that case, leucovorin administration and hydration 
should be adjusted accordingly (See Section 9.1.8). 
7.2.3 
Vincristine 
Vincristine 1.4mg/m2 intravenously will be given during cycles 1 and 2 only (total of 4 doses) 
as specified in Section 7.1. Administration will be concomitant with systemic MTX. The 
vincristine dose should be capped at 2.4 mg maximum dose.  
7.2.4 
Procarbazine 
Procarbazine 100mg/m2/day orally for 7 days will be given during each cycle as specified in 
Section 7.1. Patients will be maintained on a tyramine-free diet during procarbazine 
administration.  
7.2.5 
Cytarabine 
Two cycles (1 cycle = 28 days) of consolidation cytarabine 3 g/m2/day for 2 days (total of 4 
doses) will be given intravenously over approximately 3 hours, as specified in Section 7.1. 
The dose of cytarabine will be capped at 2 m2 or a total dose of 6 g. The use of G-CSF is 
mandatory. Pegfilgrastim (Neulasta) 6 mg SC will be given subcutaneously on day 4 of each 
cycle. Pegfilgrastim may be substituted for Filgrastim (Neupogen) 5 mcg/kg/ day for 14 days; 
in this case, if leucocytes >20,000 mm3, then Filgrastim should be discontinued.   
 
7.3 
Rituximab Agent Information (1/31/13) 
 
Refer to package insert for detailed pharmacologic and safety information. 
7.3.1 
Formulation 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed 
against the CD20 antigen present on the surface of both normal and malignant B-lymphocytes.  
Rituximab is provided as a sterile, clear, colorless, preservative-free liquid concentrate for 
intravenous administration; it is supplied at a concentration of 10 mg/ml in either 100 mg (10 ml) 
or 500 mg (50 ml) single-use vials.  The product is formulated for intravenous administration in 
9.0 mg/ml sodium chloride, 7.35 mg/ml sodium citrate dihydrate, 0.7 mg/ml polysorbate 80, and 
sterile water for injection. The pH is adjusted to 6.5. 
7.3.2 
Storage 
Rituximab vials are stored at 2°–8° C (36°–46°F), should be protected from direct sunlight, and 
should not be used beyond expiration date stamped on the carton. 
 
7.3.3 
Adverse Effects 
 
Infusion reactions: Mild to moderate fever and chills/rigors occur in the majority of 
patients during the first rituximab infusion. Other frequent infusion reaction symptoms 
include 
nausea, 
pruritus, 
angioedema, 
asthenia, 
hypotension, 
headache, 
bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, 
and hypertension. These reactions generally occurred within 30 to 120 minutes of 
beginning the first infusion.  The incidence of infusion reactions decreases with each 
treatment and responds to slowing or interruption of the infusion and supportive care. 
 
B-cell depletion with lymphopenia and risk of infection 
 
Grade 3 or 4 cytopenias including lymphopenia, neutropenia, thrombocytopenia, and 
anemia; rare instances of hemolytic anemia, aplastic anemia, and prolonged 
pancytopenia have been reported. 
 
Cardiac: Hypotension, rare cardiac failure 
 
Pulmonary: Serious effects include acute bronchospasm, acute pneumonitis presenting 
1-4 weeks post-rituximab infusion, and bronchiolitis obliterans.  More common effects 
include increased cough, rhinitis, bronchospasm, dyspnea, and sinusitis. 


25 
RTOG 1114: version date September 19, 2019 
 
Immune/autoimmune events: uveitis, optic neuritis in a patient with systemic vasculitis, 
pleuritis in a patient with a lupus-like syndrome, serum sickness with polyarticular 
arthritis, and vasculitis with rash  
 
Hepatitis B virus (HBV) reactivation: HBV reactivation with fulminant hepatitis, hepatic 
failure, and death has been reported in some patients with hematologic malignancies 
treated with rituximab.  The majority of patients received rituximab in combination with 
chemotherapy.  The median time to the diagnosis of hepatitis was approximately four 
months after the initiation of the rituximab and approximately one month after the last 
dose.  
 
Other less commonly observed events: Agitation, anorexia, arthritis, conjunctivitis, 
depression, dyspepsia, edema, hyperkinesia, hypertonia, hypesthesia, hypoglycemia, 
injection site pain, insomnia, lacrimation disorder, malaise, nervousness, neuritis, 
neuropathy, paresthesia, somnolence, vertigo, weight decrease  
7.3.4 
Contraindications 
Contraindicated in patients with known anaphylaxis or IgE-mediated hypersensitivity to murine 
proteins or to any component of this product. 
7.3.5 
Supply 
Commercially available  
The use of drug(s) or combination of drugs in this protocol meet the criteria described under 
Title 21 CFR 312.2(b) for IND exemption. 
7.3.6 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
 
7.4 
Methotrexate (MTX) Agent Information (1/31/13) 
 
Refer to package insert for detailed pharmacologic and safety information. 
7.4.1 
Formulation 
MTX is available in 20 mg, 50 mg, and 1 gm vials as a lyophilized preservative-free powder.   
7.4.2 
Storage 
Once mixed, intravenous MTX will remain stable for 24 hours if kept refrigerated. 
7.4.3 
Adverse Effects 
Systemic MTX can produce myelosuppression; GI toxicity, particularly mucositis; liver 
dysfunction, renal failure, and rarely, interstitial pneumonitis. 
7.4.4 
Contraindications 
Contraindicated in patients with renal insufficiency, known hypersensitivity to methotrexate or to 
any component of this product. 
7.4.5 
Supply 
Commercially available  
The use of drug(s) or combination of drugs in this protocol meet the criteria described under 
Title 21 CFR 312.2(b) for IND exemption. 
7.4.6 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
 
7.5 
Procarbazine Agent Information (1/31/13) 
 
Refer to package insert for detailed pharmacologic and safety information. 
7.5.1 
Formulation 
Capsules, containing the equivalent of 50 mg procarbazine as the hydrochloride, which is 
ivory, are supplied in bottles of 100. 
7.5.2 
Storage 
Procarbazine is a white to pale yellow crystalline substance soluble but unstable in water or 
aqueous solution.  Procarbazine can be stored at room temperature until expiration date. 
7.5.3 
Adverse Effects 
 
Leukopenia, anemia, and thrombocytopenia occur frequently.  Nausea and vomiting are the 


26 
RTOG 1114: version date September 19, 2019 
most commonly reported side effects.  Other less frequent gastrointestinal complaints 
include anorexia, stomatitis, dry mouth, dysphagia, diarrhea, and constipation.  Pain, 
including myalgia and arthralgia, chills and fever, sweating, weakness, fatigue, lethargy, and 
drowsiness are often noted.  Intercurrent infections, effusion, ascites, edema, cough and 
other respiratory symptoms are common.  Bleeding tendencies such as petechiae, purpura, 
epistaxis, hemoptysis, hematemesis, and melena have been rare.  Dermatitis, pruritus, 
herpes, hyperpigmentation, flushing, alopecia and jaundice have also been noted.  
Paresthesias 
and 
neuropathies, 
headache, 
dizziness, 
depression, 
apprehension, 
nervousness, insomnia, nightmares, hallucinations, falling unsteadiness, ataxia, footdrop, 
decreased reflexes, tremors, coma, confusion, and convulsions have been less common.  
Hoarseness, tachycardias, retinal hemorrhage, nystagmus, photophobia, photosensitivity, 
genitourinary symptoms, hypotension, and fainting have been rare.  Isolated instances of 
diplopia, inability to focus, papilledema, altered hearing, and slurred speech have occurred. 
Coincidental onset of leukemia during procarbazine therapy has been reported in rare 
instances.  Patients receiving procarbazine must avoid alcohol, aged cheese, and bananas. 
7.5.4 
Supply  
Commercially available.   
The use of drug(s) or combination of drugs in this protocol meet the criteria described under 
Title 21 CFR 312.2(b) for IND exemption.  
7.5.5 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
 
7.6 
Vincristine Agent Information (1/31/13) 
 
Refer to package insert for detailed pharmacologic and safety information. 
7.6.1 
Formulation  
 
The dosage formulation is in 1 mg and 2 mg vials. 
7.6.2 
Storage  
 
Vincristine should be stored in a refrigerator. 
7.6.3 
Adverse Effects 
 
Vincristine is capable of producing paresthesias and numbness in the digits in its mildest 
form of toxicity ranging all the way to a profound weakness with loss or motor tone and foot 
drop in its extreme form.  Other common side effects include constipation, abdominal pain, 
jaw pain and rarely, myelosuppression.  Severe tissue damage can occur upon 
extravasation. 
7.6.4 
Supply 
 
Commercially available.  
The use of drug(s) or combination of drugs in this protocol meet the criteria described under 
Title 21 CFR 312.2(b) for IND exemption. 
7.6.5 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
 
7.7 
Cytarabine Agent Information (1/31/13) 
 
Refer to package insert for detailed pharmacologic and safety information. 
7.7.1 
Formulation  
Cytarabine is available in 100, 500, 1,000 and 2,000 mg multidose vials for intravenous use. 
7.7.2 
Storage  
The drug is stored unreconstituted at controlled room temperature, 15° to 30°C (59° to 
86°F). 
7.7.3 
Adverse Effects 
 
Cytarabine can cause myeolosupression, nausea, vomiting, cerebellar ataxia, lethargy, 
confusion, hepatic dysfunction, skin rash, conjunctivitis, chest pain, pancreatitis, pulmonary 
edema, alopecia, and painful hand-foot syndrome. 
7.7.4 
Supply 
 
Commercially available.  


27 
RTOG 1114: version date September 19, 2019 
The use of drug(s) or combination of drugs in this protocol meet the criteria described under 
Title 21 CFR 312.2(b) for IND exemption. 
7.7.5 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
 
7.8 
Dose Modifications (4/23/12) 
7.8.1 
Days 1 and 15 of each cycle will be defined by the corresponding administration of rituximab. 
Toxicity assessment for the purposes of re-treatment and dose reduction will occur on days 1 
and 15 of each cycle. Such toxicity assessment will be based on laboratory values obtained on 
the same day or the previous day. The treatment will start (or be resumed) when all of the 
following parameters are met: 
 
For day 1: 
 
ANC >1,500/mm3 
 
Platelets > 100,000/mm3 
 
Creatinine < 2.0 mg/dl 
 
Calculated or measured creatinine clearance > 50 cc/min/1.73m2 
 
All other non-hematologic toxicity related to the methotrexate or procarbazine resolved 
to grades 2 or lower 
 
 
For day 15: 
 
ANC >1,200 /mm3 
 
Platelets > 80,000/mm3 
 
Creatinine < 2.0 mg/dl 
 
Calculated or measured creatinine clearance > 50 cc/min/1.73 m2 
 
All other non-hematologic toxicity related to the methotrexate or procarbazine resolved 
to grades 2 or lower 
 
 
For days 1 and 15, the use of G-CSF is permitted for achieving ANC parameters (See 
Section 9.1). The use of transfusion for achieving treatment parameters for platelets is not 
allowed  
 
For patients not meeting treatment parameters for renal function (creatinine and creatinine 
clearance), hospital admission for intravenous hydration and nephrology consultation should 
be considered.  In case of significant delays in methotrexate elimination, at the discretion of 
treating physician, the use of glucarpidase (carboxypeptidase G2) is permitted. In that case, 
leucovorin administration should be adjusted accordingly, following the manufacturer’s 
recommendations or at discretion of treating physician. 
 
 
If any of the parameters above are not met, patients should be re-evaluated twice per week 
until parameters are met. If parameters are not met after a 2-week delay, re-starting 
treatment at reduced doses may be considered, at the discretion of treating physician.  
 
 
In addition to meeting these treatment parameters, the following modifications will be 
made in case of toxicities during the preceding cycle: 
 
 
Toxicity Observed During the Previous Cycle 
 
Rituximab 
Methotrexate 
Procarbazine 
Vincristine 
Other 
Measures 
Grades 3 or 4 
ANC 
No change 
No change 
Reduce to the 
following: 
- 1st occurrence: 
75mg/m2/ day 
 
- 2nd occurrence: 
50mg/m2/day 
 
- 3rd recurrence: 
discontinue; 
No change 
Increase 
duration of 
treatment with 
G-CSF for the 
following cycle; 
if pt on PCP 
prophylaxis,  
consider using 
pentamidine 
rather than 


28 
RTOG 1114: version date September 19, 2019 
consider 
decreasing 
methotrexate 
dose  
Bactrim, 
dapsone, or 
atovaquone.  
Grades 3 
thrombocytopenia 
No change 
No change 
Reduce to the 
following: 
- 1st occurrence: 
75mg/m2/ day 
 
- 2nd occurrence: 
50mg/m2/day 
 
- 3rd occurrence: 
discontinue; 
consider 
decreasing 
methotrexate 
dose  
No change 
If pt on PCP 
prophylaxis,  
consider using 
pentamidine 
rather than 
Bactrim, 
dapsone or 
atovaquone.  


29 
RTOG 1114: version date September 19, 2019 
 
Grade 4 
thrombocytopenia 
No change 
No change 
Reduce to the 
following: 
- 1st occurrence: 
50mg/m2/ day 
 
- 2nd occurrence:  
discontinue; 
consider 
decreasing 
methotrexate 
dose  
No change 
If pt on PCP 
prophylaxis,  
consider using 
pentamidine 
rather than 
Bactrim, 
dapsone or 
atovaquone.  
Grades 3 or 4 
creatinine  
No change 
Reduce to the following: 
- 1st occurrence: 2.6 
g/m2 
 
- 2nd occurrence: 1.7 
g/m2 
 
- 3rd occurrence: 1 g/m2 
 
-4th occurrence: 
discontinue methotrexate 
No change 
No change 
Consider 
nephrology 
consultation for 
guidance on 
increasing  
hydration 
throughout the 
cycle 
Grade 3 or 4 ALT 
or AST 
No change 
No change (if toxicity is 
observed in spite of 
reductions in 
procarbazine, consider 
reduction in MTX dose)  
Reduce to the 
following: 
- 1st occurrence: 
75mg/m2/ day 
 
- 2nd occurrence: 
50mg/m2/day 
 
- 3rd recurrence: 
discontinue; 
consider 
decreasing 
methotrexate 
dose  
No change 
 
Grade 3 or 4 
interstitial 
pneumopathy  
No change 
Consult pulmonary 
specialist, exclude other 
causes of pneumopathy, 
consider   
bronchoalveolar lavage 
to exclude PCP. 
If no other causes found 
and pneumopathy 
thought to be MTX-
related, reduce dose to 
1.7g/m2 (discontinue if 
worsening in spite of 
dose reduction)  
No change 
No change 
 
Grade 3 or 4 
confusion  
No change 
Exclude other causes 
(toxic metabolic, 
seizures, tumor 
progression, 
hydrocephalus, etc). If 
confusion clearly 
associated with 
development of 
significant 
leukoencephalopathy, 
D/C MTX 
No change 
No change 
 
Grade 3 or 4 
peripheral 
neuropathy 
No change 
No change 
No change 
Discontinue 
 
 
7.8.1.6 
At the discretion of treating physician, doses may be increased back to earlier dose 
levels if no toxicity is observed.  
 
7.9 
Modality Review (1/31/13) 
 
The Medical Oncology Co-Chair, Antonio Omuro, MD, will perform a Chemotherapy Assurance 
Review of all patients who receive or are to receive chemotherapy in this trial.  The goal of the 


30 
RTOG 1114: version date September 19, 2019 
review is to evaluate protocol compliance.  The review process is contingent on timely submission 
of chemotherapy treatment data as specified in Section 12.1. The scoring mechanism is: Per 
Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable.  A report is sent 
to each institution once per year to notify the institution about compliance for each case reviewed 
in that year.   
 
7.10 
Adverse Events (07-AUG-2018) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, 
CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS 
reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 
4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 
5.0, which can be downloaded from the CTEP web site (https://ctep.cancer.gov/ 
protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
7.10.1 
Adverse Events (AEs) Definition of an AE: Any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related.  Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product (attribution 
of unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements. February 29, 2012. 
 
 
7.10.2 
Serious Adverse Events (SAEs) Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in Section 7.11 will be reported via CTEP-AERS.  SAEs 
that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in 
Section 7.11.Contact the CTEP-AERS Help Desk if assistance is required. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results 
in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.  
 
7.10.3   Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system 
within 30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 


31 
RTOG 1114: version date September 19, 2019 
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
 
7.11 
CTEP-AERS  Expedited Reporting Requirements (07-AUG-2018) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table below will 
be reported via CTEP-AERS, the CTEP Adverse Event  Reporting System, accessed via the CTEP web 
site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 . 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology 
requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation 
therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG 
Oncology at 1-215-574-3191. An electronic report must be submitted immediately upon re-establishment 
of the Internet connection. 
• 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is electronically 
submitted within 24 hours of learning of the adverse event. Each CTEP-AERS24-hour notification 
must be followed by a complete report within 5 days.  
• 
Supporting source documentation is requested by NRG as needed to complete adverse event review. 
Supporting source documentation should include the protocol number, patient ID number, and CTEP-
AERS ticket number on each page, and fax supporting documentation to NRG Oncology at 1-215-
574-3191. 
• 
A serious adverse event that meets expedited reporting criteria outlined in the AE Reporting Tables 
but is assessed by the CTEP-AERS as “an action not recommended” must still be reported to fulfill 
NRG safety reporting obligations. Sites must bypass the “NOT recommended” assessment; the 
CTEP-AERS allows submission of all reports regardless of the results of the assessment.  
 
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table 
below. Important: All AEs reported via CTEP-AERS also must be reported on the AE section of the 
appropriate case report form (see Section 12.1). 
 
Late Phase 2 and 3 Studies: Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the last administration of protocol treatment 


32 
RTOG 1114: version date September 19, 2019 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials: 
None 
 
8.0 SURGERY 
 
Not applicable to this study. 


33 
RTOG 1114: version date September 19, 2019 
 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy (1/31/13) 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
9.1.1 
Anticonvulsants 
Patients presenting with seizures should be treated as needed for seizures control, preferably 
with non-enzyme inducing anticonvulsants such as levetiracetam. In case of nephrotoxicity, 
adjustments in level of levetiracetam should be considered, as appropriate.  
 
Prophylactic use of anticonvulsants will be left at discretion of the treating physician but is 
usually not recommended. 
9.1.2 
Antiemetics 
Prophylactic antiemetics will be used as per institutional guidelines. Prophylactic antiemetics 
should be used prior to administration of procarbazine (eg,  ondansetron 8 mg orally prior to 
chemotherapy).  
9.1.3 
Anticoagulants 
Use of anticoagulation is allowed as needed. 
9.1.4 
Hematopoietic Growth Factors 
Prophylactic use of G-CSF (Neupogen or Neulasta) is mandatory (refer to Section 7.1 for 
details). In case of significant or persistent neutropenia, increasing the duration of G-CSF 
treatment or re-starting G-CSF for achieving treatment parameters is permitted, at the 
discretion of treating physician. Other therapeutic uses of G-CSF are permitted, at discretion of 
treating physician. 
 
For days 1 and 15, the use of G-CSF is permitted for achieving ANC parameters. (The use of 
transfusion for achieving treatment parameters for platelets is not allowed; See Section 7.8.1).  
9.1.5 
Pneumocystis Jiroveci Pneumonia (PCP) Prophylaxis 
PCP prophylaxis will be left to the discretion of treating physician. PCP prophylaxis is 
recommended in patients exposed to corticosteroids (until 1 month after the last dose) and in 
patients with lymphopenia. In patients with hematotoxicity, aerosolized pentamidine is 
preferred.   
9.1.6 
Bowel Regimen 
Because of the risks of vincristine-related constipation and ileus, a prophylactic bowel regimen 
is highly recommended, as per institutional guidelines. 
9.1.7 
Hydration/Nephrology Consultation 
For patients not meeting treatment parameters for renal function (creatinine and creatinine 
clearance), hospital admission for intravenous hydration and nephrology consultation should be 
considered.   
9.1.8 
Glucarpidase (carboxypeptidase G2) 
In case of significant delays in MTX administration, the use of glucarpidase (carboxypeptidase 
G2) is permitted; in that case, leucovorin administration and hydration should be adjusted 
accordingly). following the manufacturer’s recommendations or at the discretion of the treating 
physician. 
9.1.9 
Hepatitis B Reactivation Prophylaxis  
Chemotherapies, particularly rituximab, may result in reactivation of hepatitis B. Screening for 
hepatitis B is strongly recommended and should follow institutional guidelines. In patients at 
risk for hepatitis B reactivation, hepatitis B prophylaxis (e.g. entecavir) should be strongly 
considered. Results are not needed for patient to start treatment. For reference, MSKCC 
guideline is as follows: 
- Obtain HB surface antigen and HB core antibody. If both are negative, no further action is 
needed. If either test is positive, obtain HBV PCR and start entecavir 0.5 mg PO daily 
throughout treatment and for at least 6 months after completion; consider consulting a GI 
specialist for guidance. 
 
9.2 
Non-permitted Supportive Therapy (4/23/12) 
9.2.1 
See Section 7.8.1 for stipulations concerning platelet transfusion. 
9.2.2 
Antacids 


34 
RTOG 1114: version date September 19, 2019 
It is recommended that proton pump inhibitors be used with caution or avoided during MTX 
treatment due to possible delays in elimination.  
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
NOTE: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as tissue/specimen submission or quality of life assessment.  
If the patient consents to participate in the tissue/specimen component of the study, the site is required to 
submit the patient’s specimens as specified in Section 10.0 of the protocol. Note: Sites are not permitted 
to delete the tissue/specimen component from the protocol or from the sample consent. 
 
10.1 
Tissue/Specimen Submission  
 
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. NRG Oncology encourages participants in protocol 
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides 
tissue specimens to investigators for translational research studies. Translational research 
studies integrate the newest research findings into current protocols to investigate important 
biologic questions. The NRG Oncology Biospecimen Bank also collects tissue for Central Review 
of pathology. Central Review of tissue can be for eligibility and/or analysis.  
 
 
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of 
central review (mandatory for all cases, post-registration), tissue banking (recommended), and 
translational research (recommended).  
 
10.2 
Specimen Collection for Central Review (mandatory post-registration) (1/27/15) 
The following material must be provided to the NRG Oncology Biospecimen Bank for 
Central Review: 
10.2.1 
All H & E stained slides and immunohistochemistry studies performed by local pathologist 
(unless not available per NOTE in Section 3.1.1) (slides can be a duplicate cut stained H&Es; 
they do not have to be the diagnostic slides).  
10.2.2 
A Pathology Report documenting that the submitted block, core, or slides contain tumor; the 
report must include the NRG Oncology protocol number and patient’s case number. The 
patient’s name and/or other identifying information should be removed from the report. The 
surgical pathology numbers and information must NOT be removed from the report. 
• 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.3 
A Specimen Transmittal (ST) Form stating that the tissue is being submitted for Central Review.  
The Form must include the NRG Oncology protocol number and the patient’s case number. 
10.2.4 
Central Review will be performed for every case by Dr Marc Rosenblum at Memorial Sloan-
Kettering Cancer Center, New York, NY.  
10.2.5 
Submit material for central review to the NRG Oncology Biospecimen Bank per Section 10.3.8. 
The Biospecimen Bank will forward the material to Dr. Rosenblum at the end of trial enrollment. 
After central pathology review is complete, depending on the level of patient consent, Dr. 
Rosenblum will return remaining material to the Biospecimen Bank for banking or return the 
material to the submitting institution when requested by the submitting site. Sites must provide 
return airbills for all return requests.  
 
10.3 
Specimen Collection for Tissue Banking and Translational Research (07-AUG-2018) 
For patients who have consented to participate in the banking/translational research component 
of the study. 
 
The following must be provided in order for the case to be evaluable for the NRG Oncology 
Biospecimen Bank. Additional slides and blocks are not needed for banking if they were already 
submitted for central review. They can be used for both.  
10.3.1 
All H & E stained slides and immunohistochemistry studies performed by local pathologist as 
per 10.2.1 (Required).  


35 
RTOG 1114: version date September 19, 2019 
10.3.2 
At least one paraffin-embedded tissue block of the tumor or one 2-mm diameter core of tumor 
tissue, punched from the tissue block containing tumor with a punch tool and submitted in a 
plastic tube labeled with the surgical pathology number and block ID (must correspond to one 
of the H&Es being submitted). Note: A kit with the punch, tube, and instructions (Appendix III) 
can be obtained free of charge from the Biospecimen Bank. Alternatively, 30 five micron 
unstained sections cut onto positive charged slides may be submitted. Slides, block or core 
must be clearly labeled with the pathology identification number and block ID that corresponds 
to the Pathology Report. All blocks, punches, unstained slides must be from the same block as 
one of the H&Es being submitted. 
• 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.3.3 
Submission of frozen tumor tissue and/or bone marrow samples is strongly encouraged to 
maximize the information gained from this trial. When available, frozen samples should be sent 
on dry ice to the NRG Oncology Biospecimen Bank as indicated in Appendix III. The NRG 
Oncology Biospecimen Bank will supply kits for frozen tissue when requested. To request a kit, 
contact the Biospecimen Bank at NRGBB@ucsf.edu or by phone at 415-476-7864. 
10.3.4 
A Pathology Report documenting that the submitted slides, block or core contains tumor. The 
report must include the NRG Oncology protocol number and patient’s case number. The 
patient’s name and/or other identifying information should be removed from the report. The 
surgical pathology numbers and information must NOT be removed from the report. 
10.3.5 
Two tubes of whole blood and a buccal scraping are to be collected pre-treatment (obtained at 
any time prior to start of chemotherapy) should be collected and processed. Available frozen 
CSF and bone marrow samples can also be processed. See Appendix III for collection, 
processing, and kit instructions. Collection kits can be requested free of charge from the 
Biospecimen Bank at NRGBB@ucsf.edu. Please indicate if you need the CSF or bone marrow 
kits. 
10.3.6 
A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the NRG 
Oncology Biospecimen Bank; if for translational research, this should be stated on the form. 
The form must include the NRG Oncology protocol number and patient’s case number.  
10.3.7 
Storage Conditions 
 
Store frozen specimens at -80° C (-70°C to -90°C) until ready to ship. If a -80°C Freezer is not 
available:  
• Samples can be stored short term in a -20° C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only). 
 
Please indicate on Specimen Transmittal (ST) Form  the storage conditions used and time 
stored. 
 
10.3.8 
Specimen Collection Summary  
Specimens for Central Pathology Review (mandatory post-registration) 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
All H&E stained slides 
and 
immunohistochemistry 
studies of the primary 
tumor 
Pre-treatment 
Stained slides 
Pre-treatment 
Slides shipped 
ambient 
Specimens for Tissue Banking and Translational Research (recommended) 
All H&E stained slides 
and 
immunohistochemistry 
studies of the primary 
Pre-treatment/submitted 
in conjunction with 
central review material 
above 
Stained slides 
Pre-treatment 
Slides shipped 
ambient 


36 
RTOG 1114: version date September 19, 2019 
tumor 
A paraffin-embedded 
tissue block of the 
primary tumor taken 
before initiation of 
treatment or a 2 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool  
Pre-treatment 
Paraffin-embedded 
tissue block or punch 
biopsy of block. 
Alternatively 30 
unstained slides may 
be submitted 
 
Block or punch 
shipped ambient 
 
CSF specimen 
Pre-treatment from 
unused portion of 
clinical sample 
Frozen CSF 
Sent frozen on dry ice 
via overnight carrier 
Frozen Tumor Tissue 
(including eye biopsy)  
Pre-treatment 
Frozen tissue 
Sent frozen on dry ice 
via overnight carrier 
Frozen Bone Marrow 
Specimen 
Pre-treatment from 
unused portion of 
clinical sample 
Frozen bone marrow 
stored in the original 
vial. See appendix III 
for details 
Sent frozen on dry ice 
via overnight carrier 
Whole blood for DNA: 10-
15 mL of anticoagulated 
whole blood in 2 EDTA 
tubes  (purple/ lavender 
top) and mix  
Pre-treatment. If site 
missed this collection, 
site can collect at any 
other timepoint or follow-
up visit but must note 
this on the ST Form. 
Frozen whole blood 
samples containing  1 
ml per aliquot in 1ml 
cryovials (6 to 10) 
Whole blood sent 
frozen on dry ice via 
overnight carrier 
Buccal Scrapings: 
brush/swab of oral 
mucosa placed place in 
RNAlater solution 
Pre-treatment 
Swab/RNAlater filled 
container frozen. 
Store frozen -70 º to -
80º Celsius. 
Swab/container sent 
on dry ice via 
overnight carrier 
10.4 
(07-AUG-2018) Submit materials for Tissue Banking and Translational Research as 
follows: 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter St, room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
 
10.5 
Confidentiality/Storage (23-AUG-2019) 
 
 
10.5.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank database only includes the 
following information: the number of specimens received, the date the specimens were 
received, documentation of material sent to a qualified investigator, type of material sent, and 
the date the specimens were sent to the investigator. No clinical information is kept in the 
database. 
10.5.2 
Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient 


37 
RTOG 1114: version date September 19, 2019 
withdraws consent to store and use specimens, the material will be returned to the institution 
that submitted it. 
 
10.6 
Translational Research Description (recommended but not required) 
See Sections 10.3 and 10.4 for specimen collection details 
10.6.1 
Evaluation of DASL-Based Genome Wide Expression Profiling and Immunohistochemistry for 
the Molecular Characterization of PCNSL 
Overview 
Formalin-fixed and paraffin-embedded (FFPE) tissue from all consenting patients will be 
collected and analyzed utilizing the Illumina cDNA-mediated annealing, selection, 
extension, and ligation (DASL) assay, in addition to immunohistochemistry. With the 
support of the MSKCC Computational Biology Core, samples will be analyzed for the 
following: 
 
Comparison with previously described frozen tissue-based genome-wide 
expression profiling defined for both systemic NHL and PCNSL, seeking to 
determine whether a “brain-specific” molecular signature exists. Candidate genes 
will be validated through immunohistochemistry and RT-PCR. 
 
Characterization of a dedicated genome-wide based subclassification for PCNSL 
with prognostic implications in terms of PFS and OS. 
 
Evaluation of the prognostic value of standard prognostic markers utilized in 
NHL, including BCL-6, CD-10, MUM-1 and CD-138.  
 
Rationale 
We hypothesize that FFPE PCNSL samples can be used for genome-wide expression 
profiling utilizing the Illumina DASL assay.  
Gene-expression studies in PCNSL have been limited by the small amount of available 
tissue for analysis (patients are typically diagnosed by biopsy) and lack of frozen tissue. 
Conversely, several genome-wide expression studies have been conducted in systemic 
NHL, which defined two molecular subclasses (germinal center B-cell like and activated 
B-cell like) with prognostic implications. An immunohistochemistry panel was developed 
to categorize DLBCL in these two categories, based on the expression of CD10/BCL-6 
(markers of the germinal center B-cell like, associated with a better prognosis), and 
MUM-1/CD-138 (markers of the activated B-cell like, associated with a worse prognosis). 
Immunohistochemistry studies in PCNSL have been controversial. A study applying 
standard NHL immunohistochemistry-based prognostic markers panel to PCNSL 
samples found a relatively homogenous molecular pattern, with highly frequent 
expression of MUM-1 and rare expression of CD10 and CD-138; BCL-6 was expressed 
in 50%-70% of patients (Camilleri-Broet 2006). Several studies have examined the 
prognostic value of BCL-6 expression in PCNSL, with some studies reporting an 
association with a better prognosis and others reporting a worse prognosis (Levy 2008). 
Another study applied genome-wide expression profiling in PCNSL frozen tissue and 
generated a list of genes that seemed to constitute a « CNS signature » in PCNSL that 
was distinct from systemic NHL and normal brain (Rubenstein 2006). However, other 
studies found a discordant list of genes and, therefore, this subject remains unsettled. 
This trial offers the opportunity of collecting tissue from a relatively large number of 
patients for the studies described above, aiming at improving the molecular 
characterization of PCNSL. In addition to confirming or refuting the prognostic value of a 
standard NHL immunohistochemistry-based panel (BCL-6, CD-10, MUM-1 and CD-138), 
we will analyze genome-wide gene expression profiling utilizing the Illumina DASL assay. 
This analysis will seek to determine whether a PCNSL-specific molecular signature exists 
and to define a molecular subclassification for PCNSL that has prognostic implications. 
The DASL assay is ideal for use in PCNSL, as it requires much less RNA (200-500 ng) 
and generates robust gene expression data from FFPE samples, covering more than 
24,000 annotated genes derived from RefSeq (Build 36.2, Release 22). After analysis, 
unused remaining tissue will be returned to either the NRG Oncology Biospecimen Bank 
or the submitting institution, depending on the level of patient consent.  
10.6.2 
Evaluation of Polymorphisms Influencing the Methionine Metabolism as Predictors of the 
Development of MTX-Related White Matter Changes and Neurotoxicity 


38 
RTOG 1114: version date September 19, 2019 
Overview 
Prior to start of treatment, a 5 mL blood sample will be obtained from all patients who 
consent for participation. Polymorphisms affecting the methionine metabolism will be 
evaluated through PCR, including the following: MTHFR c.677C>T, MTHFR c.1298A>C, 
Tc2 c.776C>G, DHFR c.594+59del19bp and ATIC c.346C>G. Results will be correlated 
with the development of white-matter changes on MRI as defined by central imaging 
review and neurocognitive data.  
 
Rationale 
We hypothesize that genetic variants of methionine metabolism predict the occurrence of 
white-matter changes and neurotoxicity resulting from MTX-based chemotherapy. MTX is 
a competitive inhibitor of several enzymes involved in folate and methionine metabolism. 
In a retrospective study, Linnebank et al evaluated 10 genetic variants influencing the 
methionine metabolism and correlated with the development of white-matter changes on 
the MRI in 68 patients undergoing MTX-based chemotherapy for PCNSL (Linnebank 
2009). The authors found that the following polymorphisms were statistically significantly 
associated with white matter changes: the TT genotype of methylenetetrahydrofolate 
reductase c.677C>T (χ2 = 8.67; p = 0.013; df = 2), the AA genotype of 
methylenetetrahydrofolate reductase c.1298A>C (χ2 = 13.5; p = 0.001; df = 2), and the 
GG genotype of transcobalamin 2 c.776C>G (χ2 = 19.73; p < 0.001). The relatively large 
sample in this present study, including one arm that will be treated with chemotherapy 
alone provides the opportunity of prospective validation of those findings. If confirmed, 
such polymorphism analysis would allow the identification of patients at risk for the 
development of MTX-related neurotoxicity that could be treated with a reduced number of 
treatment cycles in future studies.   
 
11.0 
PATIENT ASSESSMENTS  
11.1 
Study Parameters: See Appendix I. Details and exceptions appear below. 
11.1.1 
Follow-Up for Patients With Initial Involvement of the Eyes 
All patients with initial involvement of the eyes on baseline evaluation should have a detailed 
follow-up evaluation including dilated fundus examination and color photographs of the 
posterior pole of the eye. Repeat ophthalmologic evaluation is not required for patients without 
evidence of ocular lymphoma at baseline or interval development of ocular symptoms. 
11.1.2 
Assessment of Radiographic Response 
During treatment, MRI will be performed at the following time points: 
- 
At baseline (< 2 wks prior to start of chemotherapy) 
- 
During R-MPV: Day 28 of cycle 2; day 28 of cycle 4 
- 
During cytarabine: cycle 1 day 1 (arm B only) 
- 
Follow-up period: every 2 months, starting 26 days after the last dose of cytarabine for 
the first two years, then every 6 months till 5 years. 
 
At each assessment, the radiographic response will be assessed as per IPCLG 
recommendations (Abrey, 2005), with modifications. Use of corticosteroid will be recorded in 
the radiographic assessment form and will be utilized for the response evaluation. Patients who 
previously had evidence of ocular lymphoma will require slit lamp re-examination. Patients with 
positive CSF cytology will require repeated lumbar puncture.  
 
 
11.1.3 
Neuroimaging Techniques 
Standard MRI sequences should be obtained. Whenever possible, the exam should at least 
include T1 pre and post gadolinium axial sequences, FLAIR and T2 sequences. This will allow 
for evaluation of pre-contrast T1 hypersignal that may be misinterpreted as active, contrast 
enhancing disease.  MRI scans will be performed with and without contrast and should be 
acquired in a plane that images both the anterior and posterior commissures (along the AC-PC 
line) and should cover the entire brain.  The MRI scan should be comprised of at least 12 
slices to encompass the intracranial contents from the cranial base to the convexity. A 
technique that utilizes 5 mm cuts with a 1 mm gap is preferred on the axial images. 
 


39 
RTOG 1114: version date September 19, 2019 
Responses will be assessed at the time points corresponding to the imaging dates as detailed 
in Appendix I (during R-MPV: cycle 2, d28; cycle 4, d28; during cytarabine: cycle 1 day 1 (arm 
B only); follow-up period: every 2 months for the first 2 years and every 6 months during years 
3-5. The following timepoints will be submitted for central review for confirmation of responses 
and correlative studies:   baseline; cycle 2, d28; cycle 4, d28; cytarabine cycle 1 day 1 (arm B 
only); then every 6 months until year 5, starting 26 days after the last cytarabine dose. All 
efforts should be made to collect the MRIs  regardless of patient progression status.   
 
All neuroimaging obtained during the study should be submitted to NRG Oncology for central 
review and correlative studies.  
 
11.2 
Neurocognitive Function (NCF) Assessment 
NOTE: Sites must offer English-speaking participants the opportunity to participate in the 
neurocognitive function component of this study.  
 
If the patient consents to participate in the neurocognitive function component of the study, sites 
are required to administer the baseline NCF and functional assessments prior to the start of 
protocol treatment:  
 
The healthcare professional (e.g., nurse, psychologist) who is responsible for test administration 
in this study must be pre-certified by Dr. Denise Correa See Section 5.2 and Appendix IV for 
details. The tests in the neurocognitive test battery were selected because they are widely used 
standardized psychometric instruments that have been shown to be sensitive to the impact of 
cancer and the neurotoxic effects of cancer treatment in other clinical trials (Meyers 2004). The 
tests have published normative data that takes into account age, and where appropriate, 
education and gender. The tests are given by certified site administrators, and the total time for 
the cognitive assessment is approximately 20 minutes, as follows: 
 
Cognitive Domain Test Administration 
Memory:  Hopkins Verbal Learning Test-Revised (HVLT-R) – 5min 
Cognitive Processing Speed: Trail Making Test, Part A – 3min 
Executive Function: Trail Making Test, Part B-  5min 
Verbal fluency: Controlled Oral Word Association (COWA)- 5min 
11.2.1 
Hopkins Verbal Learning Test-Revised (HVLT-R) 
The patient is asked to recall a list of 12 words over three trials. After a delay of 20 minutes, the 
patient is asked to spontaneously recall the words. The patient is then asked to identify the list 
words from distractors. There are six alternate forms of this test to minimize practice effects. 
The test measures learning memory retrieval, and memory consolidation processes. This 
measure has been widely used in clinical trials (Benedict 1998). 
11.2.2 
Trail Making Test, Part A 
This is a test of visual-motor cognitive processing speed, requiring the patient to connect dots 
in numerical order from 1 to 25 as fast as possible (Reitan 1992).  
11.2.3 
Trail Making Test, Part B 
This test is similar to Trail Making Test Part A, with the additional requirement of shifting mental 
set (an executive function). The patient connects dots alternating numbers and letters as fast 
as possible (Reitan 1992). 
11.2.4 
Controlled Oral Word Association (COWA) 
This is a test of phonemic verbal fluency. The patient is asked to produce as many words as 
possible in 60 seconds beginning with a specified letter. There are 2 alternate forms of this test 
(Benton 1989). 
 
11.3 
Quality of Life (QOL) Assessment (10/28/13) 
NOTE: Sites must offer English-speaking participants the opportunity to participate in the 
quality of life component of this study. 
11.3.1 
EORTC 
Quality 
of 
Life 
Questionnaire-Core 
30/Brain 
Cancer 
Module-20 
(EORTCQLQ30/BCM20) 
The EORTC QLQ-C30/BCM20 were developed and validated for use in this patient population. 
The QLQ-C30 is a 30-item self-report questionnaire that has patients rate the items on a 4-point 
scale, with 1 “not at all” to 4 “very much.” The instrument measures several domains, including 


40 
RTOG 1114: version date September 19, 2019 
physical functioning, role functioning, emotional functioning, cognitive functioning, social 
functioning, fatigue, pain, nausea and vomiting, and several single items (dyspnea, insomnia, 
anorexia, constipation, diarrhea, and financial impact). The BCM20 consists of 4 scales 
comprised multiple items (future uncertainty, visual disorder, motor dysfunction, communication 
deficit) and 7 single items (headache, seizures, drowsiness, hair loss, itching, difficulty with 
bladder control, and weakness of both legs). The combined instrument takes an average of 8 
minutes to complete by patients with primary brain tumors (Osoba 1996). 
 
 
11.4 
Measurement of Response  
 
Response will be evaluated in this study using the international criteria proposed by the 
International PCNSL Study Group (Abrey 2005). In addition, MRI FLAIR or T2 sequences will be 
reviewed and scored for the development of white matter changes and leukoencephalopathy, for 
correlation with methionine metabolism polymorphisms and neuropsychological findings. 
11.4.1 
Radiographic Response (see Section 11 and Appendix I for assessment schedule) 
CR requires the following:  
 
Complete disappearance of all enhancing abnormalities on gadolinium-enhanced MRI.  
 
If the patient had previous evidence of ocular lymphoma, no evidence of active ocular 
lymphoma as defined by absence of cells in the vitreous and resolution of any previously 
documented retinal or optic nerve infiltrates may be present. Chronic changes of the 
retinal pigment epithelium in the setting of a prior retinal or optic nerve infiltrate do not 
preclude the definition of a CR. (See Section 11.1 for patients with initial involvement of 
the eyes on baseline.) 
 
Negative CSF cytology. Given the reported disparity between cytologic specimens 
obtained from the ventricular system as opposed to lumbar puncture, it is recommended 
that a negative CSF cytology be confirmed from both spaces in patients with an Ommaya 
reservoir. Patients without significant CSF abnormalities at baseline do not require repeat 
CSF evaluation provided they have not developed interval symptoms that suggest 
leptomeningeal dissemination.  
 
At the time a CR is determined, the patient should have discontinued use of all 
corticosteroids for at least 2 weeks. Rare exceptions may be made for those patients 
receiving corticosteroids for another diagnosis (eg, panhypopituitarism).  
 
 
 
CR/unconfirmed (CRu) includes those patients who fulfill the criteria for CR with the following 
features/limitations: 
 
Any patient who fulfills all criteria for CR but continues to require corticosteroid therapy at 
any dose should be considered an unconfirmed CR. This is critical because 
corticosteroids may be oncolytic in treating occult tumor. In addition, corticosteroids may 
decrease gadolinium enhancement on MRI.  
 
Some patients will have a small but persistent enhancing abnormality on MRI related to 
biopsy or focal hemorrhage. It is often difficult to ascertain whether this represents a 
residual nidus of tumor or scar tissue. Adjunctive radiologic studies such as single-photon 
emission computed tomography or positron emission tomography may be helpful, but 
often the nature of these abnormalities may only be determined by observing the patient 
with serial scans. If the type of abnormality does not change or slowly involutes over time 
without therapy and corticosteroids, it is reasonable to categorize it as a CR.  
 
Patients with a persistent minor abnormality on follow-up ophthalmologic examination 
(persistent nonmalignant cells in the vitreous, alteration of the retina/optic nerve that is 
not consistent with tumor infiltration) may be considered a CRu if this abnormality is 
unlikely to represent ocular lymphoma.  
 
Attentive review of T1 pre-gadolinium contrast sequences should be performed in order 
to differentiate contrast-enhancement from T1 pre-gadolinium hyperintensities, likely 
representing hydrated calcification and treated disease. Such T1 pre-gadolinium 
hyperintensities should not be considered when assigning response.  
 
Partial response (PR) requires all of the following: 
 
A ≥ 50% decrease in the contrast-enhancing lesion seen on MRI as compared with 
baseline imaging.  


41 
RTOG 1114: version date September 19, 2019 
 
Corticosteroid dose is irrelevant to the determination of PR.  
 
Ophthalmologic examination should show a decrease in the vitreous cell count or 
retinal/optic nerve cellular infiltrate but may continue to show persistent malignant or 
suspicious cells. Color photos of the posterior pole of the eye should be obtained to 
document improvement in retinal/optic nerve infiltrates.  
 
CSF cytologic examination may be negative or continue to show persistent malignant or 
suspicious cells in patients with a ≥ 50% decrease in the primary brain lesion. In the 
setting of primary leptomeningeal lymphoma, PR is not recognized; all patients should be 
categorized as CR, CRu, stable disease, or progressive disease.  
 
No new sites of disease.  
 
Stable disease is defined as less than a PR but not progressive disease. 
 
Progressive disease requires the following: 
 
A more than 25% increase in the contrast-enhancing lesion seen on MRI as compared 
with baseline or best response (comparison should be made to the smallest of multiple 
lesions).  
 
Progression of ocular disease as indicated by an increase in the vitreous cell count or 
progressive retinal or optic nerve infiltration.  
 
Appearance of any new lesion or site of disease (ocular, leptomeningeal or systemic) 
during or at the end of therapy.  
 
Relapsed disease (only applicable to patients with a prior CR, CRu) requires the 
following:  
 
Appearance of any new lesion. 
 
 
 
 
 
Summary of Response Guidelines  
Response 
Brain Imaging 
Corticosteroid Dose 
Eye Examination* 
CSF Cytology* 
CR 
No contrast 
enhancement 
None 
Normal 
Negative 
Cru 
No contrast 
enhancement 
Any 
Normal 
Negative 
Minimal abnormality 
Any 
Minor RPE abnormality 
Negative 
PR 
50% decrease in 
enhancing tumor 
Irrelevant 
Minor RPE abnormality or 
normal 
Negative 
No contrast 
enhancement 
Irrelevant 
Decrease in vitreous cells or 
retinal infiltrate 
Persistent or 
suspicious 
PD 
25% increase in lesion Irrelevant 
Recurrent or new ocular 
disease 
Recurrent or positive 
Any new site of disease: CNS or systemic 
Abbreviations: CR, complete response; CRu, unconfirmed complete response; RPE, retinal pigment epithelium; 
PR, partial response; PD, progressive disease. *required if previously abnormal.  
 
 
Evaluation of Leukoencephalopathy and White Matter Changes 
In addition to response evaluation, each on-study MRI will be reviewed by the local 
investigators for the presence of white matter changes and leukoencephalopathy that may 
develop as a result from chemotherapy and/or radiotherapy. To that end, T2 or FLAIR 
sequences will be evaluated for presence of white matter hypersignal and rated as per the 
scale below (modified Fazekas scale, Correa 2009). All white matter hypersignal lesions, 
including those abnormalities thought to be a result from the tumor or surgery rather than 
chemotherapy or radiotherapy should be taken into consideration for rating purposes.   
 
Modified Fazekas Scale:  
Grade 0: No white matter change 


42 
RTOG 1114: version date September 19, 2019 
Grade 1: Minimal patchy white matter foci  
Grade 2: Start of confluence of white matter disease  
Grade 3: Large confluent areas of white matter changes  
Grade 4: Confluence of white matter changes with cortical and subcortical involvement  
Grade 5: Leukoencephalopathy  
 
11.5 
Criteria for Discontinuation of Protocol Treatment (1/31/13) 
Protocol treatment will be discontinued: 
 
In case of unacceptable toxicity 
 
Patient withdrawal of consent 
 
Tumor progression  
 
If protocol treatment is discontinued, follow-up and data collection will continue as specified in the 
protocol. All patients will be asked to be followed as specified above for a total of 5 years, 
regardless of disease status and duration of treatment. History of tumor progression and 
salvage treatments will be recorded throughout 5 years.  
 
If the patient is on active treatment for recurrent disease at the time a follow-up evaluation is due, 
the follow-up evaluation may be postponed and performed after salvage treatment has been 
completed. However, the subsequent evaluations should follow the original schedule and time 
points, as described in appendix 2, and defined from the time of original start of treatment. 
Therefore, all patients will have evaluations performed at same time points in the course of their 
disease, regardless of disease progression and salvage treatments.        
 
Patients who are found to be ineligible (eg, bone marrow biopsy positive for the presence of 
lymphoma) will be removed from study and treated at the discretion of treating physician.  
 
12.0 
DATA COLLECTION (1/27/15) 
 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1720 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
12.1 
Summary of Data Submission  (8/25/15) 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks after registration  
Initial Evaluation Form (I1) 
Within 2 weeks after registration 
Pathology Report (P1) [For studies with 
pathology] 
Within 2 weeks after registration 
Treatment Form (TF) 
During treatment with R-MP(V) at the end of 
each 28 day cycle and during treatment with 
cytarabine at the end of each 28 day cycle.  
Follow-up Form (F1) 
Each 2 months starting 4 weeks after 
treatment for the first 2 years and the each 6 
months for year 3 to 5. See Section 11.5 for 
additional information. 
 
 
Quality of Life Assessments: 
EORTC QLQ30/BCM20 
 
Within 2 weeks prior the start of treatment 
(baseline).  
During treatment with R-MP(V) on d28 of 
cycle 4. 
During follow-up each 6 months for 5 years. 
Neurocognitive Assessments: 
HVLT-R 
Within 2 weeks prior the start of treatment 
(baseline).  


43 
RTOG 1114: version date September 19, 2019 
Trail Making Test Part A and B 
COWAT 
 
 
 
*NOTE. If a patient experiences disease 
progression during the study evaluation period, 
the neurocognitive and QoL assessment should 
be put on hold until the patient is clinically 
stable for 3 consecutive months, at which time 
the follow-up neurocognitive evaluation should 
be obtained. The next neurocognitive 
evaluation should be performed according to 
the next standard/planned protocol follow-up 
dates (the study calendar is not reset), but no 
sooner than 3 months from the previous 
neurocognitive evaluation. 
 
 
During treatment with R-MP(V) on d28 of 
cycle 4. 
During follow-up each 6 months for 5 years. 
 
 
 
 
 
 
 
Dosimetry Information 
 
MRI scans & reports (MR, ME)* See methods 
of submission  below for scans 
Pre-study, day 28 of R-MPV cycles 2 & 4, day 
1 of cytarabine cycle 1 ( arm B only),  every 
6mo for 5 yrs  and at the time of progression 
Radiology review form (SR) 
As each scan time point listed above 
Radiotherapy Form (T1) 
Within 1 week of RT end 
Complete Daily Treatment Record (T5) 
Within 1 week of RT end 
Composite Isodose Distribution (T6) in COLOR 
Within   1 week of RT end   
*NOTE: Copies of simulation and port films and the complete RT daily treatment record for the (site) will be 
submitted to NRG Oncology ONLY if specifically requested.  
Methods of scan submission 
NRG Oncology can provide software (TRIAD) for installation on a PC at your site that collects, anonymizes and 
submits image sets from your MRI system or from your PACS. The images are “DICOM pushed” either from the 
MRI system or from the PACS to the PC on which the software is installed. This software anonymizes and 
encrypts images as they are transferred via FTP to the NRG Oncology image archive. For more information, see  
https://triad.acr.org. 
 
TRIAD Image Submission software PC requirements: 
1. Network capability to transmit data from a scanner to a linked workstation, PC, or PACS 
2. A Windows XP PC available to transmit data (patient data, MR and PET image data) to NRG Oncology: 
a. Operating System Windows XP Pro 
b. Access to the Internet: Internet Explorer 
c. Minimum of 50 GB available hard drive 
d. At least 1 GB RAM 
e. Ability to view PDF documents 
3. Software utilities required: 
a. Windows Installer 3.1 
b. Microsoft .NET framework 2.0 
c. MDAC Type 2.8 
d. MS SQL 2005 Express 
 
Please contact the TRIAD help desk (Triad-Support@ acr.org) regarding installation requirements and to 
arrange the installation of TRIAD software prior to first accrual. 
 
For questions regarding image submission, call 215-574-3219 
 
Scans can also be submitted on CD and mailed to HQ 
 


44 
RTOG 1114: version date September 19, 2019 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Endpoints 
13.1.1 
Primary Endpoint 
Progression-free survival (PFS), defined as the interval from randomization to progression or 
death, whichever occurs first. 
13.1.2. 
Secondary Endpoints 
• 
 Overall survival (OS), defined as the interval from randomization to death due to any 
cause 
• 
 Quality of life measured by the EORTC Quality of Life Questionnaire-Core/Brain Cancer 
Module( QLQ-C30/BCM20) 
• 
 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).  
• 
 Response (partial response [PR] and complete response [CR]) rate 
• 
 Chemotherapy-related toxicity, measured by CTCAE, v.4.0. 
 
13.2 
Sample Size and Power Justification 
The sample size calculation will address whether the addition of low-dose WBRT will improve the 
median PFS in comparison to a chemotherapy-only approach. The null hypothesis is that the 
median PFS for both arms is 12 months. The alternative hypothesis is that patients receiving low-
dose WBRT will achieve a median PFS rate of 19 months. The study will be a randomized phase 
II screening trial as proposed by Rubinstein et al (2005). The randomization of experimental and 
standard arms is set as 1:1 and the randomization will occur after registration. Patients will be 
stratified according to MSKCC RPA status. With 84 eligible subjects (42 patients/arm), there will 
be 80% power to detect a 37% reduction in the hazard ratio to 0.63 at the significance level of 
0.15 (one-sided). Analysis will be performed when 67 events are reported, expected to occur 18 
to 25 months after trial closure. Guarding against up to a 5% ineligibility rate, the final targeted 
accrual for this study will be 89 cases. 
 
13.3 
Patient Accrual 
The study is projected to accrue 3 cases per month. No accrual is expected during the first 2 
months of trial activation as institutions obtain IRB approval; a total accrual of 6 patients is 
expected during the next 4 months; and thereafter monthly accrual is expected to reach 3 
patients per month. Therefore, the target accrual of 89 cases should be completed within 33 
months of study activation. If the average monthly accrual rate (excluding the first 6 months) is 
less than 1.5 patients, the study will be re-evaluated with respect to feasibility. 
 
13.4 
Stratification and Randomization 
Patients will be stratified by the MSKCC RPA classification for PCNSL based on age and KPS as 
follows (Abrey 2006) 
 
Class 1: age ≤ 50 
 
Class 2: age > 50 and KPS ≥ 70 
 
Class 3: age > 5 0 and KPS < 70 
The randomization will occur in a 1:1 ratio between the experimental arm and control arm in each 
stratum. Patients will be randomized in a permuted block design using the method of described 
by Zelen (1974). 
 
13.5 
Analyses Plans (07-AUG-2018) 
13.5.1 
Statistical Methods 
 
Overall and Progression-Free Survival 
OS and PFS rates will be estimated using the Kaplan-Meier method (Kaplan 1958), and 
differences between treatment arms will be tested by the log rank test (Mantel 1966). OS will 
be measured from the date of randomization to the date of death or, otherwise, the last 
follow-up date on which the patient was reported alive. PFS will be measured from the date 
of randomization to the date of first progression or death or, otherwise, the last follow-up 
date on which the patient was reported alive. Differences in observed severities of toxicities 
(grade 3+) between groups will be tested using a chi square test.  
 


45 
RTOG 1114: version date September 19, 2019 
Multivariate analyses with the Cox proportional hazard model (Cox 1972) for OS and PFS 
will be performed with the stratification variables as fixed variables to assess the treatment 
effect adjusting patient-specific risk factors. The covariates evaluated for the multivariate 
models are: assigned protocol treatment, RPA risk class, and other prognostic factors. 
Proportional hazard assumptions will be checked using different graphical or time-varying 
coefficients testing methods. If the data clearly do not follow proportional hazards, other 
statistical models will be used to fit the data instead. Possible alternatives are to use the 
stratified Cox proportional hazard model, to use the accelerated failure model, or to partition 
the time axis into sections where proportional hazard assumption holds.  
 
 
Analysis of Neurotoxicity and Impact on Cognitive Function and QOL 
Evaluation of neurotoxicity will occur at two levels: formal evaluation of cognitive function 
through neuropsychological and QOL evaluation, as well as evaluation of neurotoxicity as 
clinically defined by the treating physician.  
• Neuropsychological and QOL evaluation: In both arms, the cumulative incidence 
approach will be used to estimate the median time to neurocognitive failure to account for 
the competing risks of death. To that end, neurocognitive failure will be defined as the 
first cognitive failure on 2 or more of the following tests: the HVLT-R for Free Recall, 
Delayed Recall and Delayed Recognition; the COWA; and the Trail Making Test Part A or 
B. Cognitive failure for each test is defined as a change in a score that meets or exceeds 
the Reliable Change Index (RCI) value for each test indicating a performance that is 
worse than the patient’s personal baseline score. In addition, the standardized test score 
will also be calculated for each test and to determine which tests are most sensitive to 
detect cognitive impairment/change. The cut-offs for standardized scores will be 
determined through receiver operating characteristic (ROC) methods.  
 
Gray’s test will be used to test for a statistically significant difference in the distribution of 
neurocognitive failure times (e.g. neurocognitive failure at 3-year, 5-year) at the 
alpha=0.05 level (Gray RJ. 1988). Fine and Gray’s proportional subdistribution hazard 
regression model  (Fine and Gray, 1999) will be used to assess the effects of covariates 
on the progression.  
 
A similar approach will be used for symptom and HRQOL data.  For the EORTC 
QLQ30/BN20, differences of at least 10 points will be classified as the minimum clinically 
meaningful change in a HRQOL measure.  For example, an increase of 10 points or 
more on a functional scale would mean a moderate improvement, whereas a decrease of 
10 points or more would be interpreted as moderate worsening.  Furthermore, a rise in a 
symptom score means deterioration.  Changes of less than 10 points will be regarded as 
no change or as clinically irrelevant, and changes of more than 20 points will be 
considered large effects.  
 
For the quality of life, symptom and neurocognitive function endpoints, the longitudinal 
data analysis will also be performed to assess if there exists difference over time across 
the two treatment arms using hierarchical formulation of the linear mixed model. 
 
Participation in the quality of life/neurocognitive function component is not mandatory in 
this study. However, if patients agree to participate in this component, adherence to the 
component assessment schedule will be encouraged through reminders from 
participating institutions. Completion of all scheduled assessment is part of the routine 
delinquency assessment for participating institutions. The Statistics and Data 
Management Center staff will monitor proportions of missing quality of life/neurocognitive 
function information in each treatment arm at different assessment points. In spite of 
these efforts, missing data is to a certain extent expected.  The information from patients 
with missing data will be reviewed in to determine whether the data analyses will be 
biased.  Patients with missing data will be reviewed for the distributions of treatment arms 
and patient characteristics. Mean scores on the primary items will be compared for 
patients with and without missing data at different assessment points to identify whether 
missing data was preceded by a significant decline in the scores. Mean scores by 


46 
RTOG 1114: version date September 19, 2019 
assessment time for cohorts stratified by baseline score quartile will also be compared to 
investigate if the missingness is consistent with an ignorable missing data process 
(missing at random). If no missing data mechanism can be detected, the data will be 
analyzed assuming missing data is at random and the appropriate imputation for missing 
values will be conducted. The imputation methods may include: the missing value can be 
imputed from the variable mean of the completed cases, or it can be imputed from the 
mean conditional on observed values of other variables, or multiple imputation. If the 
missing data mechanism appears to be present, we will use appropriate analytic 
strategies to control for the potential bias and, if possible, to impute the missing data. The 
possible strategies for imputation and analyses will depend on the severity of the missing 
data problem and missing pattern. The imputation methods may include: worse-case 
scenario, use of mean response for individuals who withdraw from the trial from either all 
or similar (matched) patients remaining in the trial, last observation carry forward, or 
multiple imputation. The data can also are analyzed using pattern mixture models to 
estimate separate estimates for the outcome within strata based on the missing data 
pattern, and then combining estimates in a specialized way to yield appropriate an overall 
effect estimate (Little R and Rubin D. 2002). Sensitivity analyses based on the varying 
assumptions about the missing data mechanisms will also be conducted. 
• 
Evaluation of clinically defined neurotoxicity: In addition to the formal evaluation of 
cognitive function and QOL as described above, information on the incidence of 
neurotoxicity as per the investigator’s assessment will be collected in this study. The 
purpose of this analysis is to provide an estimate of neurotoxicity rate that can be 
compared to historical controls on the utilization of full-doses of WBRT, which have 
not included neuropsychological evaluation. In those studies, neurotoxicity was 
qualitatively defined by treating physicians. 
For a comparable assessment, in this study physicians will be asked to determine 
whether the patient is experiencing neurotoxicity at each clinical assessment 
throughout the 5 year followup. For this purpose, neurotoxicity will be defined as 
severe 
cognitive 
deterioration 
in 
comparison 
to 
post-treatment 
baseline, 
accompanied by psychomotor slowness and gait ataxia, and that cannot be 
accounted for by disease recurrence. 
Analysis will be descriptive, and the 3y and 5y cumulative incidence of neurotoxicity 
in each arm will be reported, accounting for death as a competing risk (as described 
above). 
 
13.5.2 
Interim Analysis to Monitor Study Progress 
Interim reports with statistical analyses will be prepared every 6 months until the initial 
manuscript reporting the treatment results has been submitted. The reports will contain: 
 
the patient accrual rate with a projected accrual completion date; 
 
accrual by institution; 
 
the pretreatment characteristics of accrued patients; 
 
the frequency and severity of toxicities; and 
 
the results of any completed study chair modality reviews. 
 
The interim reports will not contain the results from the treatment comparisons with respect to 
the efficacy endpoints (OS, PFS, treatment response).  The NRG Oncology Data Monitoring 
Committee (DMC) will review the accrual to the study and the rate of adverse events on the 
study at least twice per year until the initial results of the study have been presented to the 
scientific community. 
13.5.3 
Interim Futility Analysis 
The interim futility analysis will be performed when 50% of the required events (34 death or 
progression) are reported. The analysis will be performed on an intent-to-treat basis, with all 
eligible cases included in the treatment arm to which they were randomized regardless of what 
treatment the patients actually received.  The primary endpoint progression-free survival will be 
tested. The responsible statistician may recommend early reporting of the results and/or 
stopping accrual (if applicable) of the trial if the estimated hazard ratio favors the control arm 
(by any amount). The accrual rate, treatment compliance, safety of the treatments, and the 


47 
RTOG 1114: version date September 19, 2019 
importance of the study are also considered in making such a recommendation. The results will 
be reported to the NRG Oncology DMC with the treatment blinded. The DMC will then make a 
recommendation about the trial to the NRG Oncology Group Co-Chairs. 
13.5.4 
Interim Efficacy Analysis 
In July 2017, the result of the interim futility analysis mentioned in the section above was 
presented to the NRG Oncology DMC. At the request of the DMC, it was agreed upon that an 
interim efficacy analysis would be added at a later stage of the trial. This section addresses the 
method to be used for this interim analysis. 
 
An interim efficacy analysis will be performed when 67% of the required events (45 deaths or 
progression events) are observed. At that time, if the PFS hazard ratio is in favor of the 
experimental arm with an estimated value of 0.50 or less, then the responsible statistician may 
recommend early reporting of the results. At 45 events, a hazd ratio of 0.50 corresponds to a 
Haybittle-Peto interim monitoring boundary p-value of 0.01. The results will be reported to the 
NRG Oncology DMC. The DMC will then render the final recommendation about the trial to the 
NRG Oncology Group Co-Chairs.  
13.5.5 
Analysis for Reporting the Initial Treatment Results 
The final analysis will be performed on an intent-to-treat basis, such that all eligible cases on 
the study will be included in the arm to which they were randomized regardless of what 
treatment the patients actually received. The analysis to report the final results of treatment 
comparison between the experimental arm and the control arm will be undertaken when 67 
events (death or progression) have been reported. A one-sided log-rank test at the 0.15 
significance level will be performed to test the difference in PFS between the two treatment 
arms. If the P value is less than protocol-specified 0.15 (one-sided), the study statistician will 
reject the null hypothesis and conclude that the experimental arm has a better PFS than the 
standard arm, thereby supporting the development of a phase III trial comparing this regimen to 
the current standard at that time. All information reported in the interim analyses to monitor the 
study progress (Section 13.5.2) and treatment compliance with respect to radiation and 
chemotherapy will also be included in the final report. 
13.5.6 
CDUS Tracking 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
 
13.6 
Gender and Minorities 
In conformance with the National Institutes of Health (NIH) Revitalization Act of 1993 with regard 
to inclusion of women and minorities in clinical research, we address this issue here; both men 
and women of all races and ethnic groups are eligible for this study. The following table lists the 
projected accrual for each racial and ethnic group based upon previous RTOG PCNSL trials. 
 
 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
1 
3 
4 
Not Hispanic or Latino 
43 
42 
85 
Ethnic Category: Total of all subjects 
44 
45 
89 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
42 
41 
83 


48 
RTOG 1114: version date September 19, 2019 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Racial Category: Total of all subjects 
44 
45 
89 


49 
RTOG 1114: version date September 19, 2019 
REFERENCES 
 
 
 
Abrey LE, Yahalom J, DeAngelis LM: Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:3144-
3150, 2000 
 
Abrey LE, Batchelor TT, Ferreri AJM, et al: Report of an international workshop to standardize baseline evaluation 
and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034-5043, 2005 
 
Abrey LE, Benporat L, Panageas KS, et al. Prognostic model for primary CNS lymphoma (PCNSL): Recursive 
partitioning analysis (RPA) of the MSKCC PCNSL population. J Clin Oncol, 2006 ASCO Annual Meeting 
Proceedings Part I. Vol 24, No. 18S (June 20 Supplement): 1531, 2006 
 
Benedict RHB, Schretlen D, Groninger L, et al.  Hopkins Verbal Learning Test - Revised:  Normative data and 
analysis of inter-form and test-retest reliability. Clin Neuropsychologist. 12:43-55,1998. 
 
Benton AL, Hamsher KdeS. Multilingual Aphasia Examination. Iowa City, IA: AJA Associates; 1989. 
 
Batchelor T, Carson K, O'Neill A, et al: Treatment of primary CNS lymphoma with methotrexate and deferred 
radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044-1049, 2003 
 
Camilleri-Broet S, Criniere E, Broet P, et al: A uniform activated B-cell-like immunophenotype might explain the 
poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 107:190-6, 2006 
 
Correa DD, Rocco-Donovan M, DeAngelis LM, et al: Prospective cognitive follow-up in primary CNS lymphoma 
patients treated with chemotherapy and reduced-dose radiotherapy. J Neurooncol 91:315-21, 2009 
 
Cox DR: Regression models and life tables. J Royal Stat Soc, Series B, 34:187-229, 1972 
 
DeAngelis LM, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central 
nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643-8, 2002 
 
Fine, J. and Gray, R.  A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 
94:496-509, 1999. 
 
Gray R.J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist. 
16:1141-1154, 1988. 
 
Groves MD, Maor MH, Meyers C, et al. A phase II trial of high-dose bromodeoxyuridine with accelerated 
fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme. Int J 
Radiat Oncol Biol Phys 45:127-35, 1999. 
 
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Amer Statist Assoc 53:457-481, 
1958 
 
Levin VA, Yung WK, Bruner J, et al. Phase II study of accelerated fractionation radiation therapy with carboplatin 
followed by PCV chemotherapy for the treatment of anaplastic gliomas. Int J Radiat Oncol Biol Phys 53:58-66, 
2002. 
 
Levy O, Deangelis LM, Filippa DA, et al: Bcl-6 predicts improved prognosis in primary central nervous system 
lymphoma. Cancer 112:151-6, 2008 
 
Linnebank M, Moskau S, Jurgens A, et al: Association of genetic variants of methionine metabolism with 
methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma. Neuro Oncol 11:2-8, 
2009 
 
Mantel N: Evaluation of survival data and two new rank order statistics rising in its consideration. Cancer 
Chemotherapy Rep 50:163-170, 1966 


50 
RTOG 1114: version date September 19, 2019 
 
Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases 
treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 
22:157-65, 2004. 
 
Omuro AM, Ben-Porat LS, Panageas KS, et al: Delayed neurotoxicity in primary central nervous system 
lymphoma. Arch Neurol 62:1595-600, 2005 
 
Omuro A, Taillandier L, Chinot O, et al: Primary CNS lymphoma in patients younger than 60: can whole-brain 
radiotherapy be deferred? J Neurooncol, 2010 
 
Osoba D, Aaronson NK, Muller M, et al. The development and psychometric validation of a brain cancer quality-
of-life questionnaire for use in combination with general cancer-specific questionnaires. Qual Life Res 5:139-50, 
1996. 
 
Pels H, Schmidt-Wolf IGH, Glasmacher A, et al: Primary central nervous system lymphoma: results of a pilot and 
phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489-
4495, 2003 
 
Pels H, Juergens A, Glasmacher A, et al: Early relapses in primary CNS lymphoma after response to 
polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 91:299-305, 2009 
 
Reitan RM. Trail Making Test. Manual for Administration and Scoring. Reitan Neuropsychology Laboratory; 
Tucson, Arizona, 1992 
 
Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II 
screening trial. J Clin Oncol 22:7199-7206, 2005. 
 
Rubenstein JL, Fridlyand J, Shen A, et al: Gene expression and angiotropism in primary CNS lymphoma. Blood 
107:3716-23, 2006 
 
Shah GD, Yahalom J, Correa DD, et al: Combined immunochemotherapy with reduced whole-brain radiotherapy 
for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730-5, 2007 
 
Thiel E, Korfel A, Martus P, et al: High-dose methotrexate with or without whole brain radiotherapy for primary 
CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11:1036-47, 2010 
 
Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with 
glioblastoma multiforme at first relapse. Br J Cancer 83:588-93, 2000. 
 
Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365-375, 1974. 


51 
RTOG 1114: version date September 19, 2019 
 
APPENDIX I (8/25/15) 
STUDY PARAMETER TABLES 
 
Pretreatment Assessments 
 
≤6 wks prior to 
registration 
≤2 wks prior to 
registration 
≤2 wks prior to 
start of treatment 
Histology confirmation  
See section 3.1.1 for details 
X 
 
 
History/physical 
X 
 
X 
Neurologic exam, KPS 
 
 
X 
MRI of brain, response assessment 
X 
 
X 
History of corticosteroids use 
 
 
X 
CT chest, abdomen, pelvis 
X 
 
 
Chest X-ray 
 
 
X 
Anti-HIV test   
X 
 
 
CBC w/ diff & ANC, platelets, Hgb 
 
X 
X 
Bilirubin, AST 
 
X 
X 
ALT 
 
 
X 
LDH 
 
 
X 
Serum creatinine 
 
X 
X 
Creatinine clearance 
 
X 
X 
Electrolytes, BUN 
 
 
X 
Urinalysis  
 
 
X 
Serum or urine pregnancy test (if applicable) 
X 
 
 
Complete ophthalmologic exam including slit 
lamp exam 
 
 
X 
Bone marrow biopsy see section 4.1 for 
details 
Taken pre-treatment (≤ 6 weeks); submitted post-
registration (< 1 month after start of treatment) 
Lumbar puncture see section 4.1 for details 
Taken pre-treatment (≤ 6 weeks) 
Hepatitis B screening (recommended): see 
section 4.2 for details 
 Recommended (≤ 6 weeks) pre-treatment; results not 
needed for patient to start treatment 
Informed consent 
X 
 
 
QOL assessment 
(for consenting pts) 
 
 
X 
NCF assessment 
 (for consenting pts) 
 
 
X 
Tissue (H&E, immunohistochemistry, tissue 
block, unstained slides) for central path 
review  
Taken pre-treatment; submitted post-registration 
Tissue (tumor, bone marrow, +/or eye 
biopsy) for banking/correlative studies (for 
consenting pts) 
Taken pre-treatment; submitted post-registration 
CSF for banking/correlative studies (for 
consenting pts) 
Taken pre-treatment; submitted post-registration. 
Remnant sample from clinical collection can be used. 
DNA for banking/correlative studies (for 
consenting pts) 
Taken pre-treatment; submitted post-registration 
Buccal swab (for consenting pts) 
Taken pre-treatment; submitted post-registration 
 


52 
RTOG 1114: version date September 19, 2019 
Assessments During Treatment 
A window of + 3/- 2 days is acceptable for all on-study treatments and assessments. (It is NOT applicable to pre-
treatment assessments.) 
 
R-MPV (cycles 1, 2, 3, 4) 
Consolidation 
Cytarabine (Cycles 1 &2) 
History/physical 
d 1, 15  
d 1 
Neurologic exam, KPS 
d 1, 15 
d 1 
MRI of brain, response assessment 
Cycle 2, d28  
Cycle 4, d28 
Cycle 1 d 1 (arm B) 
History of corticosteroids use 
Cycle 2, d28  
Cycle 4, d28 
Cycle 1 d 1 (arm B) 
CBC w/ diff & ANC, platelets, Hgb 
d 1, 8, 15, 22 
Repeat wkly throughout 
cycle 
Bilirubin, AST 
d 1, 15 
 
ALT 
d 1, 15 
 
Serum creatinine 
d 1, 15 (and then daily until MTX is 
cleared) 
d 1 
Creatinine clearance 
d 1, 15 
 
Electrolytes, BUN 
d 1, 15 (and then daily until MTX is 
cleared) 
d 1 
MTX levels 
d3, 17 (and then daily until MTX is 
cleared Note: the administration of 
MTX is on d 2 and 16 (see Section 
7.1) 
 
Urinalysis  
D 1, 15 
 
QOL assessment 
(for consenting pts) 
Cycle 4, d28 
 
NCF assessment 
(for consenting pts) 
Cycle 4, d28 
 
 
 
Assessments During Follow-Up 
A window of + 3/- 2 days is acceptable for all on-study treatments and assessments. (It is NOT applicable to pre-
treatment assessments.) 
 
Q 2 m for 1st  2 yrs (starting 4 
wks after cytarabine cycle 2, d 1) 
Q 6 m during  years 3-5 
History/physical 
X 
X 
Neurologic exam, KPS 
X 
X 
MRI of brain, response 
assessment 
X 
X 
Lumbar puncture 
 X* 
 X* 
History of corticosteroids use 
X 
X 
Complete ophthalmologic exam 
including slit lamp exam 
Repeated if previously positive 
Repeated if previously 
positive 
QOL assessment 
(for consenting pts) 
Q 6 months 
X 
NCF assessment 
 (for consenting pts) 
Q 6 months 
X 
*Performed at each MRI time point, until the second MRI showing CR (which confirms the CR status if tap still 
negative).  
 
NOTE. If a patient experiences disease progression during the study evaluation period, the neurocognitive and 
QoL assessment should be put on hold until the patient is clinically stable for 3 consecutive months, at which time 
the follow-up neurocognitive evaluation should be obtained. The next neurocognitive evaluation should be 
performed according to the next standard/planned protocol follow-up dates (the study calendar is not reset), but 
no sooner than 3 months from the previous neurocognitive evaluation. 


53 
RTOG 1114: version date September 19, 2019 
APPENDIX II 
 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 


54 
RTOG 1114: version date September 19, 2019 
APPENDIX III (07-AUG-2018) 
 
APPENDICES FOR NRG ONCOLOGY BIOSPECIMEN COLLECTION (as specified by the protocol). 
 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Frozen Tissue and Bone Marrow Kit Instructions 
NRG Oncology Blood Collection Kit Instructions 
NRG Oncology Buccal Scrapings Specimen Kit Instructions 
 
NRG Oncology CSF Collection Kit Instructions 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter St, room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal (ST) Form  has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include date of 
collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the 
container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap 
blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container 
the blocks are not shaking.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal 
Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT 
ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases/specimens may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs). 
There should be plenty of dry ice under and above the specimens. If the volume of specimens is 
greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any 
Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site 
will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped 
Monday through Wednesday to prevent thawing due to delivery delays. Saturday or holiday deliveries 
cannot be accepted. Samples can be stored frozen at -80° C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank 
by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271. 


55 
RTOG 1114: version date September 19, 2019 
 
 
NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen Bank. 
The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at room 
temperature. Place the punch tool on the paraffin block over the selected 
tumor area. (Ask a pathologist to select area with tumor.) Push the punch 
into the paraffin block. Twist the punch tool once around to separate the 
plug from the block. Then pull the punch tool out of the block. The punch 
should be filled with tissue sample. 
 
 
 
Step 2 
Label the punch tool with the proper pathology specimen ID and block ID.  
DON’T remove specimen from the punch. Punches must be accompanied 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if you have 
any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to address 
below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the 
entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block and return the 
remaining block to your facility.  Please indicate on the submission form the request to perform the plug procedure 
and return of the block. 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For Questions 
regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology 
Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-476-7864/Fax 415-476-5271. 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
USCF Box 1800 
2340 Sutter St, room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Frozen Specimens or Trackable shipments 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 


56 
RTOG 1114: version date September 19, 2019 
NRG ONCOLOGY FROZEN TISSUE KIT INSTRUCTIONS 
This Kit is for processing and shipping of frozen tissue specimens. 
Kit contents: 
• 
Biohazard pads/wipes 4” x 4” (orange) 
• 
Five (5) 5-mL cryovials 
• 
Disposable scalpel blades 
• 
Disposable forceps 
• 
Biohazard bags 
• 
Absorbent shipping material 
• 
Styrofoam container (inner) 
• 
Cardboard shipping (outer) box 
• 
Prepaid shipping label 
• 
UN 3373 Label 
• 
UN 1895 Dry Ice Sticker 
 
Preparation and Processing of Fresh Frozen Tissue: 
 
On sterile cutting board, lay out the underpads. 
 
Keep biohazard wipes nearby to keep area clean throughout process. 
 
Label cryovials with NRG Oncology study and case numbers 
 
Using provided disposable scalpel, evenly cut tissue into 3 to 5 separate pieces (Note: if a frozen core 
was obtained, do not cut but send it whole).  
 
Use forceps to place each piece of tissue into individual 5-mL cryovials. 
 
Snap freeze tissue samples in liquid nitrogen, a dry ice slurry (dry ice with 95% ethanol or isopentane), or 
directly on dry ice. 
 
Once frozen, place all of the cryovials into biohazard bag 
 
Use NRG Oncology provided labels to label the bag (provided when patient is registered). 
 
Storage and Shipping: 
Freezing and Storage 
 
Store at -80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available,  
 
Samples can be stored short term in a -20° C Freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only).  
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday 
only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
Shipping/Mailing: 
 
Include all NRG Oncology paperwork in pocket of biohazard bag. 
 
Place specimens and the absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7-10 
lbs.—if appropriate; double-check temperature sample shipping temperature).  Place Styrofoam cooler 
into outer cardboard box, and attach shipping label to outer cardboard box.  
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and 
clearly identified. 
 
Send frozen specimens via overnight courier to the address below. Specimens should only be shipped 
Monday through Wednesday to prevent thawing due to delivery delays.  
 
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen until ready to ship. 
 
For Questions regarding collection/shipping or to order a Frozen Tissue Kit, please contact the NRG 
Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.eduor call 415-476-7864/Fax 415-476-5271.  
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank, University of California San Francisco 
2340 Sutter St, room S341, San Francisco, CA 94115 


57 
RTOG 1114: version date September 19, 2019 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS  
 
This Kit is for collection, processing, storage, and shipping of whole blood (as specified by the protocol): 
 
Kit contents: 
• 
 2 Purple Top EDTA tubes for Whole Blood 
• 
Ten (10) 1 ml cryovials 
• 
Biohazard bags (1) and Absorbent shipping material (1) 
• 
Styrofoam container (inner) and Cardboard shipping (outer) box 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal (ST) Form and Kit Instructions 
 
PREPARATION AND PROCESSING OF WHOLE BLOOD: 
 
 
Whole Blood for DNA: 2 Purple Top EDTA tubes 
 
Label as many 1ml cryovials (6 to 10) as necessary for the whole blood collected. Label them with 1NRG 
Oncology study and case number, collection date/time, and time point, and clearly mark cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood 
collected (6 to 10) labeled with NRG Oncology study and case numbers, collection date/time, time 
point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80° Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on ST 
Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80°C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available,  
 
Samples can be stored short term in a -20°C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday 
only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday to prevent thawing due to delivery delays. 
Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
 
Wrap frozen specimens of same type (i.e., all whole bloods together) in absorbent shipping material and 
place each specimen type in a separate biohazard bag.  Place specimen bags into the Styrofoam cooler 
and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  Add padding to avoid the dry ice from 
breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
(continued on next page) 


58 
RTOG 1114: version date September 19, 2019 
 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 
 
For questions, call 415-476-7864,e-mail: NRGBB@ucsf.edu, or Fax 415-476-5271 
  


59 
RTOG 1114: version date September 19, 2019 
  
NRG ONCOLOGY BUCCAL SCRAPINGS SPECIMEN KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of Buccal Specimens. 
 
Kit Contents 
 
 One screw-top container filled with RNAlater 
 
Styrofoam container (inner) 
 Buccal brush/swab 
 
Cardboard shipping (outer) box 
 Biohazard bags 
 
Return shipping label 
 Absorbent shipping material 
 
Specimen Transmittal (ST) Form 
 
Preparation and Processing of Buccal Scrapings: 
• 
Brush or swab the oral mucosa generously to collect cells. 
• 
The swab with the specimen will then be placed into a cup/vial with RNAlater solution. 
• 
Swish the swab in the solution to free the cells. 
• 
The handle of the swab may be cut or bent to fit into the container. 
• 
The specimen should then be stored frozen at -70 º to -80º Celsius until ready to ship. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with NRG Oncology study and case 
numbers, collection date/time, and time point collected (e.g., pretreatment, post-treatment). 
 
Storage and Shipping: 
 
Freezing and Storage: 
 
Store at -80°C (-70°C to -90°C) until ready to ship. If a -80°C freezer is not available: 
 
Samples can be stored short term in a -20° C freezer (non-frost free preferred) for up to one week 
(please ship out Monday-Wednesday only). 
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out 
on Monday-Wednesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday to prevent thawing due to delivery delays. 
Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
 
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum). Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal 
Investigator and Clinical Research Assistant of the submitting institution. The institution should send a 
subsequent sample, collected as close as possible to the original planned collection date. 
 
For questions regarding ordering, collection, or shipping of a Buccal Collection Kit, please e-mail 
NRGBB@ucsf.eduor call 415-476-7864 or Fax 415-476-5271. 
 
Shipping Address: FedEx/UPS/Courier address  (all courier packages & frozen samples) 
NRG Oncology Biospecimen Bank at UCSF 
2340 Sutter St, room S341 
San Francisco, CA  94115 
Contact Phone 415.476.7864/Fax 415-476-5271 


60 
RTOG 1114: version date September 19, 2019 
NRG ONCOLOGY CSFAND BONE MARROW COLLECTION KIT INSTRUCTIONS 
 
This Kit contains: 
• 
Five (5) 5mL cryovials 
• 
Parafilm 
• 
Sterile Disposable Pipette  
• 
Biohazard bags 
Cerebrospinal Fluid (CSF) and Bone Marrow Specimens: 
Preparation for collecting CSF and Bone Marrow: 
• 
 Sterile CSF and bone marrow specimens will be collected according to individual site protocol. 
Processing 
• 
After CSF specimen has been obtained, use the following instructions: 
o 
Aliquot CSF using a sterile pipette into 5 different 5mL vials, each containing a minimum of 1mL  
o 
If CSF is already frozen, perform a controlled thaw and aliquot specimens according to above 
instructions.  Indicate on paperwork if specimen had to be thawed/refrozen.  
o 
Bone marrow specimens will be collected following institutional SOPs for collection of frozen bone 
marrow specimens, and may be shipped in the original vial. While the provided cryovial can be 
used, specimens should not be aliquotted or thawed.     
 
• 
Label the specimens with the NRG Oncology study and case number, collection date and time, and 
clearly mark specimen as “CSF” or “bone marrow”. 
• 
If available, use parafilm to seal the aliquots and to prevent leakage. 
• 
Place CSF and bone marrow samples into biohazard bag and seal the bag. 
• 
Immediately freeze specimens at -80 ºC  
• 
Store specimens frozen until ready to ship. 
Storage: 
 
Store at –80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available,  
 
Samples can be stored short term in a -20° C Freezer (non-frost free preferred) for up to one 
week (please ship out Monday-Wednesday only). 
- OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out 
on Monday-Wednesday only). 
- OR: 
 
Samples can be stored in liq. nitrogen vapor phase (ship out Monday-Wednesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping Instructions for all specimens: 
CSF and Bone Marrow Specimens: Specimens should be wrapped in an absorbent material (e.g., paper 
towels) and placed in an airtight plastic freezer bag (i.e., re-sealable bag). Pack the frozen specimens in a 
heavy grade Styrofoam box with dry ice (4-5 lbs/2-2.5 kg minimum). Seal the box with plastic tape. All NRG 
Oncology paperwork should be placed in a plastic bag, sealed, and taped to the outside of the Styrofoam box. 
Pack the Styrofoam box in a cardboard box. Note: Specimens requiring specific infectious precautions should 
be clearly labeled, with specific sources of infectious concerns listed, if known. Mark the outer cardboard box 
“biohazard”.  
 
Send specimens by overnight express to the address below. Only ship Monday through Wednesday to 
prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted. Samples 
received thawed will be refrozen and held.   A notification will be sent immediately to the Principal Investigator 
and CRA of the submitting institution. The institution should send a subsequent sample, collected as close as 
possible to the original planned collection date, if possible. 
 
Sites must submit the required documentation with specimens. Specimens are shipped on Dry Ice 
to: 
  
NRG Oncology Biospecimen Bank/University of California San Francisco (FedEx/UPS Courier 
address) 
2340 Sutter Street, rm 341 
San Francisco, CA  94115 


61 
RTOG 1114: version date September 19, 2019 
(contact: 415-476-7864) 
 
 
APPENDIX IV (8/25/15) 
 
CERTIFICATION AND ADMINISTRATION PROCEDURES FOR THE NEUROCOGNITIVE TEST BATTERY 
 
STEP 1 – EXAMINER CERTIFICATION FOR RTOG 1114  
Institutions with patients participating in the quality of life/neurocognitive function components of this study must 
meet certification requirements for administering neurocognitive assessments. The healthcare professional (e.g., 
nurse, psychologist) who is responsible for test administration in this study must be pre-certified by Dr. Correa 
(See Section 5.1.4). Examiners who have completed the full certification procedure to perform these tests for 
RTOG 0525, 0534, 0614, 0834 or 0825 during the past 6 months do not need to complete the full certification 
procedure again, but the certification worksheet for 1114 must be faxed to Dr. Correa (fax number 646-888-3175) 
for documentation purposes with information regarding the examiners prior certification (protocol number, date of 
certification). If these criteria are met, each examiner and NRG Oncology will be notified of the examiner’s 
recertification status for 1114. Examiners who have not completed the full certification procedure for RTOG 0525, 
0534, 0614, 0834 or 0825 within the past 6 months must complete the full certification procedure to be recertified 
to ensure continued familiarity with study procedures. 
 
Prior to registering and/or testing a patient, potential examiners must: 
(1) Read Section 11.2 of the protocol 
(2) Read Appendix IV (Certification and Administration Procedures for the Neurocognitive Test Battery) 
(3) Go to the NRG Oncology/RTOG web site and use your username and password to access the link entitled, 
“Neurocognitive Training Procedure Letter” on the 1114 forms section of the website. This letter will provide you 
with the web address for the training video. 
(4) Obtain copies of the HVLT-R, TMT and COWA from the NRG Oncology/RTOG website 
(5) Watch the training video 
(6) Complete the training video post test 
(7) Complete a “practice” assessment 
(8) Complete the Certification Worksheet (Appendix V) 
(9) All materials (i.e., post test, completed practice assessment and scoring forms, certification worksheet) must 
be faxed to Dr. Correa, who will review it and correct any procedural errors with the trainee. 
(10) If the trainee demonstrates competency, he/she will be notified of the certification approval to administer the 
tests to study subjects as part of RTOG 1114. A certification approval notice will be sent to NRG Oncology for the 
registration process and to ensure that only RTOG 1114-approved examiners are testing subjects on protocol 
RTOG 1114. 
(11) After you are certified, please fax all neurocognitive test and summary forms for the first study 
patient you test on RTOG 1114 to Dr. Correa (646-888-3175) for centralized review. 
 
STEP 2 – ALTERNATE TEST FORMS/VERSIONS 
Two of the tests to be administered have alternate forms or versions in order to reduce the effects of practice. See 
the table below for the versions to be administered at each session. The forms should continue to be alternated in 
this order for the duration of the study. The forms packet will contain alternate versions of these 
neuropsychological tests. 
 
TIME TABLE FOR COGNITIVE EVALUATIONS AND ALTERNATE FORMS TO BE USE AT EACH VISIT 
 
 
TEST 
≤2 wks prior to start of 
treatment 
R-MPV (Cycle  4, d28) 
Every 6 months up to 
year 5 (starting 4 wks 
after cytarabine cycle 2, 
d 1)  
HVLT-R 
Form 1 
Form 2 
Form 3 ** 
COWA 
“C-F-L” 
“P-R-W” 
“C-F-L” *** 
** HVLT-R: Continue to alternate order at subsequent 6-month intervals: Form 4. Form 5, Form 6, Form 1, Form 
2, Form 3, Form 4, Form 5, Form 6 
 


62 
RTOG 1114: version date September 19, 2019 
***COWA: Continue to alternate order at subsequent 6-month intervals: ‘P-R-W’, ‘C-F-L’, ‘P-R-W’,‘C-F-L’, ‘P-R-
W’,‘C-F-L’,‘P-R-W’,‘C-F-L’, ‘P-R-W’.  
 
 
STEP 3 — TEST INSTRUCTIONS AND ADMINISTRATION PROCEDURES 
Additional comments: 
1. Testing must be completed in one session. Test instructions must be followed verbatim with every patient at 
every study visit. All tests should be completed in black pen. 
2. Tests should be administered in the following order to every patient and at every study visit: 
HVLT-R Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWA; HVLT-R Part B 
(Delayed Recall); and the HVLT-R Part C (Delayed Recognition). 
3. You may fill the delay interval between COWA and HVLT-R Part B (Delayed Recall) with EORTC QLQ-
C30/BCM20 questionnaire.   
4. Follow the instructions on the Forms Packet Index before submission of forms to NRG Oncology. 
5. Please keep all original test forms. In the event of questions, contact Dr. Correa. Copies of the test forms and 
summary sheets for the first case from each certified examiner must be faxed for review to Dr. Correa (646-888-
3175 Additional test forms are not submitted to Dr. Correa nor to NRG Oncology. Results remain on file at the 
institution as source documentation pending request for submission by NRG Oncology or a study chair. 
6. All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is found in the 
Forms Packet. Study/case-specific labels must be applied to all forms. 
7. Patients should not be given copies of their tests to avoid learning the material between test administrations. 
8. Before dismissing the patient, thank the patient for his/her cooperation. 
9. In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the 
Neurocognitive Evaluation Summary Form (CS). 
 
1. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


63 
RTOG 1114: version date September 19, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
2. TRAIL MAKING TEST [Timed Test] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


64 
RTOG 1114: version date September 19, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. CONTROLLED ORAL WORD ASSOCIATION (COWA) [Timed Test] 
 
 
 
 


65 
RTOG 1114: version date September 19, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
 
 
 
 
 
 
 
 
 
 


66 
RTOG 1114: version date September 19, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCF/QOL ENDPOINT FLOW DIAGRAM 
 
 
≤2 wks prior to start of treatment 
R-MPV (Cycle 4, d28) 
Every 6 months up to year 5 
(starting 4 wks after cytarabine 
cycle 2, d 1) 
NCF/QOL 
NCF/QOL 
NCF/QOL 
 
 
NCF/QOL= neurocognitive function and quality of life battery 
 
NOTE. If a patient experiences disease progression during the study evaluation period, the neurocognitive and 
QoL assessment should be put on hold until the patient is clinically stable for 3 consecutive months, at which time 
the follow-up neurocognitive evaluation should be obtained. The next neurocognitive evaluation should be 
performed according to the next standard/planned protocol follow-up dates (the study calendar is not reset), but 
no sooner than 3 months from the previous neurocognitive evaluation. 


67 
RTOG 1114: version date September 19, 2019 
  
APPENDIX V 
 
CERTIFICATION WORKSHEET FOR TEST ADMINISTRATOR 
 
RTOG 1114 
This worksheet must be completed and signed by the person requesting certification and submitted to Dr. Correa 
prior to the registration of any patients to RTOG 1114. Refer to Appendix IV for details. 
 
      (Y) 
 
1. Have you reviewed the Administration Procedures for the Neurocognitive Test Battery in 
Appendix IV of the protocol? 
      (Y/N)  
2. Have you completed the full certification to perform the Neurocognitive Battery for RTOG 
0525, 0534, 0614, 0834, or 0825 during the past 6 months? 
      (Y) 
 
3. Have you watched the Neuropsychological Test Administration video? 
      (Y) 
 
4. Have you completed and submitted the post test associated with the training video and a 
“practice” Neuropsychological Assessment? 
 
PLEASE PRINT 
Name of test administrator:                                
 
NRG institution number/name:                                
 
NCI code:                               
 
Telephone number of test administrator                           
 
Fax number of test administrator:  
                          
 
E-mail address of test administrator:  
                          
 
____________________________________________  
___________________ 
Signature of test administrator  
 
 
 
Date 
(person who read Appendix IV, watched video and completed a “practice” Assessment) 
 
If you have any questions regarding the certification, please contact Dr. Correa. Once you have completed this 
form, please attach both the Neuropsychological Assessment forms from the “practice” subject and the training 
video post test and submit to: 
Denise Correa, PhD; Phone 646-888-3177; FAX 646-888-3175; corread@mskcc.org 
 
For Drs. Correa’s/ Wefel’s Use Only (to fax to 215-569-0206, CTSU) 
 
 
(Y/N)The above individual has been certified for administering the neurocognitive assessments for this 
study. 
 
Signature 
 
Date 
 
 


68 
RTOG 1114: version date September 19, 2019 
APPENDIX VI 
  
PATIENT’S MEDICATION DIARY 
 
 
 
Today’s date _____________________ 
Agent:  Procarbazine  
Patient Name___________________(initials acceptable)   Patient Study ID __________________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take procarbazine tablets for 7 days. You should take the tablets on an empty stomach 
at approximately the same time each day.  
 
Dose (each tablet contains 50 mg):   
Day 1: take ___ tablets. 
Day 2: take ___ tablets. 
Day 3: take ___ tablets. 
Day 4: take ___ tablets. 
Day 5: take ___ tablets. 
Day 6: take ___ tablets. 
Day 7: take ___ tablets. 
 
3. 
Record the date, the number of tablets of each size of tablet that you took, and when you took 
them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments 
column.   
5. 
Please bring this form and your bottles of procarbazine tablets when you return for each 
appointment. 
 
Day 
Date 
Time of 
dose  
# of 50 mg tablets taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
 
 
Patient’s signature   
 
_________________________________________________________________________ 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment ________________________________________________
2. Date patient was removed from study _________________________________________________
3. Patient’s planned total dose during this cycle ____________________________________________
4. Total number of tablets taken this cycle  _______________________________________________
5. Physician/Nurse/Data Manager’s Signature  ____________________________________________
 
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 

ICF_001.pdf: 
NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 1114 
 
(ClinicalTrials.gov NCT #: 01399372) 
 
 
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 
 
 
 
Amendment 10:  September 19, 2019 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 1 of 16 
 
 
 
 
 
RTOG 1114 
 
Informed Consent Template for Cancer Treatment Trials (NCI Template Date: August 2009) 
(English Language) 
 
 
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  
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you.  Clinical trials 
include only people who choose to take part. Participation in this study is entirely voluntary. Please take your time 
to make your decision about taking part.  You may discuss your decision with your friends and family.  You can 
also discuss it with your health care team.  If you have any questions, you can ask your study doctor for more 
explanation.  
 
You are being asked to take part in this study because you have primary central nervous system lymphoma 
(PCNSL). 
 
Why is this study being done? 
PCNSL is a disease that can be cured in less than half of patients with a combination of chemotherapy and 
standard brain radiation. Unfortunately, the combination of chemotherapy and standard brain radiation may cause 
serious damage to the brain. When this occurs, patients develop progressive memory and other neurologic 
problems that can be fatal. Because of this risk, many patients and physicians prefer to avoid radiotherapy. 
However, this results in higher risks of disease coming back. Many patients end up requiring radiotherapy 
anyway. 
 
As a new alternative, radiotherapy has been used in significantly lower doses. In a previous study, this seemed to 
achieve the same rates of cure as full doses of radiotherapy but with much less risk of neurologic side effects.   
 
The purpose of this study is to determine the effects, good and/or bad, of the combination of low-dose whole brain 
radiation plus chemotherapy on you and your tumor compared with chemotherapy alone, to find out which is 
better. In this study, you will either get the experimental treatment (chemotherapy plus reduced-dose whole brain 
radiation) or chemotherapy alone.     
 
How many people will take part in the study? 
About 89 people will take part in this study.   
 
What will happen if I take part in this research study?   
You will be "randomized" into one of the study groups described below. Randomization means that you are put 
into a group by chance. A computer program will place you in one of the study groups.  Neither you nor your study 
doctor can choose the group you will be in.  You will have an equal chance of being placed in any group. 
 
If you are in group 1 (often called "Arm A") …  
You will receive chemotherapy with rituximab, methotrexate (MTX), procarbazine, and vincristine. You will receive 
the chemotherapy for four 28-day cycles (for approximately 4 months total) on several days each cycle as follows: 
 
▪ 
Day 1: Rituximab (given by vein, as an outpatient). The first treatment will last approximately 5 hours, 
but subsequent treatments may be shorter, according to your physician. 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 2 of 16 
 
 
 
▪ 
Day 2: MTX and vincristine (vincristine is given during cycles 1 and 2 only). These will be given by 
vein in the hospital. MTX is given over 2 hours and vincristine is given over approximately one 
minute. You will need to stay in the hospital for approximately 3-5 days, until the MTX is eliminated 
from your body. 
▪ 
Days 2-8: Procarbazine (given by mouth, once a day, on an empty stomach). While you are on 
procarbazine: 
- You should not to drink alcoholic beverages while you are taking procarbazine since it may 
cause nausea, vomiting, and serious flushing. 
- You will need to avoid foods with high tyramine content such as wine, yogurt, ripe cheese 
and bananas. 
- You will need to avoid over-the-counter drug preparations containing antihistamines or 
sympathomimetic drugs (drugs are used to treat low blood pressure and cardiac arrest, 
reduce nasal stuffiness, delay premature labor, and treat other things).  Ask your physician 
or pharmacist before using any over-the-counter drug. 
- You will be asked to keep a diary where you will record the number of procarbazine pills you 
take each day. At your next clinic visit, you will be asked to bring the diary and the 
procarbazine bottle with the remainder of pills left.  
  
▪ 
Day 15: Rituximab (given by vein, as an outpatient)  
 
▪ 
Day 16: MTX and vincristine (vincristine is given during cycles 1 and 2 only). These will be given by 
vein in the hospital, as described above. 
 
When you have finished receiving the four cycles of chemotherapy with rituximab, MTX, procarbazine, and 
vincristine, you will receive two 28-day cycles (approximately 2 months total) of additional chemotherapy on 
several days each cycle as follows: 
 
▪ 
Days 1 and 2: Cytarabine (given by vein as an outpatient). Cytarabine is given over 3 hours.  
 
 
If you are in group 2 (often called "Arm B")…  
You will receive chemotherapy with rituximab, methotrexate (MTX), procarbazine, and vincristine as described 
above. 
 
If your tumor has not grown during the chemotherapy, you will then receive the reduced-dose radiation therapy to 
your brain daily for a total of 13 days. If however your tumor has grown, your doctor will discuss other treatment 
alternatives with you. 
 
When you have finished the radiation therapy, you will receive chemotherapy with cytarabine as described above. 
 
 
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the study.  
These exams, tests or procedures are part of regular cancer care and may be done even if you do not join 
the study.  If you have had some of them recently, they may not need to be repeated.  This will be up to 
your study doctor. 
▪ 
MRI of your brain 
▪ 
CT scan of your chest, abdomen, and pelvis 
▪ 
History and physical examination 
▪ 
Blood tests for bone marrow function, liver function, and renal function 
▪ 
HIV test 
▪ 
Pregnancy test (if are a woman of childbearing potential) 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 3 of 16 
 
 
 
In addition, when you enter the study, you will need to agree to permit your doctors to send the block of tumor 
tissue obtained at the time of your brain tumor surgery to a central pathology site. There, a pathologist will confirm 
that the tumor is the type of tumor being studied in this trial. 
 
During the study … (1/31/13) 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then 
you will need the following tests and procedures.  These exams, tests or procedures are part of regular 
cancer care and may be done even if you do not join the study.  If you have had some of them recently, 
they may not need to be repeated.  This will be up to your study doctor.  
Within 2 weeks before starting treatment 
▪ 
Blood tests for bone marrow function, liver function, renal function, electrolyte levels,  
▪ 
Urine test 
▪ 
Chest X-ray 
▪ 
MRI scan of your brain 
▪ 
History and physical examination, including neurologic examination, assessment of ability to carry out 
activities of daily living, and history of corticosteroid use   
An examination by an eye doctor, to see if there are cancer cells in the eyes 
 
Within 6 weeks before starting treatment 
▪ 
A spinal tap will be required, for examination of the cerebrospinal fluid (a fluid that bathes the brain and 
the spinal cord). This procedure is routinely done to see if there are cancer cells in cerebrospinal fluid. 
You will receive local anesthesia for that.   
▪ 
A bone marrow biopsy will be required, to look for cancer cells in the bone marrow.   
▪ 
A blood test for hepatitis B screening is recommended. 
 
Every week during treatment with rituximab, methotrexate, procarbazine and vincristine   
▪ 
Blood tests for bone marrow function 
 
Every 2 weeks during treatment with rituximab, methotrexate, procarbazine and vincristine   
▪ 
History and physical examination, including neurologic examination 
▪ 
Blood test to determine the level of methotrexate in your blood (and then daily until the methotrexate is 
cleared) 
▪ 
Blood tests for liver function, renal function, and electrolyte levels (and then daily until the methotrexate is 
cleared) 
 
Every other month during treatment with rituximab, methotrexate, procarbazine and vincristine   
▪ 
MRI scan of your brain 
▪ 
Assessment of ability to carry out activities of daily living 
▪ 
History of corticosteroid use 
 
Every week during cytarabine treatment 
▪ 
Blood tests for bone marrow function 
 
Every month during cytarabine treatment 
▪ 
History and physical examination, including neurologic examination 
▪ 
Assessment of ability to carry out activities of daily living 
▪ 
Blood tests for liver function, renal function, and electrolyte levels 
 
Once during cytarabine treatment (for patients assigned to Arm B/whole brain radiation treatment) 
▪ 
MRI scan of your brain 
▪ 
History of corticosteroid use 
 
 
When you are finished taking all of the chemotherapy…(1/27/15) 
When you are finished with the treatment, you will need to come back to clinic for the following tests and 
procedures.  They are part of regular cancer care: 
 
Every 2 months for the first 2 years, then every 6 months for the next 3 years 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 4 of 16 
 
 
 
▪ 
History and physical examination, including neurologic examination 
▪ 
MRI scan of your brain 
▪ 
History of corticosteroid use 
▪ 
Spinal tap (if you previously had cancer cells in the spinal fluid) will be obtained every 2 months until you 
have 2 MRIs showing no sign of disease  
▪ 
An examination by an eye doctor, to see if there are cancer cells in the eyes (if you previously had 
evidence of cancer cells in the eyes) 
 
You will need these tests and procedures that are either being tested in this study or being done to see 
how the study is affecting your body: 
 
Every 2 months for 3 years, starting at the end of the first two years 
▪ 
Telephone call: a study assistant will call you and ask questions about your disease status and other 
treatments you have received since your last visit to the doctor, if any. We may collect medical records, if 
you have received additional treatments.    
 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 5 of 16 
 
 
 
Study Plan 
 
Another way to find out what will happen to you during the study is to read the chart below.  Start reading at the 
top and read down the list, following the lines and arrows.  
 
Start Here 
↓ 
Diagnosis of Primary Central Nervous System Lymphoma 
↓ 
Randomize 
(You will be in one Group or the other) 
 
 
 
 
 
Group A 
Chemotherapy with rituximab, methotrexate (MTX), 
procarbazine, and vincristine as follows: 
▪ 
Day 1: Rituximab 
▪ 
Day 2: MTX and vincristine*  
▪ 
Days 2-8: Procarbazine  
▪ 
Day 15: Rituximab  
▪ 
Day 16: MTX and vincristine* 
*vincristine given during cycles 1 and 2 only 
 
Every 28 days cycles for 4 cycles 
Group B 
Chemotherapy with rituximab, methotrexate (MTX), 
procarbazine, and vincristine as follows: 
▪ 
Day 1: Rituximab 
▪ 
Day 2: MTX and vincristine*  
▪ 
Days 2-8: Procarbazine  
▪ 
Day 15: Rituximab  
▪ 
Day 16: MTX and vincristine* 
*vincristine given during cycles 1 and 2 only 
 
Every 28 days cycles for 4 cycles 
↓ 
↓ 
Chemotherapy with cytarabine on days 1 and 2 
 
Every 28 days cycles for 2 cycles 
Whole brain radiation therapy  
(13 treatments) 
↓ 
Chemotherapy with cytarabine on days 1 and 2 
 
Every 28 days cycles for 2 cycles 
 
How long will I be in the study? 
You will receive treatment for about 6-7 months. You will be seen in follow-up visits beginning 4 weeks after the 
start of cytarabine. You will be seen every 2 months for the first 2 years and every 6 months for the next 3 years.  
. 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide to 
stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the chemotherapy and/or 
radiation can be evaluated by him/her.  Another reason to tell your study doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow the study rules; or if the study is stopped. 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 6 of 16 
 
 
 
 
What side effects or risks can I expect from being in the study? (8/25/15) 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully for any 
side effects.  However, researchers don’t know all the side effects that may happen.  Side effects may be mild or 
very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go 
away soon after you stop taking the chemotherapy and/or radiation. In some cases, side effects can be serious, 
long lasting, or may never go away. There also is a risk of death. 
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
 
Possible Side Effects of Rituximab (Table Version Date: June 16, 2014) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab,  
more than 20 and up to 100 may have: 
• 
Nausea 
• 
Chills, fever 
• 
Reaction during or following infusion of the drug 
• 
Infection, especially when white blood cell count is low 
• 
 
• 
Numbness and tingling of the arms and legs 
• 
Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, from 4 to 20 may have: 
• Anemia which may require blood transfusions 
• Bruising, bleeding 
• Abnormal heartbeat 
• Heart attack or heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• Sores in eye 
• A tear or a hole in the stomach that may require surgery 
• Diarrhea, vomiting 
• Pain 
• Swelling of the body 
• Hepatitis which may cause yellow eyes and skin 
• Dizziness, headache 
• Kidney damage which may require dialysis 
• Cough 
• Scarring of the lungs 
• Stuffy nose 
• Blockage of internal organs which may cause shortness of breath, wheezing, vomiting 
• Increased sweating 
• Itching, rash, blisters on the skin 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the body 
• Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving Rituximab , 3 or fewer may have: 
• Damage to the brain caused by a virus which may result in tiredness, weakness, changes in thinking, and 
disability.  This is called progressive multifocal leukoencephalopathy (PML). 
• Heart stops beating 
 
Additional information 
In people who have ever been infected with hepatitis B virus, there is a risk that the virus can flare up during 
treatment with drugs that affect your immune system, such as rituximab. This could lead to liver failure or even 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 7 of 16 
 
 
 
death. The risk of hepatitis B virus flaring up may continue for several months after you stop taking rituximab. If 
you become jaundiced (yellowing of the skin and eyes) or develop viral hepatitis while taking rituximab or after 
stopping treatment, you should tell your study doctor immediately. Your study doctor will discuss this risk with you 
and explain what testing is recommended to check for hepatitis. 
 
Other symptoms may occur, usually within 30 to 120 minutes of beginning the first infusion, and include nausea, 
vomiting, itching, hives, swelling of the lips or throat, lowered blood pressure, increased blood pressure, 
headache, difficulty breathing, throat irritation, running nose, rash, decreased appetite, muscle aches, or 
dizziness.  These symptoms generally improve with each treatment and respond to slowing or interrupting the 
therapy and treating the symptoms. 
 
 
Possible Side Effects of Methotrexate (Table Version Date: October 8, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Methotrexate, more than 20 and up to 100 may have: 
• Increased risk of sunburn, rash 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Methotrexate, from 4 to 20 may have: 
• Scarring of the lungs which may cause shortness of breath  
• Fluid around heart 
• Internal bleeding which may cause belly pain, black tarry stool, blood in vomit 
• Nausea, vomiting, diarrhea 
• Sores in mouth which may cause difficulty swallowing 
• Liver damage which may cause yellowing of eyes and skin 
• Scarring of the liver 
• Hepatitis  
• Hair loss 
• Bruising, bleeding 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require transfusion 
• A new cancer resulting from treatment of earlier cancer 
• Confusion 
• Seizure 
• Kidney damage which may require dialysis 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the body 
• Blood clot which may cause swelling, pain, shortness of breath 
•  
 
RARE, AND SERIOUS 
In 100 people receiving Methotrexate, 3 or fewer may have: 
• Dizziness 
• Damage to the brain which may cause tiredness, changes in thinking 
 
 
Possible Side Effects of Procarbazine (Table Version Date: October 8, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Procarbazine, more than 20 and up to 100 may have: 
• Nausea, vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Procarbazine, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require blood transfusions 
• Infection, especially when white blood cell count is low 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 8 of 16 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Procarbazine, from 4 to 20 may have: 
• Bruising, bleeding 
• A new cancer resulting from treatment of earlier cancer 
• Muscle weakness 
• Confusion 
• Sores in mouth which may cause difficulty swallowing 
• Diarrhea 
 
RARE, AND SERIOUS 
In 100 people receiving Procarbazine, 3 or fewer may have: 
• None 
 
NOTE: You will be required to avoid some foods, such as alcohol, some cheeses and banana that can cause 
high blood pressure or nausea and vomiting when eaten with procarbazine. You will be given written diet 
instructions.  
 
Possible Side Effects of Vincristine (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, more than 20 and up to 100 may have: 
• Constipation 
• Hair loss 
• Pain or redness at the site of injection 
• Numbness and tingling of fingers or toes 
• Headache, jaw pain and/or muscle pain 
• Weakness and difficulty walking 
• Swelling of lower legs 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require transfusion 
• Drooping eyelids 
• Hoarseness 
 
RARE, AND SERIOUS 
In 100 people receiving Vincristine, 3 or fewer may have: 
• Seizure 
 
 
Possible Side Effects of Cytarabine (Table Version Date: July 27, 2015) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine, more than 20 and up to 100 may have: 
• Blood clot 
• Rash 
• Swelling in the rectum which may cause rectal pain 
• Diarrhea, loss of appetite, nausea, vomiting 
• Sores in mouth which may cause difficulty swallowing 
• Anemia which may cause tiredness, or may require blood transfusions 
• Fever 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine, from 4 to 20 may have: 
• Infection, especially when white blood cell count is low 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 9 of 16 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine, from 4 to 20 may have: 
• Bruising, bleeding 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat 
• Numbness and tingling of the arms and legs 
• Severe blood infection 
• Kidney damage which may cause swelling, may require dialysis 
• Headache 
• Dizziness 
• Chest pain 
• Hair loss 
• Liver damage which may cause yellowing of skin or eyes 
• Swelling and redness of the eye 
 
RARE, AND SERIOUS 
In 100 people receiving Cytarabine, 3 or fewer may have: 
• Coma 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 10 of 16 
 
 
 
 
 
Possible Side Effects of Whole Brain Radiation 
COMMON, SOME MAY BE SERIOUS                                                      
In 100 people receiving Whole Brain Radiation, more than 20 may have: 
• 
Scalp redness or soreness  
• 
Hair loss, which may be temporary or permanent  
• 
Short term hearing loss 
• 
Tiredness 
• 
Temporary increase of brain tumor symptoms such as headaches, seizures, or weakness  
 
 
OCCASIONAL, SOME MAY BE SERIOUS                                                  
In 100 people receiving Whole Brain Radiation, from 4 to 20 may have: 
• 
Change in thinking patterns 
• 
Permanent hearing loss 
• 
Cloudiness of the eye, visual disturbancesChange in behavior 
• 
Nausea, vomiting 
• 
Dry mouth, changes in taste 
 
 
RARE, AND SERIOUS 
In 100 people receiving Whole Brain Radiation, 3 or fewer may have: 
• 
Damage to the brainVisual loss 
• 
A new cancer resulting from treatment of earlier cancer 
 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study because the drugs in 
this study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  It is important 
you understand that you need to use birth control while on this study.  Check with your study doctor about what 
kind of birth control methods to use and how long to use them.  Some methods might not be approved for use in 
this study. . A pregnancy test will be required if you are a woman of childbearing potential. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While researchers hope that the addition of 
whole brain radiation to chemotherapy will be more useful against cancer compared to chemotherapy alone, there 
is no proof of this yet. We do know that the information from this study will help researchers learn more about 
radiation and chemotherapy as a treatment for cancer.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
 
• 
Getting treatment or care for your cancer without being in a study   
• 
Taking part in another study 
• 
Getting no treatment 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries 
to improve how you feel.  Comfort care tries to keep you as active and comfortable as possible.   
 
Talk to your study doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private? (4/17/14) 
Data are housed at NRG Oncology Statistics and Data Management Center in a password-protected database.  
We will do our best to make sure that the personal information in your medical record will be kept private.  


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 11 of 16 
 
 
 
However, we cannot guarantee total privacy.  Your personal information may be given out if required by law.  If 
information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
• 
NRG Oncology 
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug 
Administration (FDA), involved in keeping research safe for people 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results.  You can search this Web site at any time. 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local 
institution.  The regulations may or may not be included in the informed consent form depending on local 
institutional policy.] 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your 
cancer in this study.  Some health plans will not pay these costs for people taking part in studies.  Check with your 
health plan or insurance company to find out what they will pay for.  Taking part in this study may or may not cost 
your insurance company more than the cost of getting regular cancer treatment.  
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You can print a 
copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you 
have been injured because of taking part in this study.  You can tell the study doctor in person or call him/her at 
__________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your health 
plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.   No matter what decision you make, there 
will be no penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your 
medical care.  You can still get your medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or your willingness to 
continue in the study. 
 
A Data Safety Monitoring Board will be regularly meeting to monitor safety and other data related to phase I, I/II, 
and II NRG Oncology clinical trials. The Board members may receive confidential patient information, but they will 
not receive your name or other information that would allow them to identify you by name. 
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 12 of 16 
 
 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing 
this form.   
 
 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study 
doctor __________________ [name(s)] at __________________ [telephone number]. 
 
 
For questions about your rights while taking part in this study, call the ________________________ [name of 
center] Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ (telephone number).  [Note to Local Investigator: Contact information for patient 
representatives or other individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 13 of 16 
 
 
 
Please note:  This section of the informed consent form is about additional research that is being done 
with people who are taking part in the main study.   You may take part in this additional research if you 
want to.  You can still be a part of the main study even if you say ‘no’ to taking part in this additional 
research. 
 
You can say “yes” or “no” to each of the following studies.  Below, please mark your choice for each 
study.   
 
 
Consent Form for Quality of Life Study/Neurocognitive Function Study (8/25/15) 
We want to know your view of how your life has been affected by cancer and its treatment. This “quality of 
life/neurocognitive function” sub-study looks at how you are feeling physically and emotionally during your cancer 
treatment.  It also looks at how you are able to carry out your day-to-day activities.  Patients participating in the 
main part of the study will be asked to participate by having their symptoms, quality of life, and neurocognitive 
function evaluated.  
 
This information is very important and will help doctors better understand how patients feel during treatments and 
what effects the medicines are having.  In the future, this information may help patients and doctors as they 
decide which medicines to use to treat cancer. 
 
If you agree to participate in this part of the study, you will be asked to complete a neurocognitive assessment 
and two quality of life questionnaires at the following times throughout the main part of the study:  
 
▪ 
Before you begin treatment; 
▪ 
During Treatment with R-MP(V) on d28 of cycle 4 and every 6 months for the next 5 years. 
 
The quality of life questionnaires and the symptom assessment will take approximately 30 minutes to complete. If 
any questions make you feel uncomfortable, you may skip those questions and not give an answer. 
 
If you decide to take part in this sub-study, the only thing you will be asked to do is fill out the questionnaires and 
undergo the assessment.  You may change your mind about completing the questionnaires and undergoing the 
assessment at any time.  You may stop participating in this part of the study at any time without affecting your 
care or your participation in the main part of the study. 
 
Just like in the main study, we will do our best to make sure that your personal information will be kept private. 
 
Please circle your answer. 
 
I choose to take part in the Quality of Life/Neurocognitive Function Study.  I agree to fill out the Quality of 
Life/Neurocognitive Function Questionnaires. 
 
YES 
 
 
 
 
NO 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 14 of 16 
 
 
 
 
Consent Form for Use of Tissue for Research 
 
About Using Tissue and Other Specimens for Research (1/27/25) 
To determine if you have cancer, you have had, or are going to have, the following procedures: 
▪ 
A biopsy (or surgery) to remove tumor tissue 
▪ 
A lumbar puncture to remove cerebrospinal fluid 
▪ 
A bone marrow or eye biopsy to remove tissue  
The results of these tests will be given to you by your doctor and will be used to plan your care.  
 
We would like to keep some of the tissue and cerebrospinal fluid that is left over for future research. If you agree, 
this material will be kept and may be used in research to learn more about cancer and other diseases. An 
information sheet about using tissue for research is available at  
http://www.cancer.gov/cancertopics/factsheet/clinicaltrials/donating-tissue-research 
 
As a result of your participation in the trial, you will have blood tests performed before you start treatment. We 
would like to collect for future research an extra blood sample (about one tablespoon) the next time you have a 
blood test performed. If you agree, the extra blood sample will be kept and may be used in research to learn more 
about cancer and other diseases. 
 
In addition, at your next office visit in conjunction with the trial, we would like to collect some cells from inside your 
cheek. If you agree, the study staff would gently brush the inside of your cheek with a soft toothbrush. The cells 
will be kept and may be used in research to learn about cancer and other diseases. 
 
The specimens collected from your body may be helpful for research whether you do or do not have cancer. The 
research that may be done with the specimens is not designed specifically to help you. It might help people who 
have cancer and other diseases in the future.  
 
Reports about research done with your specimens will not be given to you or your doctor. These reports will not 
be put in your health record. The research will not have an effect on your care.  
 
Things to Think About  
The choice to let us keep the specimens for future research is up to you. No matter what you decide to do, it will 
not affect your care or your participation in the main part of the study.  
 
If you decide now that your specimens can be kept for research, you can change your mind at any time. Just 
contact us and let us know that you do not want us to use the material. You can do so by writing to your study 
doctor. Then any material that remains will no longer be used for research and will either be returned to the 
institution that submitted it or will be destroyed. 
 
In the future, people who do research may need to know more about your health. While the doctor/institution may 
give them reports about your health, it will not give them your name, address, phone number, or any other 
information that will let the researchers know who you are.  
 
Sometimes specimens are used for genetic research (about diseases that are passed on in families). Even if your 
specimens are used for this kind of research, the results will not be put in your health records.  
 
Your specimens will be used only for research and will not be sold. The research done with your specimens may 
help to develop new treatments for cancer in the future.  
 
Benefits  
 
 
The benefits of research using bodily specimens include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.  


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 15 of 16 
 
 
 
 
Risks (10/28/13) 
 
The greatest risk to you is the release of information from your health records. We will do our best to make sure that your 
personal information will be kept private.  The chance that this information will be given to someone else is very small.  
 
Some of your genetic and health information may be placed in central databases that may be public, along with 
information from many other people. Information that could directly identify you will not be included. The samples 
are given a code to protect your privacy before they are used. Any related information given to researchers will 
also be coded.  Researchers will receive the code instead of any information that might directly identify you.  
 
There can be a risk in knowing genetic information.  New health information about inherited traits that might affect 
you or your blood relatives could be found during a research study. Even though your genes are unique, you 
share some of the same genes with your blood relatives.   
 
Although we are not able to know all of the risks from taking part in research on inherited traits, we believe that 
the risks to you and your family are very low, because your samples will be coded. Research results will not be 
returned to you or your doctor. 
 
Very rarely health or genetic information could be misused by employers, insurance companies, and others. For 
example, life insurance companies may charge a higher rate based on this information.  
Many states have laws to protect against genetic discrimination [list appropriate state information if your state or 
locality has such laws]. Additionally, a federal law called the Genetic Information Non-Discrimination Act, or GINA, 
is in effect.  This law prohibits health insurer or employer discrimination.  The law does not include other types of 
misuse by life insurance, disability, or long term care insurance. To learn more about the GINA Law, please ask 
[Note to local investigator: Contact information for patient representatives or other individuals in a local institution 
who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] 
 
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No". 
If you have any questions, please talk to your doctor or nurse, or call our research review board at 
__________________________ [IRB's phone number].  
No matter what you decide to do, it will not affect your care. 
1. My specimens may be kept for use in research to learn about, prevent, or treat cancer, as follows: 
• Tumor tissue                            Yes    No 
• Bone marrow/eye biopsy         Yes    No 
• Cerebrospinal fluid                  Yes    No 
• Blood                                    Yes     No 
• Cells from inside my mouth    Yes     No 
 
2. My specimens may be kept for use in research to learn about, prevent or treat other health problems (for 
example: diabetes, Alzheimer's disease, or heart disease), as follows:  
• Tumor tissue                            Yes    No 
• Bone marrow/eye biopsy         Yes    No 
• Cerebrospinal fluid                  Yes    No 
• Blood                                    Yes     No 
• Cells from inside my mouth    Yes     No 
 
3. Someone may contact me in the future to ask me to take part in more research.  
                    Yes  No 


 
Protocol Version Date: September 19, 2019 
RTOG-1114 
 
Page 16 of 16 
 
 
 
 
Where can I get more information? (4/23/12) 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237)  
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
• 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
• 
For NCI’s general information about cancer, go to http://www.cancer.gov/cancertopics/ 
 
You will get a copy of this form.    If you want more information about this study, ask your study doctor. 
 
Signature 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have read it or it 
has been read to me.  I understand the information and have had my questions answered.  I agree to take 
part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________