Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer
Phase: PHASE2
Conditions: Extensive Stage Small Cell Lung Carcinoma, Limited Stage Small Cell Lung Carcinoma
Sponsor: NRG Oncology

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NRG ONCOLOGY 
NRG-CC003 
(ClinicalTrials.gov NCT #02635009 (11Aug2017) 
 
RANDOMIZED PHASE II/III TRIAL OF PROPHYLACTIC CRANIAL IRRADIATION 
WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE FOR  
SMALL CELL LUNG CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Cancer Research Group; and SWOG.  
 
Coordinating Center:  
NRG Oncology 
Four Penn Center 
1600 JFK Blvd, Suite 1020 
Philadelphia, PA 19103 
 
Study Team (15-JUNE-2020) 
 
Principal Investigator/Radiation Oncology 
Vinai Gondi, MD 
Northwestern Medicine Cancer Center 
Warrenville  
4405 Weaver Parkway 
Warrenville, IL 60555 
630-352-5350/Fax 630-352-5349 
vgondi@chicagocancer.org  
Co-Principal Investigator/Radiation Oncology 
Minesh P. Mehta, MD 
Miami Cancer Institute, Executive Office 
8900 N. Kendall Dr. 
Miami, FL 33176 
786-527-8014/Fax 786-533-9416 
MineshM@baptisthealth.net  
 
 
Medical Physics Co-Chair 
Wolfgang A. Tomé, PhD, FAAPM 
Institute for Onco-Physics, Montefiore 
Medical Center/Albert Einstein College of 
Medicine 
1300 Morris Park Ave, Block Bldg. Rm 106 
Bronx, NY 10461 
718-430-3188/Fax 718-405-8561 
wtome@montefiore.org  
Quality of Life Co-Chair 
Shannon Fogh, MD 
University of California, San Francisco 
505 Parnassus Avenue, Room L-08 
San Francisco, CA 94143 
415-353-8950/Fax 415-353-8679 
FoghSE@radonc.ucsf.edu  
 
 
Neurocognitive Co-Chair 
Jeffrey S. Wefel, PhD 
Univ of Texas MD Anderson Cancer Center 
Department of Neuro-Oncology 
1515 Holcombe Blvd, Unit 431 
713-563-0514/Fax713-794-4999  
jwefel@mdanderson.org  
 

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NRG ONCOLOGY  
NRG-CC003 
 
RANDOMIZED PHASE II/III TRIAL OF PROPHYLACTIC CRANIAL IRRADIATION 
WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE FOR  
SMALL CELL LUNG CANCER 
 
Study Team (Continued)  
 
Imaging Co-Chair 
Tammie L.S. Benzinger, MD, PhD 
Mallinckrodt Institute of Radiology 
Washington University School of Medicine 
510 S. Kingshighway Blvd. 
Campus Box 8131 
St. Louis, MO 63110 
314-362-5949/Fax 314-362-4886 
benzingert@wustl.edu  
Imaging Co-Chair 
Joseph Bovi, MD 
Medical College of Wisconsin 
9200 W Wisconsin Ave 
Milwaukee, WI 53226 
414-805-4477/Fax 414-805-4369  
jbovi@mcw.edu  
 
 
 
Imaging Co-Chair 
Clifford G. Robinson, MD 
Washington University School of Medicine 
4921 Parkview Place, Box 8224 
St. Louis, MO 63110 
314-362-8567/Fax 314-362-8521 
crobinson@radonc.wustl.edu  
 
Lung Co-Chair 
Alex Sun, MD, FRCPC 
Princess Margaret Cancer Centre 
610 University Avenue 
Toronto, Ontario, Canada M5G2M9 
416-946-2126/Fax 416-946-6561 
Alex.sun@rmp.uhn.on.ca  
Cost-Effectiveness Co-Chair 
Andre A. Konski, MD, MBA, MA FACR 
University of Pennsylvania  
Perelman School of Medicine 
The Chester County Hospital  
701 E. Marshall Street 
West Chester, PA 19380 
610-431-5530/Fax 610-431-5144 
andre.konski@uphs.upenn.edu  
Translational Science Co-Chair 
Andrew B. Lassman, MD 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
710 W. 168th Street 
New York, NY 10032 
212-342-057l/Fax 212-342-1246 
Abl7@cumc.columbia.edu  
 
 
Alliance for Clinical Trials in Oncology Co-
Chair 
John Grecula, MD 
Ohio State University/ James Cancer Hospital 
460 W 10th Avenue 
Columbus, OH 43210 
614-293-3250/Fax 614-685-2400 
john.grecula@osumc.edu  
ECOG-ACRIN Co-Chair 
Kristin J. Redmond, MD, MPH 
The Johns Hopkins University 
401 N. Broadway, Suite 1440 
Baltimore, MD 21231 
410-614-1642/Fax 410-502-1419 
kjanson3@jhmi.edu  
 

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NRG ONCOLOGY  
NRG-CC003 
 
RANDOMIZED PHASE II/III TRIAL OF PROPHYLACTIC CRANIAL IRRADIATION 
WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE FOR  
SMALL CELL LUNG CANCER 
 
Study Team (Continued)  
SWOG Co-Chair 
Laurie E. Gaspar, MD 
University of Colorado School of Medicine 
1665 Aurora Court, Suite 1032, MS F706,  
Aurora, CO  80045 
720-848-0115/Fax 720-848-0222   
laurie.gaspar@ucdenver.edu  
Senior Statistician 
Stephanie Pugh, PhD  
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0850/Fax 215-928-0153 
pughs@nrgoncology.org  
 
 
 
NRG Oncology Contact Information (13-APR-2021) 
Data Management 
For questions concerning eligibility or data 
submission  
 
Apsara Nair and Rachel Issa 
NRG Oncology 
50 South 16th Street, Suite 2800  
Philadelphia, PA 19102  
215-717-0858 (A. Nair)/215-940-8889 (R. Issa) 
Fax: 215-940-8809  
naira@nrgoncology.org/issar@nrgoncology.org 
 
RTQA 
For questions concerning RT data 
submission 
 
Denise Manfredi, BS, RT(T) 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3219 
dmanfredi@acr.org  
 
 
RT Credentialing 
 
http://irochouston.mdanderson.org  
OR 
IROC-Credentialing@mdanderson.org  
 
 
Data submission to TRIAD 
Triad-Support@acr.org  
 
Protocol Development 
For questions concerning protocol and 
informed consent versions & amendments 
 
 
Fran Bradley, BA 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8893 
bradleyf@nrgoncology.org 

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NRG Oncology Cancer Prevention and 
Control Committee Chair 
Lisa Kachnic, MD, FASTRO 
Department of Radiation Oncology 
Columbia University Irving Medical Center 
622 W 168th St. 
New York, NY 10032 
212-305-4894/Fax:  212-305-0015 
lak2187@cumc.columbia.edu  
 
 
 
 
 

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NRG ONCOLOGY  
NRG-CC003 (11Aug2017) 
 
RANDOMIZED PHASE II/III TRIAL OF PROPHYLACTIC CRANIAL IRRADIATION 
WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE FOR  
SMALL CELL LUNG CANCER 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
N/A 
 
 
 
 
 
 
Participating Sites: 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Broadcast Date 
Amendment 5 
July 1, 2022 
N/A 
Amendment 4 
April 13, 2021 
N/A 
Amendment 3 
June 15, 2020 
N/A 
Amendment 2 
February 14, 2019 
N/A 
Amendment 1 
August 11, 2017 
September 25, 2017 
Activation  
September 10, 2015 
December 7, 2015 
Pre-Activation 
September 10, 2015 
November 4, 2015 
 
 
 
 
 
 
 
 
(14-FEB-2019) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
The following investigators participate in this trial as NCTN Group Study Champions:  
 
ALLIANCE:   
John Grecula, MD 
(For contact information, see Study Team 
Alliance Co-Chair) 
 
SWOG:   
Laurie E. Gaspar, MD 
(For contact information, see Study Team, 
SWOG Co-Chair)  
 

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NRG ONCOLOGY 
NRG-CC003 
 
RANDOMIZED PHASE II/III TRIAL OF PROPHYLACTIC CRANIAL IRRADIATION 
WITH OR WITHOUT HIPPOCAMPAL AVOIDANCE FOR  
SMALL CELL LUNG CANCER 
 
CONTACT INFORMATION (01-JUL-2022) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal.  (Sign in at 
www.ctsu.org, and select 
Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email:  
at 1-866-651-CTSU (2878) to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN).  OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email:  
1-888-823-5923, or 
ctsucontact@westat.com 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.   Refer to 
the data submission 
section of the protocol for 
further instructions.  
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific Web page of the CTSU members’ website 
(https://www.ctsu.org).  Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) 
registration system and requires user log in with a CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of 
the Lead Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  

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Table of Contents  
SCHEMA …… ................................................................................................................................9 
1. OBJECTIVES ............................................................................................................................10 
1.1 
Primary Objective  .................................................................................................10 
1.2 
Secondary Objectives  ...........................................................................................10 
1.3 
Exploratory Objectives   ........................................................................................10 
2.  BACKGROUND .......................................................................................................................10 
2.1 
Rationale for Proposed Study ................................................................................10 
2.2 
Significance of the Study  ......................................................................................14 
2.3 
Risk of Relapse in the Hippocampal Avoidance Region .......................................14 
2.4 
Proposed Seamless Randomized Phase II/III Study Design ..................................14 
2.5 
Translational Research ...........................................................................................16 
3.   PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .......................18 
3.1 
Patient Selection Guidelines ..................................................................................18 
3.2 
Eligibility Criteria  .................................................................................................18 
3.3       Ineligibility Criteria  ..............................................................................................20 
4.  REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP .................20 
5.  TREATMENT PLAN/REGIMEN DESCRIPTION.................................................................23 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy  .........................23 
5.2 
Radiation Therapy  .................................................................................................23 
5.3 
Surgery ...................................................................................................................29 
5.4 
General Concomitant Medication and Supportive Care Guidelines  .....................29 
5.5 
Duration of Therapy ...............................................................................................30 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................30 
7.  ADVERSE EVENTS REPORTING REQUIREMENTS .........................................................30 
7.1       Protocol Agents ......................................................................................................30 
7.2       Adverse Events and Serious Adverse Events ........................................................31 
7.3 
Expedited Reporting of Adverse Events  ...............................................................31 
8.  REGISTRATION AND STUDY ENTRY PROCEDURES  ...................................................33 
8.1       Investigator and Research Associate Registration with CTEP  .............................33 
8.2 
Pre-registration Requirements  ..............................................................................37 
8.3       RT-Specific Pre-Registration Requirements .........................................................38 
8.4       Patient Enrollment  ................................................................................................40 
9.  DRUG INFORMATION ..........................................................................................................41 
10. PATHOLOGY/BIOSPECIMEN .............................................................................................41 

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10.1     Biomarkers  ............................................................................................................41 
10.2 
Biospecimen Submission Table  ............................................................................42 
11. SPECIAL STUDIES (NON-TISSUES) ..................................................................................43 
11.1    Patient-Reported Outcomes  ...................................................................................43 
11.2    Optional Online Completion of Patient-Reported QOL Assessments  ...................46 
11.3    Imaging Biomarkers ...............................................................................................48 
12. MODALITY REVIEWS ..........................................................................................................49 
12.1     Radiation Therapy Quality Assurance Reviews ....................................................49 
13. DATA AND RECORDS .........................................................................................................49 
13.1     Data Quality Portal  ...............................................................................................49 
13.2     Data Submission/Data Reporting  ..........................................................................50 
13.3     Summary of Data Submission ...............................................................................51 
13.4     Global Reporting/Monitoring ................................................................................51 
14. STATISTICAL CONSIDERATIONS ....................................................................................51 
14.1 
Study Design  .........................................................................................................51 
14.2 
Study Endpoints  ..................................................................................................51 
14.3 
Primary Objectives Study Design ......................................................................52 
14.4 
Study Monitoring of Primary Objectives ..........................................................54 
14.5 
Accrual/Study Duration Considerations ...........................................................55 
14.6 
Secondary or Exploratory Endpoints  ...............................................................55 
14.7     Exploratory Hypotheses and Endpoints  ...........................................................64 
14.8     Statistical Analysis Plan for Translational Research Endpoints  ....................64 
14.9     Gender/Ethnicity/Race Distribution  .................................................................64 
REFERENCES  .............................................................................................................................66 
APPENDIX I: CERTIFICATION PROCEDURES FOR THE NEUROCOGNITIVE TEST 
BATTERY  ............................................................................................................76 
 
 
 
 

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Histologic proof or unequivocal cytologic proof of SCLC 
Arm 2 
PCI with Hippocampal Avoidance 
using IMRT (25 Gy in 10 Fractions) 
Arm 1 
PCI Alone (25 Gy in 10 
Fractions) 
STEP 1 REGISTRATION 
STEP 2 REGISTRATION/RANDOMIZATION 
Baseline neurocognitive assessment: HVLT-R, TMT, COWA (required) 
Note: Neurocognitive assessments must be uploaded prior to Step 2 Registration and 
can be uploaded at the time of Step 1 Registration. 
 
STRATIFICATION 
Stage: Limited vs. Extensive 
Age: < 60 years old vs. ≥ 60 years old 
Planned Concurrent Memantine Use: Yes vs. No 
NRG ONCOLOGY 
NRG-CC003 
 
A Randomized Phase II/III Trial of Prophylactic Cranial Irradiation with or without 
Hippocampal Avoidance for Small Cell Lung Cancer 
 
 
SCHEMA (11AUG2017) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE:  If the trial proceeds to the phase III component, all patients enrolled on the 
randomized phase II component will be included in the primary and secondary 
endpoint analysis of the phase III component. 
 
 

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1. OBJECTIVES  
1.1 
Primary Objective (11Aug2017) 
1.1.1 Randomized Phase II Component (Non-Inferiority): Determine whether the 12-month 
intracranial relapse rate following HA-PCI is non-inferior to the rate following PCI for 
patients with SCLC. 
1.1.2 Phase III Component (Efficacy): Determine whether HA-PCI reduces the likelihood of 6-
month deterioration from baseline in HVLT-R delayed recall compared to PCI for 
patients with SCLC.  
 
1.2 
Secondary Objectives  (15-JUNE-2020) 
1.2.1 Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, COWA 
test, and TMT Parts A and B), after PCI versus HA-PCI in SCLC. 
1.2.2 Compare time to cognitive failure as separately measured by each test (HVLT-R for 
Total Recall and Delayed Recognition, COWA test, and TMT Parts A and B), after PCI 
versus HA-PCI for SCLC. 
1.2.3 Compare patient-reported cognitive functioning and other quality of life domains 
(assessed by the EORTC QLQ-C30 and BN20) between PCI versus HA-PCI for patients 
with SCLC. 
1.2.4 Compare overall survival after PCI versus HA-PCI for patients with SCLC. 
1.2.5 Compare 12-month intracranial relapse rate (at completion of phase III) and time to 
intracranial relapse after PCI versus HA-PCI for patients with SCLC. 
1.2.6 Evaluate adverse events according to CTCAE criteria. 
1.2.7 Correlate changes in HRQOL domains with changes in cognitive testing outcomes 
following PCI versus HA-PCI for patients with SCLC. 
1.2.8 Assess cost-effectiveness of HA-PCI (MRT) and PCI (3DCRT) using the EuroQOL-5D 
health state classification (EQ-5D-5L). 
1.2.9 Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI 
and HA-PCI 
1.2.10 Evaluate APOE genotyping as potential predictor of neurocognitive decline, hippocampal 
atrophy after brain irradiation and/or differential benefit from hippocampal avoidance.  
1.2.11 Evaluate baseline MR imaging biomarkers of white matter injury and hippocampal 
volumetry as potential predictors of cognitive decline and differential benefit from HA-
PCI as compared to PCI. 
 
1.3 
Exploratory Objectives  (01-JUL-2022) 
1.3.1 Collect serum and whole blood for future translational research analyses. 
1.3.2    Compare levels of hopefulness between PCI versus HA-PCI for patients with SCLC. 
1.3.3    Feasibility of remote neurocognitive testing. 
 
 
2.       BACKGROUND 
2.1 
Rationale for Proposed Study  
Cognitive Effects of Prophylactic Cranial Irradiation 
Intracranial failure is a frequent problem in patients with small cell lung cancer (SCLC) 
(Hochstenbag 2000).  The burden of brain metastases impacts on quality and length of 
survival.  Multiple clinical trials of prophylactic cranial irradiation (PCI) in patients with 

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limited-stage SCLC (LS-SCLC) (Auperin 1999) and extensive stage SCLC (ES-SCLC) 
(Slotman 2007) have consistently shown a reduction in the incidence of brain metastases 
and a prolongation in survival with the use of PCI. These data provide compelling 
evidence for the use of PCI in SCLC. 
 
However, a potential adverse effect of PCI can be cognitive toxicity.  In a recent 
international phase III trial of standard-dose versus high-dose PCI for LS-SCLC (Le 
Pechoux 2009), patients from North America enrolled through the RTOG (RTOG 0212) 
underwent evaluation for cognitive toxicity and quality of life effects. Compared to 
patients receiving standard-dose PCI, patients receiving higher-dose PCI arms were 
found to have a 25% increase in the rate of chronic cognitive toxicity (Wolfson 2011).  
However, even among the patients receiving standard-dose PCI, 62% (95% confidence 
interval 50-74%) developed cognitive toxicity, with a 68% relative increase in the 
percentage of patients experiencing decline in memory function, assessed by the Hopkins 
Verbal Learning Test (HVLT) delayed recall. These data suggest that even standard-dose 
PCI is associated with relatively high rates of cognitive toxicity.  Similar findings have 
been reported with the use of PCI for locally advanced non-small cell lung cancer. RTOG 
0214 was a phase III comparison of PCI versus observation in patients with locally 
advanced non-small-cell lung cancer. Despite not reaching target accrual, this trial also 
demonstrated a significantly greater decline in HVLT total recall and delayed recall in the 
PCI arm at 3, 6, and 12 months follow-up (Sun 2011).   
 
Observations of cognitive decline after PCI appear similar to those seen after whole-brain 
radiotherapy (WBRT) for brain metastases. Li, et al (2007) published a detailed analysis 
of the time course of cognitive decline in 8 prospectively measured domains in 208 brain 
metastases patients treated with 30 Gy of WBRT. They observed memory-related 
cognitive domains, specifically HVLT Total recall and delayed recall, as weakly 
associated with tumor reduction and most susceptible to early decline, even in patients 
with non-progressive brain metastases. Further evidence of the susceptibility of memory 
to cranial irradiation was recently demonstrated by Chang and colleagues (2009). They 
reported a single-institution phase III trial of stereotactic radiosurgery (SRS) with or 
without WBRT in patients with 1 to 3 brain metastases, with the principal objective of 
comparing cognitive decline between the 2 arms.  Utilizing the HVLT-Revised (HVLT-
R) as a cognitive metric for learning and memory, their study was halted early due to an 
interim observation of a 2-fold increase in the mean probability of HVLT-R Total Recall 
deterioration at 4 months (49%, SRS+WBRT, vs. 23%, SRS alone).  
 
The sum of these PCI and WBRT findings suggests that memory-related cognitive 
domains may be differentially sensitive to the effects of cranial irradiation and that 
strategies meant to preserve these susceptible cognitive domains warrant further 
investigation.  
 
Rationale for Hippocampal Avoidance during PCI 
Emerging evidence suggests that the pathogenesis of radiation-induced cognitive deficit 
may involve radiation-induced injury to proliferating neuronal progenitor cells in the 
subgranular zone of the hippocampus (Mizumatsu 2003, Raber 2004). It has been found 

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that relatively small doses of radiation cause apoptosis in the subgranular zone of young 
rats and mice (Ferrer 1993, Nagai 2000, Mizumatsu 2003). On the other hand, little to no 
apoptosis is observed in other areas of the cerebrum (Nagai 2000).  In particular, it has 
been noted that irradiation causes a sharp and prolonged decline in neurogenesis in the 
subgranular zone (Ferrer 1993, Abayomi 1996, Peissner 1999, Nagai 2000, Tada 2000, 
Monje 2002, Madsen 2003). Clinical studies suggest that radiation-induced damage to the 
hippocampus plays a considerable role in the cognitive decline of patients. In particular, 
deficits in learning, memory, and spatial processing observed in patients who have 
received cranial irradiation are thought to be related to hippocampal injury (Roman 1995, 
Abayomi 1996).   
 
Moreover, irradiation of the hippocampus has been associated with pronounced cognitive 
impairment in the learning and memory domain in patients receiving radiation therapy for 
nasopharyngeal tumors (Lee 1989, Leung 1992), maxillary tumors (Sakata 1993), 
pituitary tumors (Grattan-Smith 1992), and base of skull tumors (Meyers 2000).  In a 
recent study from our research group, patients treated with cranial irradiation for low-
grade or benign brain tumors were prospectively evaluated with a battery of cognitive 
function tests up to 18 months post-treatment, and potential correlations between 
radiation dose to the hippocampus and cognitive function were assessed (Gondi 2013).  
In this analysis, a significant dose-response relationship was established, with dose to 
40% of the hippocampus predicting an 18-fold increased risk of subsequent decline in a 
memory test similar to HVLT.   
 
Monje and colleagues (2002) found that radiation injury to the hippocampus in Fisher 
344 rats leads to structural alterations of the microenvironment of the “stem cell niche” of 
the hippocampus that regulates progenitor-cell fate; one consequence of this is decreased 
neurogenesis. Monje and colleagues (2003) went on to show that neurogenesis is 
inhibited by inflammation in the area surrounding the stem or progenitor cells. This 
inhibition occurred whether the inflammation was induced by radiation injury or by 
bacterial lipopolysaccharide. Hence, inflammatory injury of the hippocampus putatively 
represents a possible mechanism for the domain-wise differential effect in cognitive 
function, as well as the temporal sequence of events, following PCI.  
 
We propose to use intensity modulated radiotherapy (IMRT) to conformally avoid the 
hippocampal region during PCI (HA-PCI) to reduce the dose to the hippocampus, thereby 
putatively limiting the radiation-induced inflammation of the hippocampal region and 
subsequent alteration of the microenvironment of the neural progenitor cells.  We 
hypothesize that HA-PCI may delay or reduce the onset, frequency, and/or severity of 
cognitive decline, as measured with clinical cognitive tools.  
 
Feasibility and Preliminary Results of Hippocampal Avoidance 
HA-PCI poses important challenges in conformally avoiding the centrally located 
hippocampus, with its unique anatomic shape, while allowing for uniform dose delivery 
to the remainder of the brain.  We have developed novel techniques to achieve HA-PCI 
using multiple IMRT delivery systems widely available at multiple academic and 
community radiation oncology practices.  In recent dosimetric analyses, we and other 

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institutions have demonstrated the ability of these IMRT techniques to reduce mean dose 
received by the hippocampus by at least 80%, while providing acceptable coverage and 
homogeneity of radiotherapy to the remaining whole brain parenchyma (Gondi 2010, Hsu 
2010). In addition, we have disseminated knowledge and provided experience with these 
techniques through RTOG 0933, a completed phase II trial of hippocampal avoidance 
during WBRT for brain metastases.  In addition to accruing 113 patients in 19 months, 
this trial built a technological infrastructure at RTOG to credential 113 physicians and 84 
RTOG sites spanning community, academic, and international institutions in the 
techniques of hippocampal contouring and hippocampal avoidance treatment planning.  
 
As a single-arm phase II study with a pre-specified statistical comparison to a historical 
control of brain metastasis patients treated with WBRT without hippocampal avoidance, 
RTOG 0933 sought to provide preliminary observations on the potential cognitive benefit 
of hippocampal avoidance in the setting of WBRT for brain metastasis.  This study 
successfully completed accrual in November 2012. The primary endpoint of RTOG 0933 
was mean relative decline in HVLT-R delayed recall score from baseline to 4 months, 
defined as follows ∆𝐻𝑉𝐿𝑇𝑖=
𝐻𝑉𝐿𝑇𝐵−𝐻𝑉𝐿𝑇𝐹
𝐻𝑉𝐿𝑇𝐵
, where B=baseline and F=follow-up with a 
positive change indicating a decline in function. Based upon historical control data of 
30% mean relative decline in HVLT-R Delayed Recall at 4 months compared to baseline 
in patients treated with WBRT without hippocampal avoidance, RTOG 0933 
hypothesized that hippocampal avoidance during WBRT would lead to a 50% relative 
improvement over historical control, with a mean relative decline of 15% or less.   
 
RTOG 0933 demonstrated that hippocampal avoidance during WBRT was associated 
with a mean relative decline in HVLT-R Delayed Recall score from baseline to 4 months 
of 7.0% (95% confidence interval (CI): -4.7% to 18.7%), which was highly significant in 
comparison to the historical control (p=0.0003) (Gondi 2014). The memory preservation 
benefit of hippocampal avoidance was maintained at 6 months follow up, with a mean 
relative decline in HVLT-R Delayed Recall score from baseline to 6 months of 2.0% 
(95% CI: -9.2% to 13.1%).  Similar memory preservation also was observed in the 
remaining HVLT-R domains. For instance, probability of HVLT total recall deterioration 
(defined as > 5 point drop in Total Recall score from baseline to follow-up assessment) 
was 19% at 4 months after HA-WBRT, which compared favorably to the 49% rate 
following SRS+WBRT in the Chang et al. study (Chang 2009) and 13.8% at 6 months 
after HA-WBRT, which compared favorably to the 28.6% rate following WBRT + 
memantine in RTOG 0614 (Brown 2013). 
 
In addition to HVLT, RTOG 0933 included other assessments of memory function, 
including verbal learning memory (International Shopping List Task) and visuo-
perceptual and spatial learning and memory (One Card Learning Test), both of which 
demonstrated no significant change from baseline following HA-WBRT (Caine 2014).  
HA-WBRT also was associated with preservation of patient-reported quality of life, 
assessed using the Functional Assessment of Cancer Therapy and its validated brain 
subscale and the Barthel Activities of Daily Living (Gondi 2014). Review of survival 
outcomes for RTOG 0933 found no difference in median PFS (5.9 months) and OS (6.8 
months) compared to historical controls.  Two grade 3 toxicities of fatigue and headache 

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were observed; there were no grade 4 or higher toxicities. Three patients (4.5%) 
experienced progression in the hippocampal avoidance region after HA-WBRT.  This 
4.5% risk of hippocampal/perihippocampal relapse was lower than prior published 
estimates of 8.6% (95% CI 5.7-11.5%) (Gondi 2010). 
 
2.2 
Significance of the Study (11Aug2017) 
In spite of clinical evidence demonstrating an overall survival benefit from PCI (Auperin 
1999, Slotman 2007), a recent study demonstrated that 40% of eligible LS-SCLC 
patients do not receive PCI (Wu 2013).  Concerns about cognitive toxicity from PCI—
on the part of both patient and physician—were found to be the primary reasons for not 
receiving PCI, underscoring the importance of studying novel approaches to mitigating 
PCI-associated cognitive toxicity.  Building upon extensive preclinical and clinical data 
supporting the memory-specificity and radiosensitivity of the hippocampal neural stem 
cell compartment, RTOG 0933 demonstrated highly promising memory-preservation 
results with the application of IMRT techniques to conformally avoiding the 
hippocampus during cranial irradiation.  We propose a randomized study that addresses, 
in a placebo-controlled trial of SCLC patients receiving PCI, the hypothesis that 
hippocampal avoidance may prevent radiotherapy-induced memory toxicity. 
 
2.3 
Risk of Relapse in the Hippocampal Avoidance Region 
The potential risk of attenuating the benefit of PCI due to the development of metastatic 
disease within the hippocampal avoidance region following HA-PCI for SCLC requires 
better definition, as such a comprehensive data set does not exist. Prior assessments of 
SCLC patients presenting with brain metastases have observed a 4.8%-10.5% incidence 
of brain metastases within the hippocampal avoidance region (Gondi 2010, Kundapur 
2013). If we assume that the risk of developing brain metastasis in the hippocampal 
avoidance region scales in the same proportion as that at presentation, these data suggest 
that the absolute increase in risk of intracranial relapse following HA-PCI may be 10% or 
less. The Auperin meta-analysis of PCI trials for SCLC (Auperin 1999) demonstrated an 
overall survival benefit associated with a 23% absolute reduction in 12-month 
intracranial relapse rate with PCI as compared to no PCI.  Given the effectiveness of 
salvage radiosurgery for intracranial relapse in SCLC (Wegner, Olson, et al. 2011; 
Serizawa, Ono, et al. 2002), should HA-PCI be associated with an elevated risk of 
intracranial relapse, we hypothesize that this risk will be sufficiently small so as to not 
compromise the established survival benefit of PCI for SCLC.  
 
2.4 
Proposed Seamless Randomized Phase II/III Study Design 
To reliably address the objectives of both intracranial relapse and prevention of memory 
toxicity with HA-PCI, we propose a seamless randomized phase II/phase III study of PCI 
versus HA-PCI for patients with SCLC. With a primary endpoint of 12-month 
intracranial relapse risk, the phase IIR component will be designed as a non-inferiority 
study to determine if the relapse risk following HA-PCI is not inferior to that following 
PCI.  If the pre-specified non-inferiority margin is not exceeded, then the trial will 
reactivate and transition to the phase III efficacy component, in which the cognitive 
function outcomes of patients enrolled on the phase IIR component will be utilized for 

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the primary endpoint analysis of the phase III trial. The primary endpoint of the phase III 
component will be HVLT-R delayed recall at 6 months post-treatment. 
 
Structuring the proposed study as a seamless phase IIR/III design provides the following 
advantages:  
1) An overall sample size of 304 randomized SCLC patients for this phase IIR/III 
remains feasible; 
2) The use of concurrent rather than historical controls permits more accurate 
comparison of both phase IIR and phase III endpoints;  
3) The trial closure when the phase IIR component reaches accrual provides sufficient 
follow-up time to assess 12-month intracranial relapse risk before proceeding with the 
phase III component;  
4) Utilization of the cognitive outcomes data from the phase IIR component to address 
the phase III primary and secondary endpoints limits overall sample size, while 
providing greater power for the phase III endpoints.   
 
To remain consistent with the memory-specific toxicity of cranial irradiation observed in 
prior clinical trials and memory-specific benefits of hippocampal avoidance demonstrated 
in RTOG 0933, this proposed phase IIR/III study will utilize HVLT-R, the same 
memory-specific measurement tool used in prior studies, as the primary endpoint of the 
phase III component.   
 
HVLT-R incorporates 6 different forms, helping to mitigate practice effects of repeated 
administrations.  Each form includes 12 nouns (targets) with 4 words drawn from 3 
semantic categories, which differ across the 6 forms.  The test involves memorizing a list 
of 12 targets for 3 consecutive trials (immediate recall), recalling the 12 targets after a 20-
minute delay (Delayed Recall), and then identifying the 12 targets from a list of 
semantically related or unrelated items (delayed recognition). Raw scores are derived for 
total recall, delayed recall, and a delayed recognition discrimination index.  Each patient 
will serve as her/his own control, as the difference in HVLT-R scores obtained at 
baseline and post-treatment intervals will be calculated with the Reliable Change Index 
(RCI) to define deterioration (Jacobsen 1991). 
 
Other cognitive instruments, including the Controlled Oral Word Association (COWA) 
and the Trail Making Test (TMT) Parts A and B, also will be used to complement HVLT-
R in defining the secondary endpoint of time to cognitive failure. This battery of 
instruments has been selected based on accepted standardization and psychometric 
principles, published normative data relative to routine demographics, relevance to 
general cognitive status, minimal practice effects, and brevity of the overall battery. 
Additionally, similar variations of this cognitive testing battery have been utilized in 
multiple cooperative group trials.  
 

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2.5 
Translational Research: (15-JUNE-2020) 
2.5.1    Comprehensive miRNA profiling of serum in limited stage small cell lung cancer 
patients undergoing PCI or HA-PCI for detection of biomarkers for cognitive 
decline  
 
  
MicroRNAs (miRNAs) are short, non-coding RNA sequences and have been presented as 
potential biomarkers of neurodegenerative diseases in blood in the recent years (Danborg 
2014). A recent twin study of circulating miRNAs in healthy individuals has shown that 
an epigenetic miRNA signature can be detected in serum of individuals with cognitive 
decline compared to genetically matched controls (Mengel-From 2018). Additionally, 
previous studies have linked circulating miRNAs to cognitive decline in Alzheimer’s 
patients (Fransquet 2018).  This study will seek to determine as a secondary objective 
whether miRNAs can be utilized as potential biomarkers of cognitive decline following 
HA-PCI vs. PCI. 
 
2.5.2 Apolipoprotein E (APOE) 
Genomic DNA will be extracted from 400 μL peripheral blood by using the blood DNA 
extraction kit (TIANGEN) according to the manufacturer’s instructions. DNA will be 
diluted with nuclease free water to 8 ng/μL for APOE genotyping analysis.  Direct 
sequencing of APOE will be performed using previously tested primer pairs (16).  Cycle 
sequencing products will be run on an ABI 3730 XL DNA analyzer and the resultant 
chromatograms will be analyzed with FinchTV v1.4 (Geospiza, Seattle, WA).  
Insufficient DNA amplification can result from low concentrations of DNA or impure 
DNA.  This will be corrected with re-extraction and/or re-purification of DNA.  Positive 
controls will be added at the beginning and end of each plate of samples. 
 
The APOE gene encodes for APOE and is located on chromosome 19. ApoE is involved 
in the uptake, transport and distribution of lipid, is expressed at high levels in the brain, 
and is believed to play an important role in neuronal repair and synaptic function (1, 2).  
APOE is polymorphic and has three major alleles, APOE2, APOE3, APOE4.  The E4 
allele has been associated with cognitive dysfunction after damaging events such as 
cardiac bypass surgery (3) and traumatic brain injury (4, 5).  Additionally, testing of 
middle-aged E4 carriers reveals cognitive difficulties (6).  Finally, the E4 allele is an 
established risk factor for Alzheimer’s dementia (7). Data suggest that patients having the 
APOE4 isoform realize Alzheimer’s dementia far earlier than those without it (8).  
 
Preclinical studies have demonstrated an association between APOE4 and hippocampal 
neurogenesis and function.  In one study, neurogenesis in the hippocampal dentate gyrus 
was studied in transgenic mice expressing APOE4 or APOE3 in the setting of 
environmental stimulation.  Environmental stimulation increased neurogenesis in the 
dentate gyrus of APOE3-transgenic and wild-type mice, but triggered apoptosis in the 
dentate gyrus of APOE4-transgenic mice.  These APOE-dependent effects on 
neurogenesis were specific to the hippocampal dentate gyrus and were not observed in 
the subventricular zone (9).  Hippocampal responses to “negative” stimuli such as 
traumatic brain injury or irradiation also demonstrated similar APOE-dependence.  In a 

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microarray analysis, Crawford et al. observed genomic changes consistent with a loss of 
reparative function and impaired neurogenesis in the hippocampus of APOE4-transgenic 
mice, compared to APOE3-transgenic mice (10).  Villasana and colleagues irradiated 
APOE2-, APOE3-, and APOE4-transgenic mice and assessed hippocampal-dependent 
spatial learning and memory tasks.  Irradiated APOE4-transgenic mice performed poorly 
on hippocampal-dependent tasks relative to sham-irradiated APOE4-transgenic mice and 
to all other transgenic mice (11).  These preclinical data suggest that APOE4 plays a 
critical role in neurogenesis within the hippocampal dentate gyrus and in hippocampal-
dependent memory function. 
 
In clinical studies, APOE4 allele status has been linked with rates of progressive 
hippocampal atrophy, which in turn has been demonstrated to be a sensitive marker of 
early Alzheimer’s dementia and predictive of cognitive decline.  In one study by Mori 
and colleagues (12), 55 patients with probable Alzheimer’s disease were followed with 
serial annual MRI scans.  The status of the APOE4 allele significantly correlated with the 
rate of hippocampal atrophy, implicating APOE4 allele status as relevant to the 
progression of hippocampal atrophy in the setting of Alzheimer’s dementia.  Similar 
findings were observed by Van der Pol and colleagues in patients with mild cognitive 
impairment (13).   
 
RTOG 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- 
memantine), performed neurocognitive function testing at baseline, 8, 16, 24, and 52 
weeks, and included an optional blood draw for APOE genotyping. APOE results were 
available for 45% (n = 227/508) of patients. No pretreatment differences were detected 
between patients with APOE available versus not available. Preliminary analysis 
demonstrated that 29.5% of brain metastasis patients receiving WBRT had one or more 
APOE4 alleles (14). Mixed effects modeling showed that APOE4 allele carriers exhibited 
greater declines in episodic memory as assessed by the HVLT-R total recall (Figure 1, 
p=0.0081), immediate recall (p=0.0382), and delayed recognition (p=0.0265), executive 
functioning as assessed by Trail Making Test Part B (p=0.021), and the summary 
neurocognitive Clinical Trial Battery Composite score (Figure 2, p=0.0254) after WBRT. 
A study by Correa et al (15) of patients with glioma found approximately the same 
distribution of patients (30%) with APOE4 alleles. As with our preliminary work, their 
findings suggest that glioma patients treated with brain irradiation may experience 
worsening in attention and executive functions several years after treatment, and that the 
APOE4 allele may modulate cognitive decline. 
 
This study will validate these preliminary findings using centrally collected blood and 
serum specimens.  This trial offer a unique opportunity to determine if the individual risk 
of neurocognitive toxicity following WBRT with or without hippocampal avoidance can 
be determined based on APOE genotyping and/or serum APOE levels.  Using blood 
specimens, APOE genotyping will be performed to assess whether a subgroup of patients 
exists that is genetically predisposed to developing neurocognitive decline and/or 
differential neuroprotection from hippocampal avoidance. Another objective on this trial 
is hippocampal volumetric changes from pre- to post-treatment using centrally collected 
MR imaging and these changes will bed correlated with APOE genotyping. 

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3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the protocol title page). For radiation therapy-
related eligibility questions, please contact RTQA (via the contact list on the protocol title 
page).  
3.1 
Patient Selection Guidelines  
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception during the therapy (PCI alone or 
PCI with hippocampal avoidance) part of the trial. 
3.1.3    Submission of serum and whole blood is strongly encouraged for all patients. Samples 
will be submitted for banking for the translational research portion of this protocol and 
for future studies. (See Section 10 for further details). 
 
3.2 
Eligibility Criteria (13-APR-2021) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Prior to Step 1 Registration 
3.2.1    Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two 
positive sputa) of SCLC within 250 days prior to Step 1 registration; 
• High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted. 
3.2.2    Patients must have received chemotherapy and be registered to Step 1 registration no 
earlier than 7 days and no later than 56 days after completing chemotherapy. Note: 
• Post-chemotherapy restaging imaging must be completed no more than 56 days prior 
to Step 1 registration. 
• For patients with extensive-stage small cell lung cancer who are being considered for 
consolidative thoracic radiotherapy after chemotherapy, concomitant administration 
of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial 
irradiation with or without hippocampal avoidance is permitted.  
3.2.3 Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled 
gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field 
echo (TFE) MRI scan (see section 11.3 regarding axial T2/FLAIR sequence).  To yield 
acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, 
MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness 
not exceeding 1.5 mm.  Sites may contact the Imaging Co-Chairs for further information 
or assistance if needed.   

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• This MRI must be obtained within 56 days prior to Step 1 registration.   
 
Note: The MRI study is mandatory irrespective of randomization to the experimental or 
control arm of this study. 
 
3.2.4    Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage            
or extensive-stage SCLC after clinical staging evaluation involving the following: 
a. History/physical examination; 
b. CT of the chest and abdomen with contrast (does not have to be done if the patient 
has had a PET/CT scan prior to initiating chemotherapy or thoracic radiotherapy); 
c. MRI of the brain with contrast or diagnostic head CT with contrast; 
d. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and 
brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage 
SCLC. 
3.2.5   After chemotherapy, patients must be restaged prior to Step 1 registration using the same 
diagnostic work-up as required pre-chemotherapy (see Section 3.2.4).  Repeat PET/CT or 
bone scan is not required.  Patients must have: 
• History/physical examination within 30 days of Step 1 registration; 
• No CNS metastases (Repeat MRI required; see Section 3.2.3 for details) within 56 
days prior to Step 1 registration;  
• No progression in any site; 
• Radiographic partial or complete response to chemotherapy in at least one disease site 
within 56 days prior to Step 1 registration.  
o If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of 
the chest and abdomen with contrast can be obtained for response assessment. 
o Patients who underwent resection for limited-stage SCLC prior to chemotherapy 
and have no radiographically evident disease for response assessment remain 
eligible if post-chemotherapy imaging demonstrates no progression. 
3.2.6   Zubrod performance status 0-2 within 30 days prior to Step 1 registration; 
3.2.7   Age ≥18; 
3.2.8   Women of childbearing potential must have a negative qualitative serum pregnancy test ≤ 
14 days prior to Step 1 registration. 
3.2.9   Patients who are primary English or French speakers are eligible.   
3.2.10 Patients must sign a study-specific informed consent prior to study entry. 
 
Prior to Step 2 Registration 
3.2.11 The following baseline neurocognitive assessments must be completed and uploaded 
within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, 
delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive 
assessments will be uploaded into the NRG Oncology RAVE System for evaluation by 
Dr. Wefel.  Once the upload is complete, within 3 business days, a notification email will 
be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed 
recall must be able to be scored (i.e. completed without error) in order to be eligible. 
3.2.12 Patients must have a baseline raw score greater than 2 on the HVLT-R Delayed Recall, as 
determined by central assessment by the Neurocognitive Co-Chair, Dr. Wefel. 

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3.3     Ineligibility Criteria (14-FEB-2019) 
  Patients with any of the following conditions are NOT eligible for this study.  
3.3.1 Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap 
of radiation fields; 
3.3.2 Radiographic evidence of CNS metastases; 
3.3.3 Radiographic evidence of hydrocephalus or other architectural distortion of the 
ventricular system, including placement of external ventricular drain or 
ventriculoperitoneal shunt; 
3.3.4 Planned concurrent chemotherapy during PCI; 
• Concurrent atezolizumab permitted 
3.3.5 Concomitant invasive malignancy or invasive malignancy within the past five years other 
than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductal carcinoma 
in situ of breast, in situ carcinoma of the cervix, vulva or larynx) is permitted. 
3.3.6 Contraindication to MR imaging, such as implanted metal devices or foreign bodies or 
severe claustrophobia; 
3.3.7 Severe, active comorbidity, 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; 
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
• Uncontrolled, clinically significant cardiac arrhythmias; 
• HIV positive with CD4 count < 200 cells/microliter;  
➢ Note: Patients who are HIV positive are eligible, provided they are under 
treatment with highly active antiretroviral therapy (HAART) and have a CD4 
count ≥ 200 cells/microliter within 30 days prior to Step 1 registration.  
➢ Note: HIV testing is not required for eligibility for this protocol. 
3.3.8  Pregnant or lactating women or women of childbearing potential and male participants 
who are sexually active and not willing/able to use medically acceptable forms of 
contraception; this exclusion is necessary because the radiation treatment involved in this 
study may be significantly teratogenic. 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (01-
JUL-2022) 

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PRE-TREATMENT ASSESSMENTS 
Prior to Step 1 Registration (calendar days; may also be required for eligibility) 
Histo/cyto proof of SCLC 
250 
History/physical examination 
30 
Restaging imaging, per Section 3.2.5 
56 
MRI of the brain 
Thin slice MRI required as outlined in 
Section 3.2.3 
56 
Zubrod performance status 
30 
Serum pregnancy test, (if applicable) 
14 
 
Prior to Step 2 Registration(calendar days) 
Baseline neurocognitive: HVLT-R, TMT, 
COWA (upload required to proceed to 
Step 2) 
7 
(and within 10 days after or at time of 
Step 1 registration) 
English or French must be the patient’s 
primary language.  
 
 
Intention to use memantine concurrently 
with PCI or PCI with hippocampal 
avoidance 
 
 
Prior to Start of Treatment 
QOL: EORTC QLQ-C30 ,  BN20, AHS, 
and PHQ 2 
(Must be completed in hard-copy) 
 
Cost-Effectiveness: EQ-5D-5L and WPAI 
Questionnaire.  Patient diary must be 
given to patient prior to start of treatment. 
 
Whole blood and serum collection (If 
patient consents) 
 
 
 
 

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ASSESSMENTS IN FOLLOW UP  
 
Assessments 
From start of PCI or HA-PCI:  
 
At 3, 6, 12, 18 and 24 
months 
q3 months until 12 months; q6 
months until 3 years; thereafter 
annually until death 
History/physical examination 
 
X  
Zubrod performance status 
 
X 
Brain MRI w/ contrast or head CT 
with contrast  
Thin slice MRI (as outlined in 
Section 3.2.3) is not required in 
follow up 
 
X 
Required Neurocognitive: 
HVLT-R, COWA, TMT 
X 
 
QOL: EORTC QLQ-C30,  and 
BN20   
(Can be completed online)*  
X 
 
QOL: AHS and PHQ 2 
(Can be completed online)* 
At 6 months 
 
Cost-effectiveness: EQ-5D-5L*, 
Work Productivity & Activity 
Impairment (WPAI) 
Questionnaire and health resource 
utilization diary 
(The first diary must be given to patient 
prior to start of RT and is due at the end 
of RT. The next patient diary must be 
given to the patient when the previous 
diary is collected.) 
At end of RT, 6, 12, 
and 24 months 
 
Serum  collection (If patient 
consents)  
At  3, 6, 12, and 18 
months from start of 
PCI or HA-PCI  
 
 
*Note: Patients have the option of completing quality of life (QOL) forms online from any 
location, including home, via VisionTree Optimal Care (VTOC) (see Section 11.2 for 
details). 
 
Definition of Disease Assessments 
Intracranial relapse is defined as the development of a new brain metastasis as documented on 
brain MRI with contrast or head CT with contrast. 
 

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5. TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy (15-JUNE-2020) 
Concurrent use of memantine is permitted but not required (see Section 5.4.1).  
Otherwise, no chemotherapy, hormonal therapy or other agent-based therapy will be 
permitted during or within 7 days before or after PCI or PCI with hippocampal avoidance 
except for atezolizumab as outlined in Section 3.3.4. 
 
5.2 
Radiation Therapy (15-JUNE-2020) 
Protocol treatment must begin within 28 calendar days after randomization. 
 
NOTE 1: Patients only can be enrolled by treating institutions that have passed pre-
enrollment benchmark cases for HA-PCI treatment planning and that have at least one 
treating physician who has passed pre-enrollment benchmark cases for hippocampal 
contouring (credentialed physician).  Each institution can have at most two credentialed 
physicians. Treating institutions and physicians credentialed for NRG-CC001 or RTOG 
0933 also will be credentialed for NRG-CC003, since benchmark cases are similar 
between these trials. See Section 8.3 for further details.  
 
NOTE 2: While credentialing has been limited to 2 physicians per institution, there is no 
limit on the number of physicians who can enroll patients. Any physician can accrue 
patients and develop the hippocampal contours and hippocampal avoidance IMRT plan 
(should the patient be randomized to the experimental arm). If a non-credentialed 
physician enrolls a patient, then a credentialed physician at the same site must review the 
contours/plan to ensure they meet protocol criteria, and both the treating physician and 
the reviewing credentialed physician must be entered on OPEN during case registration. 
 
NOTE 3: The first patient enrolled or reviewed by a credentialed physician and 
institution in Arm 2 (HA-PCI) will require a Pre-Treatment Review. The patient cannot 
start treatment until they have received approval from the Imaging and Radiation 
Oncology Core (IROC)-Philadelphia RT. The Pre-Treatment Review process requires 5 
business days from the receipt of complete data.  If an unacceptable deviation occurs, the 
next case may require a Pre Treatment Review. See Section 8.3 for specifics on 
submission requirements. 
 
NOTE 4: Credentialed physicians who have passed one (1) pre-treatment review of a 
patient enrolled on the hippocampal avoidance arm of NRG-CC001 will be permitted to 
enroll patients or serve as reviewing credentialed physician for patients enrolled on NRG-
CC003 without pre-treatment case review. Note: If the institution has not enrolled a case 
on NRG-CC001, then one pre-treatment review is required. 
 
5.2.1 Treatment Technology 
This protocol requires photon treatment.  3DCRT is required in Arm 1. Field-in-field 
approaches to 3DCRT to optimize homogeneity are permitted for Arm 1.  Inverse 
planned IMRT is not allowed for Arm 1. IMRT is required for Arm 2.  Fixed-gantry 
IMRT, helical tomotherapy or VMAT can be used for Arm 2.  All participating sites must 
be credentialed for IMRT. 

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Megavoltage beam of 6MV or greater must be used for Arms 1 or 2, with a minimum 
source-axis distance of 100cm.  The exception is the use of the helical tomotherapy unit 
that has a source-axis distance of 85cm.   
5.2.2 Immobilization and Simulation 
Immobilization 
Patients will be immobilized in the supine position using an immobilization device such 
as an Aquaplast mask over the head.  Patients will be treated in the immobilization 
device. 
 
Simulation Imaging  
A non-contrast treatment-planning CT scan of the entire head region using the smallest 
possible axial slice thickness not exceeding 2.5 mm will be required. For patients 
enrolled on Arm 2 (HA-WBRT experimental arm), the axial slice thickness of the 
treatment-planning CT scan must match the MRI axial slice thickness as much as 
possible.  The treatment-planning CT scan must be acquired with the patient in the same 
position and immobilization device as for treatment.  This should be obtained within 28 
days prior to initiating treatment. 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
For Arms 1 and 2:  Post-contrast gadolinium contrast-enhanced three-dimensional 
spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or 
turbo field echo (TFE) axial MRI scan and axial T2/FLAIR sequence acquisitions. 
 
To yield acceptable image quality, the pre- (if performed) and post gadolinium contrast-
enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan must use the 
smallest possible axial slice thickness not exceeding 1.5 mm.  These imaging sequences 
should be obtained with the patient in the supine position.  The MRI is required at 
baseline as an eligibility criterion for enrollment in the study.  Immobilization devices 
used for CT simulation and daily radiation treatments need not be used when obtaining 
these imaging sequences, but an attempt should be made to image the patient in as close 
to the same plane as the CT simulation as possible to facilitate fusion of the MRI and CT 
images. 
 
Downloading MRI Protocol Documents:   
If you don't currently have a three-dimensional SPGR, MP-RAGE, or TFE 
sequence on your scanner, many acceptable examples are available for download 
from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 
http://adni.loni.usc.edu/methods/documents/mri-protocols. 
 
Sites should contact the Imaging Co-Chairs for further information or assistance if 
needed. 
 
Note: The MRI study is mandatory irrespective of randomization to the experimental or 
control arm of this study. 
 

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For Arm 2, the MRI for radiotherapy planning and treatment-planning CT should be 
fused semi-automatically for hippocampal contouring. 
5.2.4 Definition of Target Volumes and Margins 
For Arm 1, the target volume shall include the entire cranial contents, with flashing 
beyond skin and a minimum margin of 0.75 cm on the skull base as visualized on the 
digitally reconstructed radiograph (DRR) from the CT simulation scan.  This flashing 
accounts for beam penumbra and day-to-day set-up variation.     
 
For Arm 2, the following structures are required and must be named for digital RT data 
submission as listed in the table below.  These structures must be contoured and 
submitted with the treatment plan. Resubmission of data may be required if labeling of 
structures does not conform to the standard DICOM name listed.  Capital letters, spacing 
and use of underscores must be applied exactly as indicated.  
Standard Name 
Description 
Detailed Specification 
CTV_2500 
CTV to receive 25 Gy 
 
 
The whole-brain parenchyma 
to the foramen magnum. 
PTV_2500 
PTV to receive 25 Gy 
 
 
The CTV_2500 excluding the 
hippocampal avoidance 
region (see Section 5.2.5).  
No set-up margin is added. 
 
5.2.5 Definition of Critical Structures and Margins 
For Arm 1, care should be taken to minimize the dose to the lens.  These can be 
contoured on the simulation CT and visualized on the DRR.   
 
For Arm 2, all structures listed in the table below must be contoured and labeled for 
digital RT data submission as listed. Resubmission of data may be required if labeling of 
structures does not conform to the standard DICOM name listed.  Capital letters, spacing 
and use of underscores must be applied exactly as indicated.  All structures should be 
contoured on the planning CT, using the fused MRI for guidance as described below.  
Due to variance in eye position between the CT and MRI, the lenses and optic nerves 
should be contoured using the CT dataset only. 
 
Standard Name 
Description 
Descriptive Details 
Hippocampi 
Bilateral 
hippocampal 
contours  
 
Bilateral hippocampal contours will be manually 
generated on the fused planning MRI/CT image set 
by the treating physician according to contouring 
instructions specified on 
http://www.rtog.org//corelab/contouringatlases/hipp
ocampalsparing.aspx. 
Hippocampi_5mm 
Hippocampa
l avoidance 
region 
Generated by three-dimensionally expanding the 
hippocampal contours by 5 mm.   
Hippo_L 
Left 
hippocampu
Bilateral hippocampal contours will be subdivided 
into Left and Right hippocampi. 

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s 
Hippo_R 
Right 
hippocampu
s 
Bilateral hippocampal contours will be subdivided 
into Left and Right hippocampi. 
Lens_L 
Left lens 
Due to variance in eye position between the CT and 
MRI, if possible, the left lens should be contoured 
using the CT dataset only. 
Lens_R 
Right lens 
Due to variance in eye position between the CT and 
MRI, if possible, the right lens should be contoured 
using the CT dataset only. 
OpticNerve_L 
Left optic 
nerve 
Due to variance in eye position between the CT and 
MRI, if possible, the left optic nerve should be 
contoured using the CT dataset only. 
OpticNerve_R 
Right optic 
nerve 
Due to variance in eye position between the CT and 
MRI, if possible, the right optic nerve should be 
contoured using the CT dataset only. 
OpticChiasm 
Optic 
chiasm 
Located above the pituitary fossa, the optic chiasm 
includes both anterior and posterior limbs.  It is best 
visualized on SPGR/MPR/TFE T1 MRI sequence, 
but should be confirmed on CT dataset due to 
potential variation in CT/MRI fusion. 
 
5.2.6 Dose Prescription 
For Arms 1 and 2, one treatment of 2.5 Gy will be given daily over approximately 2 
weeks for a total of 25.0 Gy (10 fractions). Treatment does not necessarily need to start 
on a Monday and it is acceptable for treatment to start later in the work-week. 
 
For Arm 1, dose is specified as the target dose, which shall be the dose on the central x-
ray at mid-separation for two opposed coaxial equally weighted beams.  “Compensating 
beams” that block hot spots (these hot spots are typically present along midline due to 
less tissue present in these regions compared to mid-brain) are allowed to achieve better 
dose homogeneity.  All portals shall be treated during each treatment session. 
 
For Arm 2, IMRT plan should be normalized such that 95% of the PTV_2500 volume 
receives prescription dose of 25 Gy in 10 fractions of 2.5 Gy per fraction. If ≥ 90% of the 
PTV_2500 volume receives prescription dose of 25 Gy it will be considered Variation 
Acceptable (See Section 5.2.7). 
5.2.7 Compliance Criteria 
Arm 1: There are no compliance criteria specific to radiation therapy planning or 
delivery. 
 
Arm 2: The compliance criteria listed here will be used to score each case.  Given the 
limitations inherent in the treatment planning process, the numbers given in this section 
can be different than the prescription table.  The Per Protocol and Variation Acceptable 
categories are both considered acceptable.  The Per Protocol cases can be viewed as ideal 
plans, and the Variation Acceptable category can include more challenging plans that do 

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not fall at or near the ideal results.  A final category, called Deviation Unacceptable, 
results when cases do not meet the requirements for either Per Protocol or Variation 
Acceptable. Plans falling in this category are considered to be suboptimal and additional 
treatment planning optimization is required. 
 
Accuracy of MRI/CT fusion and hippocampal contouring will be assessed subjectively 
by central physician reviewer.    If MRI/CT fusion or hippocampal contouring is not 
considered acceptable, this will be scored as a Deviation Unacceptable. 
 
NOTE: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met. 
 
Target Volume Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric 
Parameter 
Per 
Protocol 
Variation 
Acceptable 
Notes 
PTV_2500 
 
D2%(Gy) 
≤ 31.25 Gy 
≤ 33.3 Gy 
Dose to hottest 
2% of 
PTV_2500 
D98%(Gy) 
≥ 21 Gy 
< 21 Gy 
Dose to 98% of 
PTV_2500 
V25Gy (%) 
≥ 95% 
≥ 90%  
Volume 
receiving 
prescription dose 
of 25 Gy 
 
Normal Structure Constraints and Compliance Criteria 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Notes 
Hippocampi 
D100%(Gy) 
≤ 7.5 Gy 
≤ 8.5 Gy 
Dose to 100% 
of 
Hippocampus 
Dmax(Gy) 
≤ 13.5 Gy 
≤ 15 Gy 
Dose to hottest 
0.03 cc volume 
of 
Hippocampus 
OpticNerve_L 
Dmax(Gy) 
≤ 25 Gy 
≤ 36.0 Gy 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_L 
OpticNerve_R 
Dmax(Gy) 
≤ 25 Gy 
≤ 36.0 Gy 
Dose to hottest 
0.03 cc volume 
of 
OpticNerve_R 
OpticChiasm 
Dmax(Gy) 
≤ 25 Gy 
≤ 36.0 Gy 
Dose to hottest 
0.03 cc volume 
of 

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OpticChiasm 
 
Delivery Compliance Criteria 
 
Per Protocol 
Variation 
Acceptable 
Notes 
Interruptions 
0 break days 
1-3 break days 
Unscheduled break 
days 
 
5.2.8 Treatment Planning Procedures and Priorities 
Arm 1:  Three-dimensional approaches to radiotherapy planning will be used for patients 
enrolled in the PCI reference arm. There are no treatment-planning priorities. 
 
Arm 2:  Intensity-modulated radiotherapy will be used for patients enrolled in the PCI 
with hippocampal avoidance arm.  In optimizing planning, the following treatment-
planning priorities should be followed: 
 
 
1. 
OpticChiasm  
 
2. 
OpticNerve_L or OpticNerve_R 
 
3. 
Hippocampus 
 
4. 
PTV_2500 
 
5. 
Lens_L or Lens_R 
 
In the event that an OAR with higher priority than PTV_2500 cannot be constrained 
within Unacceptable Deviation limits, then D98% and/or V25Gy for PTV_2500 should 
be lowered to Variation Acceptable range to ensure that the OAR with higher priority 
does not exceed Unacceptable Deviation limits. 
5.2.9 Dose Calculations 
Arm 1: Primary dataset for dose calculation should be non-contrast treatment-planning 
CT scan of the entire head region using the smallest possible axial slice thickness not 
exceeding 2.5 mm.  Dose matrix grid size must be ≤ 3 mm in sagittal and coronal 
directions. 
 
Arm 2: Primary dataset for dose calculation should be non-contrast treatment-planning 
CT scan of the entire head region using the smallest possible axial slice thickness not 
exceeding 2.5 mm.  Dose matrix grid size must be ≤ 3 mm in sagittal and coronal 
directions.  
5.2.10 Patient-specific Quality Assurance (QA) 
Arm 1: Patient-specific QA not required but should follow guidelines of enrolling 
institution. 
 
Arm 2: Patient-specific QA is strongly recommended. QA is performed by delivering the 
plan onto a phantom and measuring the dose using an ion chamber array or other 2D/3D 
device. Measured dose distribution will be compared to planned dose distribution using a 
Gamma criterion of 4% dose difference and 3 mm distance to agreement. The pass rate 
should be at least 90% measured for the entire plan. These QA data will not be collected 
but should be held by the institution and available for review if requested. 

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5.2.11  Daily Treatment Localization/IGRT 
Verification orthogonal films or images are required.  For all forms of IMRT dose 
delivery, orthogonal films or images that localize the isocenter placement shall be 
obtained.  The length of the treatment field shall be indicated on these films.   
5.2.12 Case Review  
Arm 1: No case review will be performed. 
 
Arm 2:  Case reviews will be ongoing and performed remotely for all patients enrolled in 
Arm 2.  Case reviews will be conducted by a team of Co-Chairs. 
 
NOTE: The first patient enrolled in Arm 2 from each treating physician and institution 
will require a Pre-Treatment Review.  The patient cannot start treatment until they have 
received approval from IROC-Philadelphia RT.  The Pre-Treatment Review process 
requires 5 business days from the receipt of complete data.  See Section 8.4 for specifics 
on submission requirements. 
 
5.3 
Surgery  
Not applicable to this study. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines (11Aug2017) 
5.4.1 Use of memantine is optional and left to the discretion of the treating physician.   
However, intention to use memantine concurrently with PCI or PCI with hippocampal 
avoidance must be stated at time of Step 2 registration.  In determining intention to use 
memantine, treating physicians would be advised to consult with the patient’s pharmacy 
to determine memantine availability and coverage by the patient’s insurance. 
 
 
Both extended release memantine (Namenda XR) and twice-daily memantine dosing are 
allowed and should be administered per the package insert (see below).  If memantine 
utilization is intended per the treating physician’s discretion, then the treating physician is 
recommended to start memantine on the same day as PCI/HA-PCI and no later than 
before the fourth PCI/HA-PCI treatment. 
 
 
Twice Daily Dosing Memantine 
 
The target dose for memantine is 20 mg (10mg divided twice daily). Dose is escalated by 
5 mg per week to target of 10 mg twice daily. Dose modifications are required in the 
setting of renal insufficiency, and the package insert should be reviewed. 
 
 
Daily AM Dose 
Daily PM Dose 
Week 1 
5 mg 
None 
Week 2 
5 mg 
5 mg 
Week 3 
10 mg 
5 mg 
Weeks 4-24 
10 mg 
10 mg 
 
Patients continue on memantine for 24 weeks. 
 
Extended Release Memantine 

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The target dose for extended release memantine is 28 mg. Dose is escalated by 7 mg per 
week to target of 28 mg daily.  Dose modifications are required in the setting of renal 
insufficiency, and the package insert should be reviewed (or follow institutional 
guidelines). 
 
 
Daily Dose Extended Release 
Memantine 
Week 1 
7 mg 
Week 2 
14 mg 
Week 3 
21 mg 
Weeks 4-24 
28 mg 
 
Patients continue on memantine for 24 weeks. 
 
 
 
5.4.2   Permitted Supportive/Ancillary Care and Concomitant Medications 
 
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.  
5.4.3 Prohibited Therapies 
If memantine is prescribed, the treating physician should be aware that the clearance of 
memantine is reduced with alkaline urine conditions at pH 8 or higher. Urine pH can be 
made more alkaline with chronic use of carbonic anhydrase inhibitors (e.g. 
acetazolamide, brinzolamide, methazolamide, dorzolamide, topiramate) and sodium 
bicarbonate and hence, memantine should be used with caution with these medications.  
Concurrent use of memantine with other NMDA antagonists (e.g. amantadine, ketamine, 
or dextromethorphan) is discouraged and other medications should be considered. 
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), as described in Section 6 
• 
Patient decides to withdraw consent for participation in the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
    No information needed for patients unable to complete PCI.  
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   Protocol Agents 
 
This trial involves no investigational or commercial agents. 

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7.2   Adverse Events and Serious Adverse Events (14-FEB-2019) 
7.2.1 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.  
 
7.2.2 Definition of an Adverse Event (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).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
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. 
 
7.3 
Expedited Reporting of Adverse Events (11Aug2017) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP website,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG 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 Biostatistical/Data Management Center by phone, 1-215-574-3191. An 
electronic report must be submitted immediately upon re-establishment of the Internet 
connection. 
7.3.1 Expedited Reporting Methods 
• CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 

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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. Contact 
NRG Oncology at 1-215-574-3191 for details to submit source documentation.   
• 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.  
7.3.2 Expedited Reporting Requirements for Adverse Events  
 
 
Any Phase Study Utilizing Radiation Therapy (including chemoRT studies)1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor 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 
Not required 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
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:  

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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 3 adverse events 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements: Not applicable 
 
7.3.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.3.4 Secondary Malignancy  
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 during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
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. 
 
8.   REGISTRATION AND STUDY ENTRY PROCEDURES  
8.1 Investigator and Research Associate Registration with CTEP (01-JUL-2022) 
 
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 at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
at https://ctepcore.nci.nih.gov/rcr.   
 

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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); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as Roster Update Management System (RUMS), OPEN, Rave, 
acting as a primary site contact, or with consenting privileges; 
• 
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. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval) or consenting/treating/drug shipment investigator in OPEN, must be rostered at the 
enrolling site with a participating organization.   
 
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. 
 
8.1.1   Cancer Trials Support Unit Registration Requirements  

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This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must 
accept the NCI CIRB review to activate new studies at the site after March 1, 2019. Local 
IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or 
if the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, 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 
• 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 in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an active CTEP status; 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster; 
• If using NCI CIRB, rostered on the NCI under the applicable CIRB Signatory 
Institution(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 
in the RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 

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Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number  
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• Compliance with all protocol specific requirements (PSRs);  
• IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
to begin the modality credentialing process. 
• Neurocognitive Function Testing Certification: See Section 8.2.  
• IRB/REB Approved Informed Consent (International and Canadian sites only:  
English and native language versions*)  
Note: International and Canadian Institutions must provide 
certification/verification of IRB/REB consent translation to NRG Headquarters 
(described below). 
 
*Non-English Speaking Canadian and International Institutions: 
Translation of regulatory 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 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. 
Sites are NOT permitted to translate the Neurocognitive Tests. For sites testing native 
French speakers, the French versions of the tests must be obtained from the NRG 
Oncology website just as the English versions are obtained from the NRG Oncology 
website. 
 
Downloading Site Registration Documents:   
Download the site registration forms from the NRG-CC003 protocol page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms.   
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• Click on Protocols in the upper left of the screen;  
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select NRG, and the 
protocol number (NRG-CC003). 
• Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided.  
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 

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Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission.  
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email:  1-866-651-
CTSU (2878) in order to receive further instruction and support. 
   
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.   
• Click on Regulatory at the top of the screen;  
• Click on Site Registration; and 
• Enter the site’s 5-character CTEP Institution Code and click on Go 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with the site registration 
requirements as outlined within the protocol.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
 
8.2      Pre-registration Requirements (15-JUNE-2020) 
Neurocognitive Function Testing Certification 
At least one Clinical Research Associate (CRA) must be credentialed to administer the 
neurocognitive assessments at each institution. Only a certified test administrator is 
permitted to administer the neurocognitive tests to study participants. Test administrators 
must meet certification requirements for administering neurocognitive assessments; see 
Appendix I in this protocol, the NRG-CC003 Neurocognitive Training Procedure Letter 
and the NRG-CC003 Test Instruction and Administration Procedures document on the 
CTSU website, www.ctsu.org. Upon review and successful completion of the 
Neurocognitive Certification process, Jeffrey S. Wefel, PhD, Neurocognitive Co-Chair, 
will notify both the certified examiner and CTSU that the examiner has successfully 
completed this requirement. The certified test administrator must be proficient in the 
language (English or French) in which the test is administered to the patient. Refer to the 
protocol-specific material on the CTSU website for certification requirements. 
 
Note: Examiners who have completed the full certification procedure to perform these 
tests for RTOG 0534, 0834, 1114, NRG-BN001, or NRG-CC001 during the past 6 
months do not need to complete the full certification procedure again, but the certification 
worksheet for NRG-CC003 (available on the CTSU website) must be sent along with 
information regarding the examiners prior certification (protocol number, date of 
certification) to Dr. Wefel for approval. If these criteria are met, the healthcare 

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professional responsible for test administration and CTSU will be notified of the test 
administrator’s recertification status for NRG-CC003. Examiners who have not 
completed the full certification procedure for RTOG 0534, 0834, 1114, NRG-BN001, or 
NRG-CC001 within the past 6 months must complete the full certification procedure to 
be recertified to ensure continued familiarity with study procedures. 
 
8.3      RT-Specific Pre-Registration Requirements (01-JUL-2022) 
All sites must be IMRT credentialed. For detailed information on the specific technology 
credentialing requirements required for this study, please refer to the table below and 
utilize the web link provided for detailed instructions. The check marks under the 
treatment modality columns indicate whether that specific credentialing requirement is 
required for this study. Specific credentialing components may require you to work with 
various QA centers; however, the Imaging and Radiation Oncology Core (IROC) 
Houston will notify your institution and NRG Oncology Headquarters when all 
credentialing requirements have been met and the institution is RT credentialed to enter 
patients onto this study.  The Regulatory Support System (RSS) will be updated so 
patients can be enrolled. 
 
In order for a site to be eligible to enroll patients in this trial, the institution and its 
treating physicians must have passed benchmark testing for hippocampal contouring and 
Hippocampal Avoidance PCI (HA-PCI) treatment planning. Benchmark testing is 
limited to two (2) physicians per site. Benchmark testing for hippocampal 
contouring and HA-PCI treatment planning is no longer available. 
 
A treating physician who has not participated in or passed benchmark testing can enroll 
and treat patients on study so long as the patient’s contouring and HA-PCI treatment plan 
is reviewed by another physician who has passed benchmark testing at the treating site. 
 
Treating physicians and institutions credentialed for RTOG 0933 (Phase II study of 
hippocampal avoidance during WBRT for brain metastases) or NRG-CC001 (Phase III 
study of memantine with or without hippocampal avoidance during WBRT for brain 
metastases) can enroll patients in this trial without having to repeat the Benchmark QA 
test. However, the first case they enroll on NRG-CC003 and that is randomized to Arm 2 
(HA-PCI) will require pre-treatment review of hippocampal contouring and HA-PCI 
treatment before proceeding with protocol treatment.  
 
While the trials limit credentialing to 2 physicians per site, the trials do NOT limit accrual 
to 2 physicians per site.  Instead, we ask sites to enable any physician to accrue a patient 
to this study and to develop the hippocampal contours and hippocampal avoidance IMRT 
plan (should the patient be randomized to the experimental arm). However, we mandate 
that if a patient is enrolled by a non-credentialed physician, they ask one of the 
credentialed physicians at their site to review the contours/plan to ensure that they meet 
protocol criteria. When enrolling the patient, the system asks two questions: 1) Who is 
the enrolling the physician? and 2) Who is the credentialed physician who will be 
approving the contours?  Again, these do not need to be the same physician. 
 

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To be Grandfathered from 0933 or CC001, complete a Credentialing Status Inquiry (CSI) 
Form (see the procedures and instructions table below) must be submitted in order to 
receive a letter and have RSS updated.  
NRG-CC003 
RT 
Credentialin
g 
Requiremen
ts 
 
Web Link for Procedures and Instructions:  
http://irochouston.mdanderson.org  
 
Treatment Modality 
Key Information 
 
 
3DCRT 
(Arm 1) 
IMRT 
Mandator
y for all 
sites 
(Arm 2) 
Facility 
Questionnai
re 
 
✓  
The IROC-Houston electronic facility questionnaire 
(FQ) should be completed or updated with the most 
recent information about your institution. To access 
this FQ, go to 
http://irochouston.mdanderson.org/questionnaires. 
Credentialin
g Status 
Inquiry 
Form (CSI) 
 
✓  
To determine whether your institution needs to 
complete any further credentialing requirements, 
please complete the “Credentialing Status Inquiry 
Form” found under credentialing on the IROC 
Houston QA Center website 
(http://irochouston.mdanderson.org) 
Benchmark 
Cases 
 
✓  
In order for a site to be eligible to enroll patients in 
this trial, the institution and its treating physicians 
must have passed benchmark testing for hippocampal 
contouring and Hippocampal Avoidance PCI (HA-
PCI) treatment planning.  Benchmark testing for 
NRG CC003 is no longer available. 
EXCEPTION:  Treating physicians and sites 
credentialed for RTOG 0933 (phase II study of 
hippocampal avoidance during WBRT for brain 
metastases) or NRG-CC001 (phase III study of 
memantine with or without hippocampal avoidance 
during WBRT for brain metastases) will not be 
required to pass Benchmark Testing for NRG-
CC003. A CSI form should be submitted. 
Phantom 
Irradiation 
 
✓  
An anthropomorphic phantom study provided by the 
IROC-Houston QA Center must be successfully 
completed. Instructions for requesting and irradiating 
the phantom are found on the IROC -Houston 
website under credentialing 

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8.3.1 Digital Radiation Therapy Data Submission Using Transfer of Images and Data  
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images.  TRIAD anonymizes and validates the 
images as they are transferred. 
 
TRIAD Access Requirements: 
• A valid Cancer Therapy Evaluation Program (CTEP) Identify and Access 
Management (IAM)  (CTEP-IAM) account. 
• Registration type of:  Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR).  Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account and 
complete registration in RCR. 
• TRIAD site user role on an NCTN or ETCTN roster.   
 
All individuals on the Imaging and Radiation Oncology Core provider roster have 
access to TRIAD and may submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
 
TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/,   
 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.4       Patient Enrollment (01-JUL-2022) 
   
8.4.1    Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/ randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access: 
• A valid CTEP-IAM account; 
(http://irochouston.mdanderson.org). 

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• To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.   
 
Prior to accessing OPEN site staff should verify the following: 
• The following baseline neurocognitive assessments have been completed prior to 
Step 2 registration: HVLT-R, TMT, and COWA (see Section 3.2.1 for details). 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable).  
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  You may print this confirmation for your 
records.   
 
To receive site reimbursement for specific tests and/or biospecimen submissions, 
completion dates must be entered in the OPEN Funding screen post registration. Please 
refer to the protocol specific funding page on the CTSU members’ website for additional 
information. Timely entry of completion dates is recommended as this will trigger site 
reimbursement. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  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 NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
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. 
  
9.    DRUG INFORMATION  
   Not applicable for this study. 
 
10.    PATHOLOGY/BIOSPECIMEN    
10.1     Biomarkers (15-JUNE-2020) 
 

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10.1.1  miRNA Profiling of Serum 
Comprehensive miRNA profiling of serum of patients enrolled on trial will be performed 
using comprehensive miRNA microarray prior to PCI or HA-PCI and after PCI or HA-
PCI for comprehensive analysis of miRNA alterations induced by PCI or HA-PCI and to 
correlate those results with neurocognitive decline.  
 
Total RNA will be extracted from patient’s serum using a dedicated miRNA kit 
(QIAGEN Total RNA) and hybridized to GeneChip™ miRNA 4.0 Array using samples 
obtained before and after irradiation.  
 
Candidate miRNAs identified during the discovery phase will be validated using qPCR 
analysis on an independent subset of samples in triplicate. 
10.1.2 Apolipoprotein E (APOE) 
Genomic DNA will be extracted from 400 μL peripheral blood by using the blood DNA 
extraction kit (TIANGEN) according to the manufacturer’s instructions. DNA will be 
diluted with nuclease free water to 8 ng/μL for APOE genotyping analysis.  Direct 
sequencing of APOE will be performed using previously tested primer pairs (Haasl 
2008).  Cycle sequencing products will be run on an ABI 3730 XL DNA analyzer and the 
resultant chromatograms will be analyzed with FinchTV v1.4 (Geospiza, Seattle, WA).  
Insufficient DNA amplification can result from low concentrations of DNA or impure 
DNA.  This will be corrected with re-extraction and/or re-purification of DNA.  Positive 
controls will be added at the beginning and end of each plate of samples. 
 
10.2 
Biospecimen Submission Table (15-JUNE-2020) 
10.2.1  Optional Specimen Submissions 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified per protocol. Sites are not permitted to delete the specimen component from the 
protocol or from the sample consent. 
 
See detailed specimen collection/processing/shipping instructions on the protocol-
specific page of the CTSU website. 
 
 

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Optional Study: Correlation of biomarkers to the development of neurocognitive decline 
after brain irradiation 
The specimens are being collected in order to be prepared to correlate biomarkers to the 
development of neurocognitive decline after brain irradiation (see Section 10.1 for further 
details). 
 
• Required Form: ST form (include study #, case #, patient initials, NRG/NCI institution 
ID# and name, treatment time point of specimens) 
• Biospecimen Kits: Available from the NRG Oncology Biospecimen Bank-San Francisco 
- send all kit requests by email to NRGBB@ucsf.edu  
• Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada and Non-
North American). 
• Shipping costs:  One return label is provided for each case in the frozen Biospecimen kits 
provided by the bank. Batch shipping specimens from all timepoints from each case is 
encouraged. 
 
For questions, contact:  
NRG Oncology Biospecimen Bank-San Francisco 
415-476-7864/FAX 415-476-5271 
NRGBB@ucsf.edu  
 
Specimen Type 
Collection 
Time Points 
 
Collection 
Information and  
Requirements/ 
Instructions for Site 
 
Shipping 
See the protocol-specific 
page of the CTSU website for 
detailed specimen collection 
and shipment instructions. 
Specimen 1: 
Serum-red top 
tube - centrifuge 
and aliquot 
• Pre-Treatment: 
Prior to  PCI or 
HA-PCI 
• At 3, 6, 12, and 
18 months from 
start of PCI or 
HA-PCI 
Frozen serum samples 
containing minimum 
0.5 mL per aliquot in 
five (5) 1 mL cryovials 
 
Storage:  -80°C and 
ship frozen 
Serum sent frozen on dry 
ice via overnight courier to 
NRG Biospecimen Bank-San 
Francisco 
Specimen 2: 
Whole blood for 
DNA- One 5ml 
purple EDTA 
tube – mix and 
aliquot 
• Pre-treatment 
only: Prior to  PCI 
or HA-PCI 
 
Frozen whole blood 
samples containing a 
minimum of 1.0 mL 
per aliquot in three (3) 
2 mL cryovials 
Whole blood shipped frozen 
on dry ice via overnight 
courier to NRG Biospecimen 
Bank -San Francisco 
 
11.    SPECIAL STUDIES (NON-TISSUE)  
11.1  Patient-Reported Outcomes (14-FEB-2019) 
In a recent secondary analysis of 2 prior RTOG PCI trials (RTOG 0212 and 0214), PCI was 
associated with a 2- to 3-fold increased risk of deterioration in patient-reported cognitive 
functioning, as assessed on the self-reported cognitive functioning subscale of the EORTC 

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QLQ-C30, at 6 months (PCI 45% vs. no PCI 18%) and 12 months (PCI 51% vs. no PCI 
23%) (Gondi 2013). Thus, in determining whether HA-PCI will mitigate cognitive toxicity 
as compared to PCI, inclusion of this validated and sensitive patient-reported endpoint will 
complement information gained from the primary endpoint of HVLT-R Delayed Recall.   
 
EORTC QLQ-C30 
The EORTC QLQ-C30 is the instrument most frequently used to measure quality of life 
(QOL) in cancer patients, and BN20 is a supplemental questionnaire specifically developed 
for use with the general questionnaire (QLQ-C30) in patients with brain cancer. Both 
instruments have been used in previous RTOG PCI trials (RTOG 0212 and 0214) and have 
also been shown to be reliable and valid instruments in the setting of recurrent high-grade 
gliomas (Osoba 1996, Osoba 1997). In addition, QLQ-C30 has demonstrated adequate 
reliability in patients with lung and other cancer diagnoses (Osoba 1997; Aaronson 1993, 
Bergman 1992, Osoba 1994). Both the EORTC QLQ-C30 and BN20 instruments are 
copyrighted by the EORTC and translated and validated in 81 languages.  No monetary 
charge is required for use in a non-commercial setting.  Permission to use these QOL 
instruments for this proposed phase III PCI trial has been obtained.  
 
EQ-5D-5L 
The EuroQOL-5D health state classification (EQ-5D-5L) is a 2-part questionnaire that 
takes approximately 5 minutes to complete (Schultz 2002). The first part of the EQ-5D-5L 
consists of 5 items covering 5 dimensions including: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension can be graded on 5 levels 
including: 1-no problems, 2-slight problems, 3-moderate problems, 4-severe problems, and 
5-extreme problems. Health states are defined by the combination of the leveled responses 
to the 5 dimensions, generating 243 (3 to the 5th) health states to which unconsciousness 
and death are added (Badia 1998).  The second part is a visual analogue scale (VAS) 
valuing current health state, measured on a 20 cm 10 point-interval scale.  Worst 
imaginable health state is scored as 0 at the bottom of the scale and best imaginable health 
state is scored as 100 at the top. Both the 5-item index score and the VAS score are 
transformed into a utility score between 0 "Worst health state" and 1 "Best health state". 
Either the index score or the VAS score can be used in the quality adjusted survival 
analysis, or enter the cost-utility equation, depending on the health state(s) of interest (Wu 
2002). 
 
Although developed in Europe, the EQ-5D has been used in the United States and Canada 
(Glick 1999, Johnson 1998, Johnson 1998b, Johnson 2000, Trippoli 2001). The EQ-5D 
web site, http://www.euroqol.org/, lists the languages in which the form has been validated. 
The Work Productivity and Activity Impairment (WPAI) Questionnaire, a validated 
instrument to assess work and productivity (Reilly 1993), will be used to assess both the 
patient and any caregiver lost wages and productivity.  It consists of 6 questions utilizing a 
recall period of the last 7 days.  The WPAI has 4 outcomes: absenteeism (work time 
missed), presenteesism (impairment at work/reduced on-the-job effectiveness), work 
productivity loss (overall work impairment/absenteeism + presenteeism), and activity 
impairment.  These outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity.   
 

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Cost-Effectiveness 
A health resource utilization diary will be used to measure the services consumed by the 
patient.  The diary must be given to the patient at the beginning of the reporting period and 
the due dates for submission of the diary are provided in Section 4.  For example, the first 
diary must be given to the patient prior to the start of RT and is due at the end of RT.  This 
diary can also be completed by a caregiver.  The institution must collect the caregiver’s 
contact information so that the caregiver can be contacted if the diary is not completed by 
the patient.  Note that this information will not be provided to NRG Oncology. 
 
Hopefulness 
The hippocampus has been implicated as a mediator of emotional regulation, especially 
during stress, e.g. cancer and the treatment of cancer (Godsil 2013). Indeed, smaller 
hippocampal volume has been correlated with greater vulnerability to psychological trauma 
(Gilbertson 2002). If the hippocampus functions, in part, as a neurophysiological “hope 
center” then protection of the structure in the HA-PCI arm is expected to preserve 
hopefulness among those treated with this experimental approach. We hypothesize that 
HA-PCI may allow maintenance of hopefulness as measured by the Adult Hope Scale 
(AHS). 
 
The AHS was developed by Snyder and colleagues at the University of Kansas (1989). The 
tool, designed to be completed in approximately 5 minutes, assesses the core components 
of hope theory: goal-setting, path establishment, and agency (i.e. “motivation”) to attain 
said goals by pursuing an established pathway. The instrument has been validated and 
utilized in oncology studies in which links between levels of hopefulness with post-
traumatic growth and positive coping skills have been found (Ho 2012, Clayton 2008).  To 
avoid the confounding effect of depression on hope, a 2-item tool (PHQ 2) will be 
administered to determine if underlying depression is present among subjects (Gilbody 
2007).  The PHQ 2 has already been used in a depression screening trial mounted by NRG 
Oncology (RTOG 0841) and was found to be remarkably robust in detecting depressive 
symptoms. 
 
Data Collection 
Collection of the EORTC QLQ-C30 and BN20 will occur at the same time points as 
cognitive assessments: baseline (prior to Step 2 registration) and at 3, 6, 12, 18, and 24 
months from the start of treatment. The EQ-5D-5L will be collected at baseline (prior to 
Step 2 registration), at the end of RT, and at 6, 12, and 24 months from the start of 
treatment.  The WPAI Questionnaire will be collected at the end of RT and at 6, 12, and 24 
months from the start of treatment.  The AHS and PHQ 2 will be collected at baseline and 6 
months from the start of treatment.  Such a data collection schedule will permit comparison 
of patient-reported QOL and cognitive outcomes, as well as early and long-term patient-
reported QOL effects of HA-PCI as compared to PCI.  RTOG 0212 and 0214 collected 
QOL data at 6 and 12 months. The compliance with quality of life data collection was 
64%-67% at 6 months and 50%-56% at 12 months. To optimize data collection at the 
proposed time points, this trial will incorporate electronic data collection using VisionTree, 
a HIPPA-secure web-based technology that has demonstrated significantly improved data 
compliance (from 52% to 90%) as compared to historical standards within the RTOG 
network (Movsas 2011); see Section 11.2 below. 

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11.2  Optional Online Completion of Patient-Reported QOL Assessments (14-FEB-2019) 
Missing data are a significant problem, particularly for QOL assessments. Unlike data for 
traditional endpoints, such as survival, QOL data can never be obtained retrospectively if it 
is not provided by the patient at the appropriate time point. This limits researchers’ ability 
to accurately perform QOL statistical analyses and negatively impacts the clinical 
relevance of this effort. Typically, QOL forms are filled out in hardcopy (paper). To 
provide a more convenient method of completing QOL assessments, NRG Oncology is 
working with VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on this 
study the option of completing their QOL forms online from any location that has a 
computer with Internet access, including the patient’s home, and provides reminders to 
patients to complete the assessments. 
 
VisionTree has developed a tool, VisionTree Optimal Care (VTOC), a HIPAA-secure, user 
friendly, web-based software system (Gorgulho 2005; Gorgulho 2007; Pedroso 2006). The 
VTOC tool contains a web-based system for global patient and trial administration access, 
which allows improved compliance and accuracy of data collection, validation, and 
reporting. It is compliant with the Title 21, Code of Federal Regulations, Part 11 statistical 
process control system and provides a mobile solution for clinical trials. QOL data are 
collected with Microsoft Excel and PDF export of reports. VTOC also has mobile 
messaging and e-mail reminders. Surveys can be “pushed” to patients for completion at 
timed intervals (see http://www.visiontree.com for details). This technology allows 
consenting patients on this study to fill out their QOL forms online from any location and 
to receive e-mail reminders to complete assessments. E-mail reminders also can be sent to 
research associates (RAs) at the appropriate institutions to remind them that a QOL time 
point window is about to close so that a patient can be contacted to fill out QOL 
information on time, before it becomes “missing data”. 
 
In a pilot RTOG study (RTOG 0828), the compliance rate of patients completing QOL 
assessments at 6 months significantly improved using electronic technology. Based on this 
pilot data, NRG Oncology is offering VisionTree as an option in other studies, including 
this one. Patients preferring to complete hardcopy QOL assessments can do so. The QOL 
forms completed via VTOC are identical to the hardcopy forms; this technology does not 
add to or change the QOL assessments in this study. 
 
Patients without e-mail or Internet access are still able to complete hardcopy (paper) forms. 
Indeed, at any time, any patient may choose to fill out their QOL form using the hardcopy 
form. If the patient wishes to complete QOL assessments online, the patient must have an 
e-mail address that they consent to use for this purpose. Patients’ e-mail addresses are 
necessary so that e-mail reminders may be sent to them to remind them to fill out QOL 
forms that are due. The patient’s e-mail address also will be used for password-protected 
access to VTOC. Patients who are interested in participating but do not yet have an e-mail 
address can obtain one for free from a number of sources (e.g. Yahoo!, Hotmail, or AOL). 
 
The baseline QOL forms must be completed in hardcopy (on paper) prior to the start of 
treatment. In addition, the Adult Hope Scale (AHS) and PHQ 2 must be completed in hard 

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copy (on paper) at 6 months from the start of PCI or HA-PCI. All subsequent QOL forms 
can be completed by the patient online.  
 
The site RA is responsible for setting up the patient’s account on VTOC. The RA may do 
so by logging on the VTOC portal at the following link: https://rtog.optimalcare.com - 
medical team.  RA login information will be provided by VTOC after the first patient 
registered by the RA is randomized to the study. (Once login information is received, the 
RA can immediately set up future patients’ accounts in VTOC after registration.) The 
patient’s VTOC account must be set up within 14 days after randomization. VTOC will 
send patients e-mail reminders to complete QOL forms. The first reminder will be sent at 
the beginning of the window for completion of the form, with a second reminder sent 
halfway through the window, if the form has not yet been completed. A maximum of 3 
reminders will be sent for each of the QOL assessment time points (subsequent to the 
baseline assessments). After the patient has completed all forms, a dialogue box will appear 
thanking the patient for completing the QOL form(s), and the patient will no longer receive 
reminders for that time point. 
 
Patients will receive a login card (either printed or sent via e-mail) with which to log in 
using the secure, web-based VTOC portal. VTOC meets all HIPAA guidelines and is 
encrypted (via 128-bit SSL) for the security, privacy, and confidentiality of QOL 
information. It is similar to the secure login commonly used when performing online 
banking. The login card can then be kept and maintained by the patient. 
 
Site Research Associates (RAs) will receive training in the use of VTOC via NRG 
Oncology webinars and educational sessions.  Dates and registration for the VTOC 
webinars are found in the weekly NRG Oncology Broadcast.  The RA or study 
administrator will be informed via the VTOC “At a Glance” form management system 
when QOL forms have been completed or when the window for a particular form has 
closed. If the site RA receives a notice that forms have not been completed, she or he will 
contact the patient to remind the patient to fill out the QOL form or inquire why the forms 
have not been completed. The RA will complete the cover page for each form that was not 
completed (either via VTOC or in hardcopy) and will submit the cover page. 
 
The patient’s e-mail address only will be used by NRG Oncology for this purpose. Patients 
will be sent e-mail reminders to complete QOL forms. A typical e-mail reminder would 
read: “Your Quality of Life forms for the study, NRG-CC003, are now due. Please go to 
http://www.optimalcare.com, use your secure login, and complete the online forms. If any 
questions make you feel uncomfortable, you may skip those questions and not give an 
answer. If you have any questions, please e-mail or call your research associate at [insert 
RA e-mail address] or [insert RA telephone number]. Thank you for participating in this 
study.” The reminders will be created by NRG Oncology and placed into a study template 
that will be sent to patients at customized intervals (at the time points when QOL forms are 
due). Reminders will be sent for each of the 4 QOL time points (following the baseline 
QOL forms, which are completed in hardcopy) until the form(s) is completed or the time 
window on that time point ends. After a patient has completed all forms in the VTOC 
portal, a dialogue box will appear that says “Thank you for completing your Quality of Life 

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forms,” and the patient will no longer receive any remaining notices for that time point. 
The site RA or study administrator will be informed through the VTOC “At-A-Glance” 
form management system when QOL forms have been completed. 
 
11.3  Imaging Biomarkers (14-FEB-2019) 
 
MR imaging represents a potentially sensitive tool for monitoring cognitive injury from 
cancer therapies including cranial irradiation. Degree of white matter changes and 
hippocampal volumetry represent novel imaging biomarkers that may predict cognitive 
outcomes following neuro-protective strategies such as hippocampal avoidance. As 
exploratory objectives of this study, we plan to assess white matter injury and hippocampal 
volumetry on pre-treatment brain MRIs and correlate these imaging biomarkers with 
cognitive outcomes and potential differential benefit of HA-PCI versus PCI. 
 
 
 
In other neurodegenerative conditions, MR imaging-defined white matter changes have 
been correlated with cognitive deterioration (Carmichael 2010, Breteler 1994). Sabsevitz, 
et al. (2013) demonstrated a strong and independent relationship between white-matter 
integrity prior to cranial irradiation and the volume and severity of these post-treatment 
white matter changes. However, correlation of pre-treatment T2/FLAIR white matter injury 
with cognitive and quality of life outcomes remains poorly understood.  In addition, the 
ability of hippocampal avoidance to mitigate white matter injury has not been previously 
examined.   
 
 
A number of studies have demonstrated that MR-defined hippocampal volumetry is a 
significant predictor for cognitive decline (Kantarci 2013, Fleischman 2013). Similarly, 
serial atrophy in hippocampal volume over time also has predicted for cognitive decline.  
Wang, et al (2013) found that hippocampal loss over time was significantly greater in 
patients with mild cognitive impairment compared with age-matched normal controls.  
Additionally, in a longitudinal study of 323 subjects with mild cognitive impairment, 
patients who had factors predictive for the development of Alzheimer’s dementia had 
higher rates of hippocampal atrophy on serial MRI (van de Pol 2007). Thus, we hypothe-
size that smaller pre-treatment hippocampal volumes will predict for an increased risk of 
cognitive decline and that patients who experience serial decline in hippocampal volume, 
irrespective of pre-treatment volume, will be at a higher risk of cognitive decline. Using 
MR images obtained at baseline, we plan to quantify extent of MR-defined white matter 
changes and hippocampal volume pre-treatment, correlate these data with cognitive and 
quality of life outcomes, and evaluate differential benefit of HA-PCI as compared to PCI. 
11.3.1  Technique, Timing and Central Submission 
The study requires a SPGR, MP-RAGE, or TFE MRI scan without and with gadolinium 
contrast-enhanced T1-weighted acquisitions and standard T2-weighted FLAIR sequence 
acquisitions to be obtained within 56 days of Step 1 registration. The purpose of this 
baseline imaging study is to rule out intracranial metastases prior to enrollment and for 
hippocampal contouring should the patient be randomized to the HA-PCI experimental arm 
of this study.  This imaging study will be submitted for centralized quality assurance 
review of hippocampal contouring and HA-PCI treatment planning. For this exploratory 
analysis of imaging biomarkers, the MRI scan also will be used to provide assessment of 
white matter changes and hippocampal volumetry at baseline prior to HA-PCI as compared 
to PCI.  To yield acceptable image quality, the pre-contrast-enhanced should have a 

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resolution of 1 x 1 x 1.2 mm and should follow the protocols established by the 
Alzheimer’s Disease Neuroimaging Initiative (ADNI).   Performance of this sequence at a 
3 Tesla field strength is recommended.  Vendor-specific versions of this sequence are 
available for download from the ADNI website, http://www.adni-
info.org/scientists/MRIProtocols.aspx .  Sites may contact the Imaging Co-Chairs for 
further information or assistance if needed.  MRI scans are non-invasive and provide no 
additional risk to the patient. 
 
As exploratory objectives of this study, T2/FLAIR and SPGR, MP-RAGE or TFE 
sequences will be submitted for central analysis. Abnormal FLAIR volumes will be created 
in a semi-automated fashion by trained individuals using a consensus approach and blinded 
to the cognitive outcome data.  Automated hippocampal volumetry will be performed on 
the pre-contrast SPGR, MP-RAGE or TFE sequences using FreeSurfer (Boston, MA).  
FreeSurfer has been widely used in multiple large multi-institutional trials and, for 
hippocampal volumetry in particular, has been shown to be highly accurate compared with 
expert manual tracing (Morey 2009). 
 
Submission of imaging will be required on all patients.  See Section 8.4 for specifics on 
submission requirements and procedures. All imaging will be anonymized by TRIAD to 
ensure patient confidentiality.    
 
12. 
MODALITY REVIEWS 
12.1     Radiation Therapy Quality Assurance Reviews  
For Arm 2 Only: A team of Co-Chairs will perform an RT Quality Assurance Review 
after IROC-Philadelphia has received complete data. These reviews will be completed 
remotely and will be ongoing. The final cases will be reviewed within 6 months after this 
study has reached the target accrual or as soon as IROC-Philadelphia RT has received 
complete data for all cases enrolled, whichever occurs first. The scoring mechanism is: 
Per Protocol, Acceptable Variation, and Unacceptable Deviation.   
 
13. 
DATA AND RECORDS 
13.1     Data Quality Portal (01-JUL-2022) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports. Review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 

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To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules.  
 
13.2     Data Submission/Data Reporting (01-JUL-2022) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is granted through the CTEP-IAM system and 
role assignments.  
 
Requirements to access Rave via Medidata: 
• A valid CTEP-IAM account; and 
• Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
 
Rave role requirements: 
• Rave CRA role or CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must either click on 
the link in the email or log into iMedidata via the CTSU members’ website  under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings) and can be accessed by 
clicking on the link in the Tasks pane located in upper right pane of the iMedidata screen.  
If an eLearning is required and has not yet been taken, the link to the eLearning will 
appear under the study name in  the Studies pane located in the center of the iMedidata 
screen; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link under 
the study name. 
  
Site staff that have not previously activated their iMedidata/Rave accounts at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website under in the Data 

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Management > Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
13.3    Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting. Submit digital RT data via TRIAD; see Section 8.3 for TRIAD account access 
and installation instructions. 
 
All neurocognitive materials for every patient at every time point must be uploaded to 
Medidata Rave® within 7 days after test administration. 
 
For reporting of second primary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave; timeframes; add if loading of the pathology report is 
required. 
 
Summary of Data Submission: Refer to the CTSU website for the data submission 
summary. 
 
13.4    Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
14.       STATISTICAL CONSIDERATIONS 
14.1     Study Design (13-APR-2021) 
This is a randomized phase II/III study in which phase II patients will be used in the 
phase III analysis.  The first phase will determine the safety of the treatment of interest, 
hippocampal avoidance during PCI using a non-inferiority design, compared to the 
current standard of care, PCI alone, while the second phase will test the efficacy of the 
treatment.  For both phases, patients will be stratified according to stage (limited vs. 
extensive), age (<60 years old vs. ≥60 years old), and planned concurrent memantine use 
(yes vs. no).  Patients will then be randomized 1:1 to PCI alone (25 Gy in 10 fraction) 
using IMRT or PCI with hippocampal avoidance (HA-PCI) using IMRT (25 Gy in 10 
fractions) using a permuted block procedure (Zelen 1974).  This study is prospective and 
not blinded. The total accrual for this study will be 392 patients as described in detail in 
Section 14.3.3. The analysis population is intent-to-treat, such that all randomized 
patients will be analyzed. 
 
14.2 
Study Endpoints (01-JUL-2022) 
14.2.1 Phase II 
• Primary Endpoint: 12 month intracranial relapse rate 

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14.2.2 Phase III   
• Primary Endpoint: HVLT-R delayed recall deterioration status, defined using the 
Reliable Change Index (RCI) (Jacobson 1991, Chelune 1993) at 6 months from the 
start of treatment  
• Secondary Endpoints:  
o Time to neurocognitive failure, where a failure is defined using the RCI criteria, 
as measured by HVLT-R, Controlled Oral Word Association (COWA) test, and 
Trail Making Test (TMT) Parts A and B 
o Preservation of neurocognitive function, as measured by neurocognitive decline 
for HVLT-R, COWA test, TMT Parts A and B, and Clinical Trial Battery 
Composite (CTB COMP) score 
o Patient-reported health-related quality of life (HRQOL), as measured by the 
EORTC Quality of Life Questionnaire (QLQ-C30) and BN20 
o Correlation of changes in HRQOL domains measured by the EORTC QLQ-C30 
and BN20 with changes in cognitive function 
o Cost-effectiveness as measured by the EuroQOL-5D health state classification 
(EQ-5D-5L) 
o Overall survival 
o Intracranial relapse rate 
o Adverse events, as measured by the CTCAE v.4 
o Correlation of miRNA signatures with neurocognitive decline 
o Correlation of APOE genotyping with neurocognitive decline  
o Effect of baseline white matter injury and hippocampal volume on neurocognitive 
function 
• Exploratory Endpoints:  
o Hopefulness as measured by the Adult Hope Scale (AHS) 
o Feasibility of Remote Neurocognitive Testing 
 
14.3 
Primary Objectives Study Design (15-JUNE-2020) 
14.3.1 Primary Hypothesis and Endpoints 
• Phase II 
The primary hypothesis of the phase II trial is that HA-PCI has a similar 12-month 
intracranial relapse rate compared to PCI for patients with small cell lung cancer 
(SCLC).   
• Phase III 
The primary hypothesis for the phase III trial is that HA-PCI reduces the likelihood of 
6-month deterioration from baseline in HVLT-R Delayed Recall compared to PCI for 
patients with SCLC. 
14.3.2 How Primary Endpoints Will Be Analyzed  
• Phase II 
The primary endpoint of the phase IIR portion of this study is the rate of intracranial 
relapse at 12 months.  Patients who die prior to experiencing a relapse will be 
considered as not having a relapse.  It will be compared between arms using a 
binomial test of difference in proportions at a significance level of 0.1.  If the rate of 
relapse in the HA-PCI arm is significantly greater than that of the PCI only arm, this 
study will not continue to the phase III portion.   

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• Phase III 
The primary endpoint of the phase III portion of the study is deterioration, defined as 
a change in raw score ≥ 3 points (i.e. RCI criteria) from baseline to 6 months in the 
HVLT-R Delayed Recall score (Jacobson 1991, Chelune 1993).  It will be compared 
using Fisher’s exact test at a significance level of 0.05.  Due to the inclusion of 
remote testing, sensitivity analyses will be conducted in which patients who 
completed the neurocognitive testing remotely will be considered missing. 
14.3.3 Sample Size and Power Calculations: 
• Phase II 
In the phase IIR portion of this study, the primary endpoint is the 12-month rate of 
intracranial relapse and the potential impact of HA-PCI compared to PCI.  We 
anticipate that HA-PCI may have a higher rate of intracranial relapse compared to 
PCI alone due to potential relapse in the hippocampal avoidance region.  In order to 
assess the safety of HA-PCI, a non-inferiority design will be used to determine if the 
relapse rate is similar to that of PCI only.  In RTOG 0212, 22% of patients enrolled 
on the 2.5Gy in 10 fractions arm experienced a relapse at 12 months (Wolfson 2011).  
It is assumed that the PCI-only arm will have a similar 12-month relapse rate.  The 
non-inferiority margin needs to be less than 23% due to results from Auperin’s meta-
analysis which found that a 23% absolute 12-month intracranial control benefit of 
PCI translated to an overall survival advantage (Auperin 1999).  In RTOG 0933, 
although a different patient population, a relapse rate in the HA region of 4.5% was 
observed.  Thus, a relapse rate of 4.5% higher in the HA-PCI is expected but more 
than 20% is of concern.  The hypothesis to be tested is: 
 
𝐻0: 𝑃(𝑟𝑒𝑙𝑎𝑝𝑠𝑒)𝐻𝐴−𝑃𝐶𝐼−𝑃(𝑟𝑒𝑙𝑎𝑝𝑠𝑒)𝑃𝐶𝐼> 20%   
𝑣𝑠.   𝐻𝐴: 𝑃(𝑟𝑒𝑙𝑎𝑝𝑠𝑒)𝐻𝐴−𝑃𝐶𝐼−𝑃(𝑟𝑒𝑙𝑎𝑝𝑠𝑒)𝑃𝐶𝐼= 4.5%   
 
Using a non-inferiority margin of 20% and an assumed difference in proportions of 
4.5% under the alternative, a 2-sample test of difference in proportions with a 1-sided 
alpha of 0.1 requires 164 patients to achieve 85% statistical power.  Increasing this by 
5% due to loss to follow up, 172 patients are required to ensure 164 evaluable 
patients for the phase II portion of this study.  If HA-PCI is associated with a < 20% 
absolute increase in 12-month intracranial relapse as compared to PCI, then HA-PCI 
will be deemed safe, and this trial will proceed to the phase III component.  
• Phase III 
The sample size calculations will address the specific primary hypothesis that HA-
PCI reduces probability of deterioration in HVLT-R Delayed Recall (from baseline to 
6 months from the start of treatment).  We do not expect improvement in HVLT-R 
Delayed Recall; at best, we anticipate a preservation of HVLT-R Delayed Recall.  
Data from RTOG PCI trial 0212 demonstrated deterioration, as defined by the RCI 
criteria (Jacobson 1991; Chelune 1993), in HVLT-R Delayed Recall in 29% of 
patients at 6 months following standard-dose PCI.  We anticipate that HA-PCI will 
have a lower probability of deterioration, as defined by the RCI criteria, in HVLT-R 
Delayed Recall performance at 6 months as compared to PCI alone.  Detecting a 
14.5% absolute reduction in the probability of HVLT-R Delayed Recall deterioration 
due to HA-PCI suggests a 50% relative improvement.  With alpha=0. 05 (1-sided), a 
total of 98 analyzable patients per arm would ensure 80% statistical power to detect 

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a 14.5% absolute reduction in the probability of HVLT-R Delayed Recall 
deterioration at 6 months using a test of difference in proportions. In RTOG 0933, 4% 
of patients were ineligible and 31% were non-compliant at 6 months, with 2% not 
completing the HVLT prior to the start of treatment. In RTOG 0212, 5% of patients 
were deceased by 6 months on study. The sample size for this study therefore will be 
increased by 5% due to loss to follow up, 5% due to death, and 25% due to patient 
non-compliance. Thus, the target sample size will be 392 randomized patients to 
ensure 196 randomized evaluable patients. It is expected that some patients will 
score between 0 and 2 on the HVLT-R Delayed Recall prior to Step 2 registration and 
thus not be able to experience cognitive deterioration as defined by the RCI criteria. It 
also is expected that some patients may not complete all parts of the HVLT-R.  These 
patients will not be able to register to step 2.  It is assumed that 10% of registered 
patients will not be randomized to step 2.   
 
Due to the higher than projected enrollment of patients with extensive-stage disease, 
the rate of death by 6 months is higher than initially estimated.  Thus the number of 
evaluable patients will be increased by 5% due to loss to follow up, 20% due to death, 
and 25% due to patient non-compliance. Thus, the target sample size will be 392 
randomized patients to ensure 196 randomized evaluable patients. 
 
14.4 
Study Monitoring of Primary Objectives 
(Interim Analysis) 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
 
If the phase II null hypothesis is rejected, an analysis for the phase III primary endpoint, 
6-month HVLT-R Delayed Recall deterioration, will occur at the time of the phase II 
analysis when all evaluable patients have at least 12 months of follow up.  Due to 
potential non-compliance, it is estimated that about 70% of evaluable patients for phase 
III will be available for this interim analysis. HVLT-R Delayed Recall deterioration will 
be tested using a significance level of 0.05.  The DMC will review the results from the 
interim analysis to decide if the study should be closed & reported early due to efficacy. 
 
Interim Analysis to Monitor the Study Progress   
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published. In general, the interim reports will 
contain the following information: 
• patient accrual rate with a projected completion date (while the study is still accruing) 
• total patients accrued  
• distributions of important pre-treatment and prognostic baseline variables  
• the frequencies and severity of adverse events by treatment arm 

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The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoints, time to neurocognitive failure, or any secondary 
endpoints, with the exception of reporting of adverse events. 
 
14.5 
Accrual/Study Duration Considerations (15-JUNE-2020) 
14.5.1  Accrual Rate  
RTOG 0933 is a completed phase II trial of hippocampal avoidance during WBRT for 
brain metastases. RTOG 0933 accrued 113 patients at an accrual rate of 6 patients per 
month with target accrual reached in 25% less time than initially projected. RTOG 0212 
accrued 265 patients in 5 years at an accrual rate of 4.4 patients per month but did not 
include patients with extensive-stage small cell lung cancer.  For this proposed trial, in 
which patients with extensive-stage small cell lung cancer will be permitted, accrual is 
expected to be higher.  Thus, no accrual is expected for the first 4 months after activation 
then a total of 6 patients are expected in the next 2 months while sites, physicians, and 
clinical research associates are being credentialed.  At this point, accrual is expected to 
increase to 6 patients per month for the duration of the study.  This study will be 
monitored according to DCP accrual guidelines. 
14.5.2  Accrual Goal  
The accrual goal for phase II is 172 patients and for phase III, it is 392 patients. 
14.5.3  Study Duration 
The study is projected to be open to accrual for 56 months for both phases combined, 
including the 6 month ramp-up period specified in Section 14.5.1.  Including the accrual 
hold for the phase II analysis, the phase III portion is projected to close to accrual 
approximately 70 months from activation. 
 
The average monthly accrual has been 9 patients/month and the study is on track to 
complete earlier than initially projected.  With the sample size increase, the phase III 
portion is projected to close as initially planned, approximately 70 months from 
activation. 
14.5.4  Estimated Duration for Completion of Primary Endpoint 
The projected time of analysis, 6 months from the start of treatment, is expected to occur 
about 8 months after study closure, or approximately 88 months from activation. 
  
14.6 
Secondary or Exploratory Endpoints (including correlative science aims) (15-JUNE-
2020) 
14.6.1 Secondary Hypotheses and Endpoints (phase III only):  
• Evaluation time to neurocognitive failure, where a failure is defined using the RCI 
criteria, as measured by HVLT-R, Controlled Oral Word Association (COWA) test, 
and Trail Making Test (TMT) Parts A and B.  It is hypothesized that the HA-PCI arm 
will result in a longer time to neurocognitive failure compared to the PCI only arm.  
• Evaluate neurocognitive function, as measured neurocognitive decline by HVLT-R, 
COWA test, TMT Parts A and B, and CTB COMP (the arithmetic mean of the 
HVLT-R, TMT, and COWA outcomes).  Specifically, it is hypothesized 
neurocognitive function will be preserved in the HA-PCI compared to the PCI only 
arm. 

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• Evaluate 6-month decline, defined as a reduction of 10% from baseline, in patient-
reported cognitive function, as measured by the cognitive functioning subscale of the 
EORTC QLQ-C30.  It is hypothesized that PCI will lead to a great likelihood of 
decline as compared to HA-PCI. 
• Evaluate patient-reported health-related quality of life (HRQOL), as measured by the 
global QOL, physical functioning, role functioning, emotion functioning and social 
functioning domains on the EORTC Quality of Life Questionnaire (QLQ-C30) and 
BN20. 
• Correlate changes in HRQOL domains measured by the EORTC QLQ-C30 and 
BN20 with changes in cognitive function 
• Evaluate cost-effectiveness as measured by the EuroQOL-5D health state 
classification (EQ-5D-5L) 
• Evaluate overall survival 
• Evaluate intracranial relapse rate 
• Evaluate adverse events, as measured by the CTCAE v.4 
• Correlate cognitive failure with miRNA signatures.  Specifically, it is hypothesized 
that microarray profiling of miRNAs in serum of individuals with LS-SCLC enrolled 
in NRG-CC003 who undergo PCI or HA-PCI will reveal miRNA signature 
correlating with cognitive decline. 
• Correlate neurocognitive function with APOE genotyping.  It is hypothesized that 
APOE genotyping will be predictive of neurocognitive decline after brain irradiation 
and MRI evidence of hippocampal volume loss after brain irradiation and APOE 
genotyping will identify patients who derive the most or least benefit from 
hippocampal avoidance. 
• Correlate neurocognitive function with both FLAIR volume and hippocampal 
volume.  It is hypothesized that hippocampal volume and abnormal FLAIR volume at 
baseline will be predictive of subsequent neurocognitive decline after brain irradiation 
and that baseline FLAIR volume and hippocampal volume will identify patients who 
derive the most or least neurocognitive benefit from hippocampal avoidance. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Time to Neurocognitive Failure  
Neurocognitive failure is the first failure, defined as a neurocognitive decline using the 
reliable change index (RCI) on at least one of the following assessments: HVLT-R, TMT, 
or COWA (Jacobson 1991; Chelune 1993).  The HVLT-R has 3 parts that will be 
analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition.  
The TMT has 2 parts that will be analyzed separately: Part A and Part B.   
 
The cumulative incidence approach will be used to estimate the median time to 
neurocognitive failure to account for the competing risk of death.  Gray’s test will be 
used to test for statistically significant difference in the distribution of neurocognitive 
failure times (Gray 1988).  The cause-specific Cox proportional hazards regression model 
will be used to evaluate the effect of stratification variables (age, stage, and planned 
concurrent memantine use)  and other baseline characteristics,  on time to neurocognitive 
decline (Cox 1972). 
 

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Neurocognitive Function 
Preservation of neurocognitive function will be measured by the HVLT-R, COWA, and 
TMT.  The HVLT-R has 3 parts that will be analyzed separately: Total Recall, Delayed 
Recall, and Delayed Recognition. The TMT also has 2 parts that will be analyzed 
separately: TMT Part A and TMT Part B.  The COWA has a single outcome measure that 
will be analyzed.  Standardized scores that adjust for age, education, and gender when 
necessary will be analyzed.  For discrete time point analyses, the change from baseline to 
each follow-up time point (3, 6, 12, 18, and 24 months from the start of treatment) will be 
calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-
Whitney test, depending on the normality of the data.  Neurocognitive decline using the 
reliable change index (RCI) for the HVLT-R, COWA, and TMT also will be compared 
between treatment arms at each follow-up time point using Fisher’s exact test (Jacobson 
1991; Chelune 1993). 
 
A mixed effects model will be used to assess changes of standardized neurocognitive 
scores across time using all available data while adjusting for stratification variables and 
other baseline characteristics.  Mixed models are a general class of models for analyzing 
repeated measures data, which allow modeling of the covariance among the repeated 
measures as well as random effects such as patient-specific intercepts and slopes and can 
incorporate fixed and time-varying covariates.  Fixed effects will consist of stratification 
factors (age, stage, and planned concurrent memantine use) and potentially other baseline 
covariates.  Since missing data is expected, patients with missing data will be compared 
to patients with complete data at each follow-up time with respect to baseline 
characteristics.  If any of these characteristics are found to be significantly different, then 
they will be incorporated into the mixed effects model.  Prior to performing analyses, an 
evaluation of the amount, reasons and patterns of missing data will be performed, using 
the well-known categories of missing completely at random (MCAR), missing at random 
(MAR) and missing not at random (MNAR) (Fairclough 2010, Verbeke 2000).  If 
missing data are MCAR or MAR, then a mixed model using maximum likelihood is 
sufficient because all available data can be used. A joint model that allows a shared 
parameter between the repeated measurements and time to death or drop out can be used 
if considered MNAR due to the high number of patient deaths or dropouts (Rizopoulos 
2012).  Other options for MNAR data are pattern mixture and selection models 
(Fairclough 2010, Little 1995).  Sensitivity analyses will be performed to compare the 
results of different analytic strategies (Fairclough 1998).  Due to the inclusion of remote 
testing, sensitivity analyses will be conducted in which patients who completed the 
neurocognitive testing remotely will be considered missing. 
 
Health-Related Quality of Life 
The primary HRQOL endpoint will be the decline in patient-reported cognitive function 
at 6 months, as measured by the cognitive functioning subscale of the EORTC QLQ-C30.  
Since higher scores indicate better functioning, a reduction of 10% from baseline 
indicates a decline in function.  Additionally cognitive function decline at 3, 6, 12, 18 and 
24 months will also be assessed and compared using Fisher’s exact test.  Decline from 
baseline to each time point (3, 6, 12, 18, and 24 months from the start of treatment) in the 
following subscales will also be assessed and compared using Fisher’s exact test: global 

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QOL, physical functioning, role functioning, emotional functioning, and social 
functioning domains along with fatigue and pain items.  Change from baseline to each 
follow-up time point will be assessed using Wilcoxon rank sum test or a t-test if normally 
distributed.   
 
A mixed effects model will be used to examine the cognitive functioning data across time 
while adjusting for stratification factors and other baseline characteristics.  Similar 
methods described for Neurocognitive Function above will be used. 
 
Correlation of HRQOL with Neurocognitive Function 
The domains of interest, global QOL, cognitive functioning, physical functioning, role 
functioning, emotional functioning, and social functioning  as well as the two items, 
fatigue and pain, will each be correlated with the neurocognitive battery consisting of the 
3 parts of the HVLT-R, COWA test, TMT Parts A and B, and the CTB COMP score.  
Pearson correlation coefficients will be used and treatment arms will be combined. 
 
Cost-Effectiveness  
Preference scores used to obtain quality-adjusted survival will be assessed from 
participant responses to the EuroQol-5D health state classification system (EQ-5D-5L) 
completed at the end of treatment and at 6, 12, and 24 months from start of  treatment.  
Quality-adjusted life years (QALY’s) will be assessed as the area under the preference-
weighted survival curve.  Cost will be assessed using a societal perspective.  The primary 
cost-effectiveness outcome will be the pooled incremental cost-per QALY ratio for HA-
PCI versus standard PCI.  The incremental cost per QALY ratio will be calculated as the 
total cost of the HA-PCI minus total cost of standard PCI which will be divided by the 
quality adjusted survival of the patients treated with HA-PCI minus the quality adjusted 
survival of patients receiving standard PCI.  The point estimates for the ratio will be 
based on the point estimates for the difference in costs and QALY’s derived from the 
multivariable generalized estimating equations (GEE) or general linear model (GLM) 
analyses.  
 
Price weights are required for translating the measured services into cost.  Medical 
service price weights will generally be derived from Federal Fee Schedules (e.g. 
diagnosis related group payments for hospitalization, the Medicare Fee Schedule for 
physician fees, Medical Expenditure Panel survey data for emergency department visits, 
and the Federal Supply Schedule for concomitant medications).  Hospital specific cost-to-
charge ratios will be used to convert charges to costs.  A health resource utilization diary 
will be used to measure the services consumed by the patient.  The Work Productivity 
and Activity Impairment Questionnaire, a validated instrument to assess work and 
productivity, will be used to assess both patient and any caregiver lost wages and 
productivity.  Both the diary and questionnaire are collected at the end of treatment, and 
6, 12, and 24 months from the start of treatment. The method formulated by Glick, et al. 
(2015) will be followed for assessing the extent and mechanism of missingness of cost 
data and selecting an appropriate method for addressing it. 
 
Parametric failure time models will be used for the analysis of survival.  Standard 
diagnostics will be used to identify an appropriate survival distribution.  Repeated 

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measure count models (Poisson, negative binomial, and zero-inflated negative binomial 
as appropriate) will be used to assess counts of services between the 2 groups.  Assessed 
services include hospitalizations, nursing home or rehabilitation hospital admissions, 
emergency room visits, physician visits, travel, and other caregiver costs.  Use of 
repeated measures models (for these count data and for costs) facilitates use of data from 
patients before they withdraw from the study or are lost to follow up.  Repeated measure 
multivariable GEE and/or GLM will be used to analyze health care costs.  Candidate 
predictor variables include but not necessarily limited to the follow-up period during 
which the data were collected and variables used to stratify the randomization.  Separate 
multivariable analyses will be performed for the costs of the radiotherapy, 
hospitalizations, caregiver costs, foregone employment costs and long-term care.  Where 
appropriate, two-part models will be used (part 1, estimation if any costs were incurred in 
a period; part 2 estimation of the magnitude of cost if any has been incurred in the 
period).  If generalized linear models are used, links and families will be empirically fit to 
the data using diagnostic tests including the Modified Parks test, Pregibon-Link test, 
Hosmer-Lemeshow test, and Pearson’s correlation test.   
 
Parametric confidence intervals for the cost-effectiveness ratio as well as an acceptability 
curve will be derived using the point estimates of the difference in cost and QALYs, their 
standard errors and the correlation between the differences (Glick 2015). Standard errors 
and the correlation of the difference in cost and QALY’s will be derived from a 
nonparametric bootstrap.   
 
A standard 3% discount rate for both QALY and cost will be used (Libscomb 1996). The 
medical component of the consumer price index will be used to adjust for inflation.  The 
effect of the discount rate on overall outcome of the trial will be tested in sensitivity 
analysis.   The trial mandates follow up at predefined time points up to 2 years.  The 
majority of cost drivers is expected to be identified by this time point and if significance 
patients are still living past the 3-year time point the important cost drivers can be 
modelled for further analysis. 
 
Overall Survival 
Overall survival rates will be estimated using the Kaplan-Meier method (Kaplan 1958), 
and differences between treatment arms will be tested using the log rank test (Mantel 
1966). Overall survival 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. 
 
The Cox proportional hazard model (Cox 1972) will be performed with the stratification 
variables and other baseline characteristics as fixed variables to assess the treatment 
effect while adjusting for patient-specific risk factors. 
 
Intracranial Relapse 
The occurrence of intracranial relapse will be defined as the appearance of a brain 
metastasis in the brain. Intracranial relapse will be assessed at the time of the primary 
endpoint analysis, which is expected to occur once all patients have 6 months of follow 
up from the start of treatment.  The cumulative incidence approach will be used to 

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estimate the median time to intracranial relapse to account for the competing risk of 
death.  Time to intracranial relapse will be measured from the date of randomization to 
the date of intracranial relapse, death, or, otherwise, the last follow-up date on which the 
patient was reported alive.  Gray’s test will be used to test for statistically significant 
difference in the distribution of intracranial relapse times (Gray 1988).  The cause-
specific Cox proportional hazards regression model will be used to evaluate the effect of 
stratification variables (age, stage, and planned concurrent memantine use)  and other 
baseline characteristics,  on time to intracranial relapse (Cox 1972).The 12-month 
comparison in intracranial relapse rates between the treatment arms also will be assessed 
and compared using a test of proportions.   
 
Relapse in the perihippocampal regions also will be evaluated at 12 months based on site 
review.  Few events are expected based on the results of RTOG 0933 where only 4.5% of 
patients experienced progression in this region (Gondi 2013; Gondi 2014), although this 
was progression rather than relapse.  A test of proportions will be used to compare the 
rates in each treatment arm at 12 months. 
 
Adverse Events 
Adverse events (AE) will be evaluated using the CTCAE v4.0.  Counts of all AEs by 
grade will be provided by treatment arm.  Counts and frequencies will be provided for the 
worst grade AE experienced by the patient by treatment arm. 
 
miRNA Signature 
Three miRNA signatures, miR-151a-3p, miR-212-3p, and miR-1274b, will be assessed as 
both continuous and categorical (≤ median vs. > median) variables.  Categorical miRNA 
signatures will be compared on pretreatment characteristics and treatment history 
(previous chemotherapy, previous radiation) and on memantine use using chi-square 
tests.  Of primary interest is whether these signatures are correlated with time to 
neurocognitive decline.  Gray’s test will be used to test for statistically significant 
difference in the distribution of neurocognitive failure times (Gray 1988).  The cause-
specific Cox proportional hazards regression model will be used to evaluate the effect of 
each miRNA signature on time to neurocognitive decline (Cox 1972).  Treatment arm, 
the interaction between each miRNA signature and treatment, and memantine use will 
also be examined.  It’s possible that memantine use will confound the results.  Since any 
significant miRNA signature would require subsequent validation, a two-sided 
significance level of 0.05 will be used for each miRNA signature.  
 
As additional exploratory analyses, each miRNA signature will be correlated with 
neurocognitive decline of each test (HVLT-R, TMT Parts A and B, and COWA) at each 
follow-up time point (3, 6, 12, 18, and 24 months from the start of treatment).  If 
memantine use is found to confound the results, these analyses will be limited to patients 
who did not use memantine.  Continuous miRNA signatures will be assessed using t-tests 
or Wilcoxon tests if data is non-normal using a two-sided significance level of 0.05.  
Categorical miRNA signatures will be assessed used chi-square tests, also at a 
significance level of 0.05. No multiplicity adjustments will be performed due to the 
exploratory nature of these assessments. 

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APOE Genotyping 
APOE genotype, specifically APOE4 is of interest.  Patients will be scored semi-
quantitatively and categorically ordered into whether they carry or do not carry one or 
more APOE4 alleles.  APOE genotyping will be assessed as a categorical variable: 
patients with one or more APOE4 alleles vs. those with no APOE4 alleles.  Descriptive 
statistics by APOE4 status will be performed to determine the number of patients who 
received HA vs. those who did not, by neurocognitive compliance at each time point.  
Baseline neurocognition (HVLT-R Total Recall, Delayed Recall, and Recognition, TMT 
Parts A and B, COWA, and CTB Composite score) will be compared between patients 
with and without APOE4 using the t-test or Wilcoxon text if not normally distributed.  
Neurocognitive dysfunction, defined using RCI, will be compared between patients with 
and without APOE4 using a Chi-square test. 
  
Longitudinal modeling will be used to determine the effect of APOE4 status on 
neurocognitive function across time using the standardized test scores that adjust for age, 
gender, and education when necessary.  Specifically, mixed effects models utilizing 
maximum likelihood estimation will incorporate various covariates in addition to APOE4 
status such treatment with HA and a treatment with HA by APOE4 interaction. 
Depending on the amount of missing data, a joint model may be considered that will 
model the repeated measures and time to missing assessment jointly.   
  
Time to cognitive function failure, defined as the first failure on any neurocognitive test 
using RCI, will be assessed using cumulative incidence treating death as a competing 
risk.  Patients with and without APOE4 allele will be tested using Gray’s test.  A cause-
specific Cox model for time to cognitive function failure will be performed to assess the 
effects of HA treatment, APOE4 status, and treatment with HA by APOE4 interaction.  If 
the proportional hazards assumption is violated, other methods, such an inclusion of a 
time-varying covariate will be used.   
 
  Radiographic Evaluation:   
  The effect of white matter injury and hippocampal volume (see Section 11.1 for more 
detail) on time to neurocognitive failure and baseline neurocognitive function will be 
examined.  Both of these will be evaluated through MRI scans using auto-contoured and, 
only for hippocampal volume, physician-contoured scores. Concordance rates for white 
matter injury will be assessed using Kappa statistics.  The auto-contoured scores will be 
used for the remaining analyses due to the number of physicians reviewing the scans. 
White matter injury is measured by FLAIR volume change and is a continuous variable.  
Hippocampal volume is measured as a continuous variable also.  Both will be covariates 
considered in the Cox proportional hazards model to assess the impact on time to 
neurocognitive failure and the longitudinal modeling of neurocognitive function 
described in Section 14.6.2.  Pearson correlation coefficients will be used to assess the 
effect of hippocampal volume and FLAIR volume change on baseline neurocognitive 
function, as measured by the HVLT-R, COWA, and TMT, separately for each arm. 
 

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  An analysis will be conducted to determine if an appropriate cut-point for baseline 
hippocampal volume and baseline FLAIR volume exists to categorize neurocognitively 
deteriorated and not deteriorated patients.  Receiver operating curves (ROC) will be used 
to determine area under the curve (AUC) for both volumes and sensitivity and specificity 
for cutpoints.  Once a cutpoint is determined, it will be included as a covariate in 
longitudinal and cause-specific Cox models to determine the effect of the dichotomous 
hippocampal volume and FLAIR volume variables on neurocognition.  These models 
will also assess the interaction between hippocampal volume/FLAIR volume and 
treatment with HA.  The effect of hippocampal volume and FLAIR volume on the 
cumulative incidence of neurocognitive failure will be tested using Gray’s test. 
 
14.6.3 Power Calculations  
Patient-reported cognitive function decline at 6 months 
For patients with small cell lung carcinoma (SCLC) eligible for PCI, HA-PCI reduces 
decline in patient- reported cognitive functioning as assessed by the self-reported 
cognitive functioning scale within the EORTC QLQ-C30.  Patient-reported cognitive 
function decline at 6 months will be assessed using the cognitive functioning subscale of 
the EORTC QLQ-C30 and compared between patients receiving HA-PCI and those 
receiving PCI only.  Using data from RTOG 0212, 50% of patients experienced patient-
reported cognitive functioning deterioration at 6 months from the start of treatment.  The 
proposed sample size (N=198) would provide 94% power to detect a 50% relative 
reduction (PCI 50% vs. HA-PCI 25%) in the likelihood of decline in patient-reported 
cognitive functioning at 6 months using Fisher’s exact test with a two-sided alpha=0.05.   
 
Intracranial Relapse 
As part of the phase III analysis, the phase IIR primary endpoint of 12-month intracranial 
relapse risk also will be assessed as a secondary endpoint.  With an estimated 287 
evaluable patients, as death and non-compliance will not be an issue for this specific 
analysis, and an assumed difference in proportions of 4.5% under the alternative, a 2-
sample test of difference in proportions with a 1-sided alpha of 0.05 requires 80% 
statistical power to evaluate a non-inferiority margin of 17.2%. 
 
Cost-Effectiveness 
The clinical endpoint is the metric driving the power calculation for trial. With 
alpha=0.05 (1-sided) and 1 interim analysis for efficacy, a total of 98 analyzable 
patients per arm would ensure 80% statistical power to detect a 14.5% absolute 
reduction in the probability of HVLT-R Delayed Recall deterioration at 6 months using a 
test of difference in proportions.  The power to rule out cost-effectiveness ratios 
exceeding the maximum willingness to pay values described previously is of interest.  
This is given by the equation 
 
𝑍𝛽= √
𝑛(𝑊𝑄−𝐶)2
2(𝑠𝑑𝑐2 + (𝑊𝑠𝑑𝑞)2 −(2𝑊𝜌𝑠𝑑𝑐 𝑠𝑑𝑞)) −𝑍𝛼     
 
where n is the number of patients in each arm, W is the maximum willingness to pay, Q 
is the effect difference, C is the cost difference, sdc is the expected standard deviation for 

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the cost in each treatment group, sdq is the expected standard deviation for the effect and 
ρ is the expected correlation of the difference in cost and effect. We base our estimate for 
our primary sample size analysis on an expected increase of discounted QALYs during 3 
years of follow up of 0.14 (SD, 0.07), an expected increase in costs of $2441 (based on 
the expected difference in the costs of radiation therapy, and not reflecting potential cost 
offsets) (SD, 6000), a correlation of the difference in costs and QALYS of 0.05, a 
willingness to pay of $50,000 per QALY, a 2-tailed alpha of 0.05, and a sample size of 
98 per treatment group. The power to conclude that the resulting ratio is acceptable 
exceeds 99%.    
 
miRNA Signatures 
This endpoint will be powered using categorical miRNA signatures using the median as a 
cut-point.  All patients will be considered initially, but if memantine use confounds the 
results, it will be limited to only those who did not receive memantine.  About 70% are 
expected to consent and submit blood which leaves approximately 138 of the planned 
196 evaluable patients for this analysis.  About 50% of patients are expected to receive 
memantine, reducing the number of evaluable patients to 69.  The table below provides 
the statistical power to detect each of the specified HRs using a two-sided alpha=0.05 
(Schoenfeld 1983). 
 
Hazard Ratio 
Statistical Power 
if n=69 
Statistical Power 
if n=138 
1.5 
51.6% 
76.9% 
1.6 
62.1% 
86.7% 
1.7 
71.2% 
92.9% 
1.8 
78.7% 
96.5% 
1.9 
84.6% 
98.3% 
 
APOE Genotyping 
Approximately 529 patients are expected to have APOE4 status determined from 
centrally collected blood on NRG-CC003 as well as NRG/RTOG 0933 and NRG-CC001 
which will be combined for this analysis.  This includes patients who have completed at 
least baseline neurocognitive testing.  It is expected that 20% of patients (n=423) will 
either be non-compliant, have withdrawn consent, or died and thus have missing 
neurocognitive test scores at 2 months.  The prevalence of APOE4 allele is assumed to be 
30% based on results from a similar analysis on NRG/RTOG 0614 (14).  Thus, there is 
80% statistical power to detect a HR=1.35 in time to neurocognitive failure assuming a 
two-sided type I error of 0.05. 
 
Radiographic Evaluation 
Of the 98 evaluable patients, 10% are expected to be missing either the image or the 
correct image, resulting in 88 evaluable patients per arm.  Using a Bonferroni-adjusted 
type I error of 0.025 to account for both FLAIR volume and hippocampal volume, there 
is 95% statistical power to detect a correlation coefficient of 0.4 between baseline FLAIR 
volume/hippocampal volume with 6 month change in HVLT-R total recall.   

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14.7   Exploratory Hypotheses and Endpoints (01-JUL-2022) 
Hopefulness: The AHS and PHQ 2 are collected at baseline and at 6 months from the start 
of treatment.  The AHS is a 12-item tool rated on an 8-point Likert scale.  There are 2 
subscales with scores calculated by the average of the item scores: agency (items 2, 9, 10, 
and 12) and pathway (items 1, 4, 6, and 8).  The change from baseline to 6 months will be 
compared between arms using the t-test (or Wilcoxon test if not normally distributed) in 
the two subscale scores.  These scores will be correlated with the EORTC- QLQ-C30 total 
score using a Pearson correlation coefficient. 
 
Since hopefulness is closely tied with depression, the PHQ-2 will be used to assess 
depression between treatment arms.  Scores range from 0-6, with scores ≥ 3 indicating 
depressive symptoms.  The distribution of depression at baseline and 6 months will be 
compared between treatment arms using a chi-square test.  There is also an overlap 
between “belief,” “faith,” and “hope” so it is hypothesized that religious people are more 
hopeful.  A general linear model will be used to assess hopefulness, performed separately 
for the AHS subscale scores, between treatment arms while adjusting for depression, 
religion, and stratification factors.  
 
Feasibility of Remote Neurocognitive Testing: During the COVID-19 pandemic, remote 
neurocognitive testing was permitted on NRG-CC003.  The feasibility of conducting the 
remote testing will be assessed using descriptive measures, such as patient compliance, 
proportion of patients who attempted and completed remote testing, and frequency of 
disruptions.  Since no outcome data (i.e. neurocognitive test outcomes, survival, etc.) will 
be reported, this endpoint will be analyzed prior to the meeting the primary endpoint. 
 
14.8    Statistical Analysis Plan for Translational Research Endpoints (14-FEB-2019) 
MiRNA levels detected by the microarray will be processed and normalized using 
R/Biocon-ductor statistical software and appropriate analytical packages.  Data will 
undergo stringent quality control and will be normalized using quantile normalization.  
Normalized data will be used to detect differentially expressed miRNAs.  
 
Correlation with cognitive decline will be carried out using regression analysis in R 
statistical software.  
 
QPCR validation will be evaluated using standard delta-delta Ct.  
 
14.9     Gender/Ethnicity/Race Distribution (15-JUNE-2020) 
No differences across the patient subsets below are anticipated.   
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
8 
12 
20 
Not Hispanic or Latino 
149 
223 
372 
Ethnic Category: Total of all subjects 
157 
235 
392 
 
Gender 
Racial Category 
Females 
Males 
Total 

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Gender 
Ethnic Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
3 
4 
Asian 
2 
3 
5 
Black or African American 
11 
13 
24 
Native Hawaiian or other Pacific Islander 
1 
2 
3 
White 
142 
214 
356 
Racial Category: Total of all subjects 
157 
235 
392 
 
 
 

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APPENDIX I: CERTIFICATION PROCEDURES FOR THE 
NEUROCOGNITIVE TEST BATTERY (01-JUL-2022) 
 
EXAMINER CERTIFICATION FOR NRG-CC003 
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. Wefel (see Section 8.2).  Examiners who 
have completed the full certification procedure to perform these tests for RTOG 0534, 0834, 
1114, NRG-BN001, or NRG-CC001 during the past 6 months do not need to complete the full 
certification procedure again, but the certification worksheet for NRG-CC003 must be faxed to 
Dr. Wefel for documentation purposes with information regarding the examiner’s 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 NRG-
CC003. Examiners who have not completed the full certification procedure for RTOG 0534, 
0834, 1114, NRG-BN001, or NRG-CC001 within the past 6 months must complete the full 
certification procedure to be recertified to ensure continued familiarity with study procedures. 
All certified test administrators are required to attest to their proficiency in the language (English 
or French) in which the test is administered to the patient.  Only certified test administrators 
proficient in the primary language of the patient are permitted to test the patient.  
 
Prior to registering and/or testing a patient, potential examiners must:  
1) Read the protocol 
2) Read this Appendix (Certification Procedures for the Neurocognitive Test Battery) 
3) Go to the CTSU website (www.ctsu.org) and use your username and password to access 
the CC003 protocol. Access the “NRG-CC003 Neurocognitive Letter” from the Case 
Report Forms folder. This letter will provide you with the web address and study specific 
password for the training video.  
4) Obtain copies of the NRG-CC003 Test Instruction and Administration Procedures 
document, Neurocognitive Assessment Packets (containing the HVLT-R, TMT and 
COWA), the NRG-CC003 Blank Forms (containing the Neurocognitive Function 
Coversheet), and the Training Video Post Test (attached to the NRG-CC003 
Neurocognitive Letter) from the CTSU website. 
5) Watch the training video. 
6) Complete the Training Video Post Test. 
7) Complete a “practice” assessment with the Neurocognitive Assessment packet. 
8) Complete the Certification Worksheet (available on the CTSU website)  
9) All materials (i.e., Training Video Post Test, completed practice assessment and 
Neurocognitive Function Coversheet, certification worksheet) must be scanned and 
emailed (NeuropsychologyResearch@mdanderson.org) or faxed (713-794-4999) to Dr. 
Wefel, who will review it and correct any procedural errors with the trainee.   
 
 

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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 NRG-CC003.  A certification 
approval notice will be sent to NRG Oncology for the registration process and to ensure 
that only NRG-CC003-approved examiners are testing subjects on protocol NRG-CC003.  
11) All neurocognitive materials for every patient at every time point must be uploaded 
to Medidata Rave® within 7 days after test administration.