"A Phase II Trial of Hippocampal-Sparing Cranial Irradiation (PCI) for Small-Cell Lung Cancer (SCLC)"
Phase: NA
Conditions: Small-cell Lung Cancer, SCLC, Small Cell Lung Cancer Limited Stage
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  
i 
 J12127 Version: November 14, 2013  
  
A Phase II Trial of Hippocampal-Sparing Prophylactic Cranial Irradiation (PCI) for Small 
Cell Lung Cancer (SCLC)  
Protocol version date: 11/14/2013  
IRB: NA_00078659 (J-12127)  
NCT01797159  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  
ii 
 J12127 Version: November 14, 2013  
 TITLE:  A Phase II Trial of Hippocampal-Sparing Prophylactic Cranial Irradiation (PCI) for 
Limited Stage Small Cell Lung Cancer (SCLC)  
  
Research Site:  
 
 
The Johns Hopkins University School of Medicine  
Principal Investigator:  
 
 
Kristin J. Redmond, M.D.  
Department of Radiation Oncology   
401 North Broadway, Suite 1440  
Baltimore, MD 21231  
Telephone: 410-614-1642   
  
  
  
Fax: 410-502-1419  
E-mail: kjanson3@jhmi.edu   
Co-Investigators:  
 
  
 
 
Russell Hales, M.D., Department of Radiation Oncology  
Tracy Vannorsdall, Ph.D., Department of Psychiatry & 
Behavioral Sciences  
 
 
Julie Brahmer, M.D., Department of Medical Oncology   
  
 
 
Charles Rudin, M.D., Department of Medical Oncology  
 
 
Lawrence Kleinberg, M.D., Department of Radiation Oncology  
 
 
 
Christine Hann, M.D., Department of Medical Oncology  
  
Statistician:  
  
Gary Rosner, Sc.D., Division of Oncology Biostatistics and Bioinformatics  
Telephone: 410-955-4884  
  
E-mail: grosner1@jhmi.edu   
  
  
Research Managers:  
Helen Kim, MBA                        Terry Caldwell 410-614-
3950                              443-287-1889 hkim91@jhmi.edu                       
caldwte@jhmi.edu   
  
Study Coordinators:  
Katharine Oteiza                         Ryan Assadi  
  
  
  
  
 
 
Emily Griffith 410-614-3158                             410-502-8742   
  
  
 
 
  
410-955-8656   
  
 koteiza1@jhmi.edu            
   
rassadi1@jhmi.edu      
  
  
egriff22@jhmi.edu  
  
Research Nurses:  
  
Shirl DiPasquale, R.N                  Kelly Szajna, R.N., B.S.N.           Beth Griffith, R.N.  
410-614-1598                               410-502-9242                                410-502-9243  
sdipasq1@jhmi.edu  
      kszajna1@jhmi.edu          
  
bgriffit@jhmi.edu   
  
  

  
iii 
 J12127 Version: November 14, 2013  
  
  
  
 

  
iv 
 J12127 Version: November 14, 2013  
SCHEMA  
  
Patient Eligibility:   
- Histological or cytological evidence of small cell lung cancer (SCLC)  
- Zubrod performance status of < 1  
- RTOG neurological function class of 1 or 2 (Appendix A)  
- Limited disease with CR to chemotherapy and consolidative chest radiotherapy that was 
documented at least on standard chest X-rays within one month of study entry.    
- No definitive evidence of brain metastases on brain MRI or CT scan at least one month 
before protocol entry.  
  
Treatment Plan:   
  
  
Patients with limited stage SCLC s/p  chemotherapy and thoracic radiation 
 
  
  
    
 
  
Hippocampal-sparing PCI  
  
25 Gy in 10 fractions  
  
  
  
  
1) Are neurocognitive outcomes 
improved with 
hippocampalsparing PCI relative 
to historical control (RTOG 
0212) receiving standard PCI?  
  
  
  
  
  
2) Is the development of brain 
metastases in patients treated with 
hippocampal-sparing PCI greater 
than expected?  
  
  
 
Future Proposal:   
  
Consider application of concept to  
  
clinical practice for a variety of  
  
brain 
tumors 
versus 
formal 
comparative trial   
 1) Is performance on the Hopkins 
Verbal Learning Test-
Reviseddelayed recall at six months 
from the completion of PCI 
improved in patients treated with 
hippocampalsparing PCI compared 
to a historical control treated with 
standard PCI?  2) Do <25% of 
patients develop brain metastases?  
 
This concept should go no further  
  
Yes  
No  

  
v 
 J12127 Version: November 14, 2013  
  
Required sample size: 125 patients  
   
Table of Contents  
SCHEMA ...................................................................................................................................... IV  
1.  OBJECTIVES .............................................................................................................................. 2 
1.1   Primary Objectives ................................................................................................................ 2 
1.2   Secondary Objectives ............................................................................................................ 2 
2.  BACKGROUND ......................................................................................................................... 2 
2.1     Study Disease and Rationale .............................................................................................. 2 
2.2  Correlative Studies Background ............................................................................................ 4 
2.3   Additional Testing ................................................................................................................ 5 
3.  PATIENT SELECTION .............................................................................................................. 7 
3.1   Eligibility Criteria ................................................................................................................. 7 
3.2   Exclusion Criteria ................................................................................................................. 8 
3.3   Inclusion of Women and Minorities ..................................................................................... 8 
4.  REGISTRATION PROCEDURES ............................................................................................. 9 
5.  TREATMENT PLAN .................................................................................................................. 9 
5.1   Radiation ............................................................................................................................... 9 
5.2   Duration of Follow Up ........................................................................................................ 10 
5.3   Criteria for Removal from Study ........................................................................................ 10 
6.  STUDY CALENDAR................................................................................................................ 12 
7.  MANAGEMENT OF TOXICITY ............................................................................................. 13 
7.1   Acute Toxicity .................................................................................................................... 13 
7.2   Late Toxicity ....................................................................................................................... 14 
8.  STATISTICAL CONSIDERATIONS ....................................................................................... 15 
8.1   Study Design/Endpoints ...................................................................................................... 15 
8.2   Sample Size/Accrual Rate ................................................................................................... 16 
8.3   Stratification Factors........................................................................................................... 17 
8.4  Statistical Methods of Analysis ........................................................................................... 17 
8.5   Safety Monitoring ............................................................................................................... 18 
9.  ADVERSE EVENTS AND RECORDING ............................................................................... 19 
9.1  Definition of Adverse Event (AE) ....................................................................................... 19 
9.2  Radiation Related Adverse Events ...................................................................................... 19 
10.  SERIOUS ADVERSE EVENTS (SAE) AND REPORTING ................................................. 20 
10.1 Serious Adverse Event ........................................................................................................ 20 
10.2 SAE Reporting Guidelines for Johns Hopkins Hospital ..................................................... 20 
11.     DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS ................. 20 
11.1  Data Quality Monitoring .................................................................................................... 20 
11.2   Data Safety Monitoring .................................................................................................... 21 
11.3 Data Reporting .................................................................................................................... 21 
REFERENCES ............................................................................................................................... 21 
APPENDIX A ................................................................................................................................. 26 
APPENDIX B ................................................................................................................................. 27 
APPENDIX C ................................................................................................................................. 28 

  
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 J12127 Version: November 14, 2013  
APPENDIX D ................................................................................................................................. 30 
 
  
  
  

2 J12127 Version: November 14, 2013  
 
1.  OBJECTIVES  
  
 
1.1   
Primary Objectives   
Evaluate performance on the Hopkins Verbal Learning Test-Revised for delayed 
recall (HVLT-R-delayed recall) at 6 months following hippocampal-sparing PCI 
relative to a historical control receiving standard PCI.  
  
 
1.2   
Secondary Objectives  
  
  
1.2.1 Evaluate performance on HVLT-R delayed recall at 12 months following 
hippocampal-sparing PCI relative to historical control receiving standard PCI.  
  
1.2.2 Evaluate composite cognitive function at 6 and 12 months following 
hippocampal-sparing PCI relative to a historical control receiving standard 
PCI  
  
1.2.3 Evaluate quality of life following hippocampal-sparing PCI relative to a 
historical control receiving standard PCI.   
  
1.2.4 Determine whether development of brain metastases following 
hippocampalsparing PCI is higher than expected.   
  
1.2.5 Determine whether development of leptomeningeal carcinomatosis following 
hippocampal sparing PCI is higher than expected  
  
1.2.6 Evaluate overall survival following hippocampal sparing PCI.  
  
 
2.  BACKGROUND  
  
2.1     Study Disease and Rationale  
  
The current standard of care for treatment of limited stage small cell lung cancer consists 
of chemotherapy plus thoracic irradiation (1), followed by prophylactic cranial irradiation 
(PCI).  The recommendation for PCI is based on the results of a meta-analysis in patients 
with limited stage small cell lung cancer which demonstrated a 5.4% increase in overall 
survival with the addition of PCI to chemo-radiation therapy for the primary lung tumor  
(2).    
  
Unfortunately, it is well documented that whole brain radiation therapy is associated with 
neurocognitive toxicity (3-7) and that there is a direct relationship between 
neurocognitive dysnfunction and worsening quality of life (8).  This toxicity is 
particularly important in patients being treated with PCI for SCLC since they represent a 
potentially curable patient population who have a relatively high likelihood of surviving 
long enough to develop the long-term sequalae of therapy.   

3 J12127 Version: November 14, 2013  
  
The precise mechanism of radiation induced neurotoxicity remains unclear and the effect 
is likely multi-factorial.  However, emerging data suggests that radiation induced damage 
to neural progenitor cells within the hippocampus may play a role.  Animal studies have 
shown that new neurons and glia are produced throughout adult life from neural stem cell 
precursors in the subventricular zone of the lateral ventricles and the subgranular zone of 
the hippocampal dentate gyrus (9-11).  These cells play an important role in injury repair 
within the central nervous system (12,13).  Similarly, these cells migrate to the site of 
inflammation caused by irradiation or brain injury (13).  
  
Multiple animal studies have shown that neural progenitor cells are extremely sensitive to 
radiation (14-17).  Tada et al. showed that 2 Gy of radiation effectively killed 
proliferating cells in both the SVZ of the lateral ventricles (14) and the subgranular zone 
of the dentate gyrus (15). The anti-proliferative effects last for up to 15 months after a 
single radiation treatment (18) and are dose dependent (19,20). There is repair over time 
following low doses of radiation, suggesting likely recovery of cells with fractionation 
(14).    
  
There is an association between radiation-induced neural progenitor cell impairment and 
neurocognitive decline after central nervous system irradiation in rodents.  Cranial 
irradiation significantly decreases hippocampal neurogenesis and is associated with 
impaired performance of hippocampal-dependent tasks 19-22, indicating that newly born 
cells may be essential for normal hippocampal functioning.    
  
Several studies suggest that neurogenic areas similar to those described in the rodent 
brain exist in the human brain as well.  For example, Eriksson et al. (23) demonstrated 
that progenitor cells in the human dentate gyrus divide to form new neurons, while Sanai 
et al. (24) found that astrocytes in the human SVZ of the lateral ventricles divide in vivo 
and act as multipotent progenitor cells in vitro.  Human studies have likewise 
demonstrated cognitive deficits following cranial irradiation, most notably in children 
(25-28).  This decline includes diminished capability to learn and memorize new tasks 
and information, as well as a dramatic reduction in full-scale IQ (29).   
  
Recent human studies have demonstrated that it is possible to use intensity modulated 
radiation therapy (IMRT) to reduce the radiation dose to the hippocampus during 
radiation therapy for brain tumors (30-32).  In addition, preliminary data using a mouse 
model has suggested that NPC sparing radiation may allow improved survival of neural 
progenitor cells compared to conventional radiation treatment plans, at least at an early 
time point (33).  Similarly, recent data from a prospective study in children treated with 
radiation therapy to the brain suggests an inverse relationship between radiation dose to 
the hippocampus and performance on neurocognitive testing (34), and a randomized trial 
comparing 25 Gy versus 36 Gy of PCI found that the risk of chronic neurotoxicity was 
significantly higher in the 36 Gy arm (35).  
  

4 J12127 Version: November 14, 2013  
The purpose of this study is to evaluate performance on neurocognitive testing following 
hippocampal-sparing PCI relative to the historical experience of patients (RTOG 0212) 
who received standard PCI.  
  
  
  
2.2 Correlative Studies Background  
  
Correlative studies include a neurocognitive function test battery that has been validated 
in a multi-institutional phase III study by the Radiation Therapy Oncology Group 
(RTOG) in the context of brain metastases (36,37).  The tests will be performed by a 
trained examiner.  The tests utilized in this protocol are described briefly below:  
  
  
2.2.1 Mini Mental State Examination  
  
  
  
  
  
The Mini Mental State Examination (38) is designed to evaluate global 
function.  It consists of six tasks designed to evaluate short-term memory 
retention and recall, attention, and language.  The maximum score is 30.  
Scores fall into 4 categories:  
  
● 24-30: “Normal” range  
● 20-23: Mild cognitive impairment  
● 10-19: Moderate cognitive impairment  
● 0-9: Severe cognitive impairment  
  
  
  
  
2.2.2    Trail Making Test  
  
  
  
  
  
  
The Trail Making Test A is designed to evaluate visual motor scanning speed 
and the Trail Making Test B is designed to evaluate executive function 
(39,40).  These tests require patients to connect circles in numerical (part A) 
or alternating numerical and alphabetical sequence (part B) within a timed 
interval of less than 5 minutes for each test.  Results are reported as the 
number of seconds required to complete the task with higher scores reflecting 
higher degrees of impairment.  
  
  
Average  
Deficient  
Rule of Thumb  
Trail A  
29 seconds  
>78 seconds  
Most in 90 seconds  
Trail B  
75 seconds  
>273 seconds  Most in 3 minutes  
  
  
  
  
2.2.3 Controlled Oral Word Association Test  
  
The Controlled Oral Word Association Test (COWAT) is designed to evaluate 
letter-cued verbal fluency.  It requires patients to name words beginning with 
a specific letter with increasing associated activity, in three 1minute periods.  

5 J12127 Version: November 14, 2013  
Scoring is based on the number of words named during the 1minute periods, 
with adjustments for education and age.  Individual scores are categorized as 
intact, low average, borderline, deficient, or seriously deficient, based on their 
scores after these adjustments (41).    
  
  
  
  
2.2.4 Hopkins Verbal Learning Test-Revised  
  
The Hopkins Verbal Learning Test-Revised is designed to evaluate memory.   
It requires patients to memorize a list of 12 items for three consecutive tests  
(recall), to identify the same 12 items from a list of semantically related or 
unrelated items (recognition), and to recall the same 12 items after a 15minute 
delay (delayed recall).  Scoring and interpretation are simple, and outlined in a 
professional manual (42).  
  
  
  
  
2.2.5 EORTC Quality of Life questionnaire (QLQ-C30) and the 
Brain Cancer Module 20  
  
 The EORTC Quality of Life questionnaire (QLQ-C30, Appendix B) is a 30 
item questionnaire designed for and validated in cancer patients.  It consists of 
9 multi-item scales—1 global scale, 5 functional scales (physical, role, 
emotional, cognitive and social), 3 symptom scales (nausea, pain, fatigue).  
The remaining 6 questions are single items addressing other symptoms and 
financial impact.  The Brain Cancer Module 20 (BN 20, Appendix C) is a 20 
question addendum to QLQ-C30 designed specifically for patients with brain 
tumors.  It assesses neurologic deficits, future uncertainty and disease and 
treatment related symptoms.  
  
 
2.3   
Additional Testing  
 The following tests will be administered to the subject after those outlined in 
Section 2.2 have been completed.  
  
2.3.1 Brief Visuospatial Memory Test-Revised  
The Brief Visuospatial Memory Test-Revised is designed to evaluate 
nonverbal/visuospatial learning and memory. It serves as a non-verbal 
analogue to the HVLT-R, and is generally more sensitive to right 
hippocampal functioning. It requires patients to learn a series of six figures 
printed on a page over the course of three exposure trials (immediate recall), 
recall those same six figures after a 15-20 minute delay (delayed recall), and 
identify the figures from among an equal number of foils (recognition). 
Scoring and interpretation are simple, and outlined in a professional manual 
(43).  
  

6 J12127 Version: November 14, 2013  
2.3.2 Category-cued verbal fluency  
The Category Fluency Test is designed to evaluate semantically-guided verbal 
generativity and is often administered in conjunction with the COWAT. It 
requires patients to name as many different category exemplars as they can in 
2 60-second trials. Scoring involves tallying the number of acceptable words 
reported for the two trials and interpretation is simple and outlined in a 
professional manual (44).  
  
2.3.3 Brief Test of Attention  
The Brief Test of Attention is designed to evaluate auditory divided attention 
and can be used with individuals with visual and motor impairments that 
preclude tests requiring visual scanning or manual dexterity. It requires 
patients to count numbers or letters from lists read aloud consisting of both 
types of stimuli. The number of correctly monitored lists is tallied, with raw 
scores ranging from 0 to 20. Interpretation is simple and outlined in a 
professional manual (45).  
  
2.3.4 Hopkins Adult Reading Test  
The Hopkins Adult Reading Test is designed to evaluate pre-illness intellect. 
It requires patients read aloud a series of 35 printed, phonetically irregular 
words. The number of correctly pronounced words is tallied and entered into 
a formula along with demographic characteristics to estimate WAIS-III Full 
Scale IQ [(86.664 + 0.145(age) − 6.136(sex) − 8.642(race) + 0.564(educ) +  
0.862 + 1.140(HART), when age is coded in years; sex is coded 1 (male) or 2 
(female); race is coded 1 (non-black) or 2 (black); education is coded in years 
as the highest grade completed] (46).   
  
2.3.5 Perceptual Comparison Test  
The Perceptual Comparison Test is designed to evaluate mental processing 
speed. It requires patients make speeded same/different distinctions in 
response to pairs of letter strings and pairs of patterns over the course of two 
90-second trials. Scoring involves tallying the number of correct responses 
across the two trials, with higher scores reflecting faster processing speed 
(47).   
  
  
  
 

7 J12127 Version: November 14, 2013  
 
3.  
PATIENT SELECTION  
  
 
3.1   
Eligibility Criteria  
  
3.1.1 Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy, or           
two positive sputa) of SCLC  
  
3.1.2 Patients must have limited disease SCLC after clinical staging evaluation:  
clinical TNM stages I-IIIB (i.e., confined to one hemithorax, but excluding T4 
tumor based on malignant pleural effusion and N3 disease based on contralateral 
hilar or contralateral supraclavicular involvement) according to AJCC 1997 staging 
manual to be consistent with RTOG 0212  
  
3.1.3  Patients must have completed all of their prescribed chemotherapy at least one  
week prior to study entry; the plan for PCI should be such that PCI begins no more 
than 240 days from the start of induction chemotherapy  
  
3.1.4    Patients must have achieved a complete response to induction chemotherapy (+/-  
thoracic radiation therapy) assessed according to local habits (at least on a chest 
xray) at the time of study entry.  
  
3.1.5  Patients may have started consolidative chest irradiation by the time of study                
entry.  
  
3.1.6    Age ≥ 18 years.  
  
 
3.1.7  Zubrod performance status ≤ 1  
  
3.1.8    No definitive evidence of brain metastases on brain CT scan or brain MRI < 1 
month prior to study entry  
  
3.1.9  Neurological function class of 0-2 (Appendix A)  
  
3.1.10 Patients of childbearing potential (male or female) must practice adequate   
contraception due to possible harmful effects of radiation and chemotherapy on an     
unborn child.  
  
3.1.11 Neuropsychological tests will be performed by a trained examiner.  
  
3.1.12 Long-term follow up must be possible.  
  
3.1.13 Patients must sign a study-specific informed consent prior to study entry.  
  
  
  

8 J12127 Version: November 14, 2013  
3.1.14 All patients must be informed of the investigational nature of this study and must  
be given written informed consent in accordance with institutional and federal 
guidelines.  
  
3.1.15 If a woman is of child-bearing potential, a negative urine or serum pregnancy test  
must be demonstrated prior to treatment. Women of childbearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) for the duration of study participation and for up to 12 weeks following the 
study. Should a women become pregnant or suspect she is pregnant while participating in 
this study she should inform her treating physician immediately.  
     
  
 
3.2   
Exclusion Criteria  
  
3.2.1 Patients receiving prior external beam irradiation to the head or neck, including any           
form of stereotactic irradiation  
  
3.2.2 Radiographic evidence of brain metastases and/or ipsilateral lung             
metastases/malignant pleural effusion  
  
3.2.3 Planned concurrent chemotherapy or antitumoral agent during PCI  
  
3.2.4 Concomitant malignancy or malignancy within the past five years other than            
nonmelanomatous skin cancer or carcinoma in situ of the cervix  
  
3.2.5 Patients with minimal pleural effusion evident on CXR; minimal pleural effusion           
visible on chest CT is allowed.  
         
  
3.2.6 Patients with epilepsy requiring permanent oral medication  
  
3.2.7 Patients must not have a serious medical or psychiatric illness that would, in the            
opinion of the investigator, prevent informed consent or completion of protocol           
treatment, and/or follow-up visits.  
  
3.2.8 Patients may not take Memantine.  This is the only eligibility criterion that has been     
added to those of RTOG 0212, since some physicians might now prescribe Memantine.     
This medication would not have been given at the time of enrollment on RTOG 0212    
and its administration could confound the results of this study.  
  
  
 
3.3   
Inclusion of Women and Minorities  
  
Both men and women and members of all races and ethnic groups are eligible for this 
trial.    
  

9 J12127 Version: November 14, 2013  
  
  
 
4.  REGISTRATION PROCEDURES  
  
Patients will be accrued from Johns Hopkins Medical Institutes.  Contact information for the 
Principal Investigator is listed on the cover page.    
  
To register the patient, the following documents must be completed and faxed or e-mailed to 
the Study Coordinator:    
  
• 
Copy of operative note and pathology report  
• 
Source documentation verifying eligibility  
• 
Eligibility checklist  
• 
Signed patient consent form  
• 
HIPAA authorization form  
  
If the patient is deemed eligible for the study, the Study Coordinator will register the patient 
and assign a study number  
  
  
 
5.  TREATMENT PLAN  
  
 
5.1   
Radiation   
  
5.1.1 Radiation Simulation and Prescription  
  
  
  
Patients will be treated to a total dose of 25 Gy with a once daily 
fractionation schedule of 2.5 Gy per fraction, administered five days per week.  
All patients will undergo CT simulation.  They will be treated in a supine 
position using an aquaplast mask system for immobilization.  
  
5.1.2    Hippocampal sparing  
  
The hippocampus will be defined according to the RTOG atlas.  It will be 
contoured on the simulation CT scan using a coregistered MRI as a reference.  
A treatment plan will be generated in which the mean radiation dose to the 
true hippocampus avoidance region is < 8 Gy  
  
  
  
       5.1.3    Equipment, Radiation Technique, and Dosimetry  
  
Patients will be treated using a megavoltage linear accelerator with nominal 
beam energy of 6 MV.  At least 90% of the whole brain should receive 90% 
of the prescription dose.  
  

10 J12127 Version: November 14, 2013  
5.1.4 Beam Verification  
  
Either on-line cone beam CT guidance or weekly portal imaging will be used 
for precise patient setup.  
  
  
  
5.1.5 Therapy Interruption  
  
For radiation therapy interruptions of up to and including 14 days, irradiation 
should be completed to the full prescribed dose.  On the last day, the total 
number of fractions and the reasons for interrupting therapy must be 
documented  
  
If radiation therapy interruption goes beyond 14 days, the patient will be 
removed from the protocol treatment.  Resumption and completion of 
treatment will then be at the discretion of the radiation oncologist in 
consultation with the principal investigator.  All patients who initiate protocol 
treatment will be followed per the study calendar.  
  
  
5.1.6 Risks of Radiation  
  
        
      Short term toxicities of radiation therapy include fatigue, alopecia,                      
erythema or irritation of the skin, dry skin, headaches, worsening of current                    
symptoms, edema of brain requiring steroids, ear pain or discomfort, damage                    to the 
baby if patient is or becomes pregnant, seizures, neurologic deficits                    depending on 
tumor location, edema of brain requiring surgery, death.  Long                    term toxicities 
include memory loss, cataracts, edema of the brain requiring                    steroids, vision loss, 
hearing loss, necrosis of brain  requiring surgery   
                  second tumor or cancer caused 
by radiation.  
  
 
5.2   
Duration of Follow Up  
  
Patients will be followed until death or the time of data analysis.  Follow-up visits 
may be performed at outside hospitals and records sent to Johns Hopkins. Patients will 
undergo neurocognitive and QOL testing at baseline and 6 months and 12 months 
following PCI. They will have brain MRI every six months for 2 years following 
completion of PCI. It is preferred that MRIs be performed at Johns Hopkins Hospital 
but they may also be performed at outside facilities as necessary for insurance, 
scheduling, or other reasons.  
  
  
  
 
5.3   
Criteria for Removal from Study  
  
 
  
Patients will be removed from the study for the following reasons:  
  

11 J12127 Version: November 14, 2013  
5.3.1 Unacceptable toxicity from therapy.  Toxicity must be appropriately 
documented.  
  
5.3.2 Development of intercurrent, non-cancer related illness that prevents 
either continuation of therapy or regular follow-up.  
  
5.3.3 The patient may decide to discontinue enrollment in the protocol at 
any time and for any reason.    
  
  
            All reasons for discontinuation of treatment must be documented.    
  
 

12 J12127 Version: November 14, 2013  
 
6.  STUDY CALENDAR  
  
Baseline evaluations are to be conducted within approximately 30 days prior to initiation of 
radiation therapy.  Patients will be evaluated at least weekly during the course of radiation 
therapy.  Note that the study calendar is based on the ideal subject.  The schedule should be 
followed as closely as realistically possible, but may be modified due to problems such as 
scheduling delays, conflicts such as clinic closure or poor weather conditions, or other 
unforeseeable events.   
  
   
Baseline6  
Radiation  
 
 
Follow-Up  
 
Week  
1  
Week  
2  
Mo 6  
Post  
RT  
Mo 12  
Post  
RT  
Mo 18  
Post  
RT  
Mo 24  
Post  
RT  
Every 6 
months  
until patient 
death  
Demographics  
X   
   
   
   
   
   
   
   
Medical history  
X  
   
   
   
   
   
   
   
Physical Exam  
X  
   
   
X  
X  
X  
X  
X  
Vital signs  
X  
   
   
X  
X  
X  
X  
X  
Height & Weight  
X  
   
   
   
   
   
   
   
Performance status  
X  
X  
X  
X  
X  
X  
X  
X  
Neurocognitive 
testing1  
X  
   
   
X  
X  
   
   
   
Acute toxicity2  
X  
X  
X  
  
   
   
   
   
Late toxicity3  
 X  
   
   
X  
X  
X  
X  
X  
Brain MRI  
X  
   
   
X  
X  
X  
X  
   
Chest X-ray  
X  
   
   
   
   
   
   
   
CT Simulation4  
X  
   
   
   
   
   
   
   
Quality of Life5  
X  
   
   
X  
X  
   
   
   
Radiation  
   
X  
X  
   
   
   
   
   
Pregnancy test  
X  
  
  
  
  
  
  
  
1Neurocognitive testing consists of the tests outlined in Section 2.2 and Section 2.3  
2RTOG Acute Morbidity Scoring Criteria  
3RTOG Late Morbidity Scoring Criteria  
4CT simulation without contrast will be performed and coregistered with T1 weighted MRI.  Fused MRI may 
be the diagnostic MRI used prior to study entry or a dedicated treatment planning MRI.  
5EORTC Quality of Life Questionnaire (QLQ-C30), Brain Cancer Module 20 (BN20) 6Within 
approximately 30 days prior to registration  
  
  

13 J12127 Version: November 14, 2013  
  
  
 
7.  MANAGEMENT OF TOXICITY  
  
 
      7.1   
Acute Toxicity  
  
  
  
Acute morbidity potentially associated with therapy will be monitored and recorded 
on the Radiation Oncology On-Treatment Evaluation Form for all patients from 
baseline to 90 days after completion of radiation therapy.  Grading will be according 
to the RTOG Acute Morbidity Scoring Criteria as follows:  
  
Organ  
Grade 0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Skin  
No change 
over 
baseline  
Faint 
erythema, 
epilation, dry 
desquamation, 
or decreased 
sweating  
Tender or 
bright 
erythema, 
patchy moist 
desquamation, 
moderate 
erythema  
Confluent, 
moist 
desquamation 
other than skin  
folds, pitting 
edema  
Ulceration, 
hemorrhage, 
necrosis  
Eye  
No change 
over 
baseline  
Mild 
conjunctivitis 
with or 
without 
scleral 
injection, 
increased 
tearing  
Moderate 
conjunctivitis 
with or 
without 
keratitis 
requiring 
steroids 
and/or 
antibiotics, 
dry eye 
requiring 
artificial tears, 
iritis with  
photophobia  
Severe keratitis 
with corneal 
ulceration, 
objective 
decrease in 
visual acuity or 
in visual fields,  
acute 
glaucoma, 
panopthalmitis  
Loss of vision 
(unilateral or 
bilateral)  
Ear  
No change 
over 
baseline  
Mild external 
otitis with 
erythema, 
pruritis, 
secondary to 
dry 
desquamation 
not requiring 
medication.  
Audiogram 
unchanged 
over baseline.  
Moderate  
external otitis 
requiring 
topical 
medication, 
serous otitis 
media, 
hypoacusis on 
testing only  
Severe external 
otitis with 
discharge or 
moist 
desquamation, 
symptomatic 
hypoacusis, 
tinnitus, not 
drug related  
Deafness  

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CNS  
No change 
over 
baseline  
Fully 
functional 
status with 
minor  
Neurologic 
findings 
present 
sufficient to  
Neurologic 
findings 
requiring 
hospitalization  
Serious 
neurologic 
impairment 
which included  
 
 
neurologic 
findings, no 
medications 
needed  
require home 
care.  Nursing 
care may be 
required.   
Medications 
including 
steroids and/or 
antiseizure 
agents  
for initial  
management  
paralysis, coma, 
or seizures, 
despite 
medications.  
Hospitalization 
required  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
7.2   
Late Toxicity  
  
Late toxicity will be recorded on the Radiation Oncology Follow-up form at each 
follow-up visit greater than 90 days post completion of radiation therapy.  Grading 
will be according to the RTOG Late Radiation Morbidity Scoring Schema as follows:  
  
Organ  
Grade 
0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  
Skin  
None  Slight 
atrophy, 
pigmentation 
change, some 
hair loss  
Patchy 
atrophy, 
moderate 
telangiectasia, 
total hair loss  
Marked  
atrophy, gross 
telangioectasia  
Ulceration  
Death 
directly 
related 
to late 

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Subcutaneous 
Tissue  
None  Slight 
induration and 
loss of 
subcutaneous  
fat  
Moderate  
fibrosis but 
asymptomatic.  
Slight field 
contracture.  
<10% linear 
reduction  
Severe 
induration and 
loss of  
subcutaneous 
tissue.  Field 
contracture 
>10% linear 
measurement  
Necrosis  
radiation 
effect  
Spinal Cord  
None  Mild  
L’Hermitte’s 
syndrome  
Severe  
L’Hermitte’s 
syndrome  
Objective 
neurologic 
findings at or 
below cord 
level treated  
Mono-, para-, 
quadra-plegia  
Brain  
None  Mild 
headache, 
slight lethargy  
Moderate 
headache, 
great lethargy  
Severe 
headaches, 
severe CNS 
dysfunction  
(partial loss of 
power or 
dyskinesia)  
Seizures, 
paralysis, coma  
Eye  
None  Asymptomatic  
cataract, 
minor corneal 
ulceration of 
keratitis  
Symptomatic  
cataract, 
moderate 
corneal 
ulceration, 
minor 
retinopathy or 
glaucoma  
Severe  
keratitis, 
severe, 
retinopathy or 
detachment, 
severe 
glaucoma  
Panopthalmitis, 
blindness  
  
  
  
  
  
  
  
 
8.  STATISTICAL CONSIDERATIONS  
  
 
8.1   
Study Design/Endpoints  
  
  
  
  
  
8.1.1   Study Design  
This is a single-arm phase II prospective study of patients with limited stage  
SCLC to evaluate neurocognitive outcomes following hippocampal-sparing 
PCI (25 Gy in 10 fractions) relative to a historical control receiving standard 
PCI (RTOG 0212 arm receiving 25 Gy in 10 fractions).  

16 J12127 Version: November 14, 2013  
  
8.1.2 Primary Endpoint  
The primary endpoint for this study is cognitive function, specifically 
memory, six months from the completion of PCI as measured by the HVLTR-
delayed recall.    
  
8.1.3 Secondary Endpoints  
  
 
8.1.3.1   
Cognitive function, specifically memory, at 12 months from PCI as   
 
   
  
  
  
measured by the HVLT-R delayed recall  
  
8.1.3.2          A composite cognitive function endpoint using the validated               
Reliable Change Index (48,49) to include the Controlled Word    
Association Test (COWAT), the HVLT-R-delayed recall, the   
HVLT-R-trials 1-3 and Trail Making Tests part A and B (TMT)  
  
  
  
  
    
8.1.3.3          Quality of Life (QOL) as measured using the EORTC Quality of   
          Life Questionnaire (QLQ-C30) and Brain Cancer Module 20              
(BN20) at baseline, 6 months, and 12 months  
  
  
8.1.3.4          Development of brain metastases at 2 years following completion   
of radiation therapy will be coded as a binary variable (yes or no)  
  
  
  
  
  
   8.1.3.5   
Development of 
leptomeningeal carcinomatosis at 2 years following completion of 
radiation therapy will be coded as a binary variable (yes or no)  
  
8.1.3.6         Overall survival  
  
 
8.2   
Sample Size/Accrual Rate  
  
  
  
  
8.2.1  Sample Size  
     
The sample size calculations address the specific primary hypothesis that 
patients treated with hippocampal-sparing PCI for SCLC will not experience as 
much decline in neurocognitive function as reported for the historical control 
of RTOG 0212 receiving the same dose of conventional PCI.  The clinically 
meaningful difference and associated standard deviation are based on the 
RTOG study and the work of Meyers et al.  The latter reported a mean score in 
the HVLT-R delayed recall change in patients treated only with whole-brain 
radiation therapy of 0.87 (from 7.04 at baseline to 6.17 at 6 months), with a 
standard deviation of 3.19.  In RTOG 0212, the average decline in HVLT 
memory at six months is 1.13 (sd=2.80).  We expect patients receiving 
hippocampal-sparing PCI to experience a smaller decline in cognitive function 
from baseline to six months, compared to the historical control group. The 

17 J12127 Version: November 14, 2013  
onesided statistical hypothesis test is as follows: H0: Δμ = 1 vs. HA: Δμ < 1, 
where Δμ is the mean change in HVLT scores from baseline to 6 months for 
patients receiving hippocampal-sparing PCI (baseline minus 6-month score). 
With change measured in 100 patients, we will have 90% power to detect a 
meaningful change (0.88 points less change in HVLT scores over 6 months,  
i.e., mean change of 0.12) in our treated group with a one-sided test at the 5% 
level of significance, assuming a standard deviation of around 3.  Similarly, we 
will have 80% power with a one-sided 5% level test to detect a mean change of 
0.75 (with standard deviation equal to 3).  We will enroll 125 patients to allow 
for up to 20% of patients to be not evaluable at 6 months.  
  
  
        8.2.2  Accrual  
  
We anticipate enrollment of approximately 2 patients per month to the protocol 
with accrual completed in approximately 5 years.    
  
8.3   Stratification Factors  
  
  
  
  
There will be no stratification factors upon initial enrollment in the protocol.    
  
 
 8.4  
Statistical Methods of Analysis  
  
The primary objective of this study is to evaluate change in cognitive function as 
measured by the HVLT-R-delayed recall.  We will compare hippocampal-sparing 
PCI to the historical experience of patients who received standard PCI in RTOG 
0212. Each patient will be assessed pre-therapy and post-therapy, with the change at 6 
months being the primary endpoint. Patient scores on the HVLT-R delayed recall 
section are whole numbers, ranging from 0 to 12, with lower scores indicating 
declining cognitive function.   The score itself refers to the number of words a patient 
can recall from a list of 12 words.  Therefore, if a patient initially is able to recall 8 
words pre-therapy and is, at 6 months, able to only recall 6 words, their change in 
score would be 2. The primary endpoint (change score) is the difference between the 
pre-therapy and post-therapy scores. A change score of zero indicates preserved 
cognitive function.   Change scores from -1 to -12 indicated improved cognitive 
function and are not expected.  Summary statistics of the change scores, such as 
means, medians, standard deviations, and ranges will be listed separately by treatment 
(sparing PCI and historical standard PCI groups). We hypothesize that change scores 
from pre-therapy to 6 months post-therapy is lower among patients receiving 
hippocampal-sparing PCI compared to the historical PCI group in the RTOG study. 
We will use the Wilcoxon Signed-Rank test to test the change in HVLT-R scores 
over six months, relative to the expectation based on the historical information, 
according to the statistical hypotheses given in the sample size section (Section 
8.2.1).  
  

18 J12127 Version: November 14, 2013  
The analysis of the secondary outcome of HVLT-R-delay score change at 12 months 
will be performed as described above for the primary outcome.  In addition, we will 
examine if there appears to be a trend to increasing change score over time for the 
treatment groups.   
  
The Reliable Change Index will measure meaningful change between baseline and 6 
and 12 months for HVLT–R, Trail Making Test part A and B, COWAT.  The 
Reliable Change Index is derived from the standard error of measurement (SEM) for 
each test in the battery. The SEM is calculated from the test–retest reliability (r) and 
the standard deviation of test scores (SD): SEM=sqrt[SD×(1-r)].  The standard error 
of the difference (SEdiff ) is then calculated as SEdiff =sqrt[2×(SEM)2].  For each 
test in the neurocognitve battery, the Reliable Change Index value will be determined 
a priori for that particular test to determine whether a change from baseline is 
clinically meaningful.    
  
We will compute summary statistics and compare our patients to the historical 
controls based on tests that are appropriate for the type of data.  
  
Quality of Life on our study will be assessed using EORTC Quality of Life 
questionnaire (QLQ-C30) and the Brain Cancer Module 20 (BN 20) pre-therapy, at 6 
months, and at 12 months after therapy. For each module, summary statistics of the 
scores will be reported for each study time point. Change scores in quality of life 
from pre-therapy to post-therapy will be calculated and tested via paired t-tests for the 
hippocampal-sparing PCI treatment group. We may fit mixed-effect models to 
explore changes in quality of life assessments over time.   
  
We will tabulate development of brain metastases within 0.5 mm of the hippocampus.  
We will report adverse events based on CTCAE v4.0 by frequency tables.  We will 
test the proportion of patients who develop brain metastases via binomial test.  
Overall survival will be measured from the start of treatment to death or last 
followup. For subjects who alive or lost follow up at the end of study, overall survival 
will be censored at the last follow up date. Overall survival probabilities will be 
estimated via the Kaplan-Meier method; median survival and 95% confidence 
interval via Greenwood’s formula for variance will be reported.   
  
8.5   Safety Monitoring  
We have included a formal statistical stopping rule for monitoring the occurrence of 
brain metastases.  The article describing RTOG 0212 reported that the raw proportion 
of patients with brain metastases is 22% (29/131) at 1 year for the group getting 2.5 
Gy in 10 fractions.  We established a monitoring rule that will recommend 
considering stopping the study if there appears to be high probability that the risk of 
brain metastasis at 1 year is above 22%.  Specifically, if the posterior probability that 
the risk exceeds 25% of brain metastasis by 1 year after treatment is 75% or greater 
(3:1 odds), then we will consider stopping the study.  In this calculation, the number 
of patients with brain metastasis at 1 year is a binomial random variable.  The prior 

19 J12127 Version: November 14, 2013  
distribution for the risk of brain metastasis by 1 year is beta with parameters 29 & 
102.  Although we can apply the stopping rule calculation after every patient, we may 
monitor in batches of 10.  The stopping rule is illustrated in the figure below.  
  
  
 
9.  ADVERSE EVENTS AND RECORDING   
  
9.1 Definition of Adverse Event (AE)  
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition during or following an exposure to a 
treatment, whether or not considered causally related to the treatment.  An 
undesirable medical condition may be symptoms (headache, nausea), signs  
(tachycardia, enlarged liver), or abnormal results of an investigation (MRI, laboratory 
finding).  In clinical trials, from the time of signing an informed consent, an AE may 
include an undesirable medical condition, occurring at any time, even if no trial 
treatment has been administered.  
  
    9.2  Radiation Related Adverse Events   
  
All radiation related adverse events will be recorded on the local toxicity case report 
forms.  
   

20 J12127 Version: November 14, 2013  
  
  
10. SERIOUS ADVERSE EVENTS (SAE) AND REPORTING  
  
 
     10.1  
Serious Adverse Event  
  
10.1.1 Definition of Serious Adverse Event  
  
A serious adverse event is an AE occurring at any point during a clinical trial that 
fulfills one or more of the following criteria:  
  
● Results in death.  
● Is immediately life threatening.  
● Requires in-patient hospitalization or prolongation of existing hospitalization.  
● Is a congenital abnormality or birth defect.  
● Unexpected event that cause harm or place person at a greater risk of harm 
than was previously known or recognized, and which was possibly related to 
the research.  Unexpected means that the event was not described in the 
consent form or the event exceeded the expected severity.  
● Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above.  
  
 
    10.2  
SAE Reporting Guidelines for Johns Hopkins Hospital  
  
All SAE, with the exception of death, must be reported to the Johns Hopkins Hospital 
Institutional Review Board (JH-IRB) within 10 working days of the principal 
investigator learning of the event.  Reporting for the death of a patient which was 
unexpected (i.e.: not related to a risk of participation that was listed in the protocol or 
the consent document, and was more likely than not to be caused by the research 
procedure/intervention, must be reported to the JH-IRB within 3 working days of 
when the principal investigator receives the report of the death.  Reporting for death 
of a participant that was expected due to the nature of the patient’s underlying disease 
or condition, or identified as caused by a possible risk of the study 
procedure/intervention as described in this protocol or consent form, must be reported 
to the JH-IRB within 10 working days from the time the principal investigator learns 
of the event.  If death occurs 30 days after the participant has stopped or completed 
their study treatment, the principal investigator does not have to report the death until 
the time of continuing review.    
  
11.    DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS  
  
 
  
11.1   Data Quality Monitoring  
  
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(09/22/2011). The Clinical Research Office QA Group will perform an audit at the 

21 J12127 Version: November 14, 2013  
end of the first year and periodically depending on the rate of accrual and prior audit 
results. All trial monitoring and reporting will be reviewed annually by the SKCCC 
Safety Monitoring Committee.  
  
In addition to the ongoing quality assurance evaluations for each individual at the 
time of treatment, there will be regular meetings between the principal investigator, a 
medical oncologist, and the study coordinator to assess the data quality.  This meeting 
will occur annually and a monitoring report of the findings will be submitted to the 
Data Safety Monitoring Committee on an annual basis.  Any protocol deviations or 
violations will be documented in the monitoring reports.  The review will include: 
consent forms, eligibility criteria, protocol compliance, treatment administration, 
toxicity reports, response, regulatory compliance, case report forms (completeness as 
well as verifying that information coded on the case report forms are supported by 
source documents), and all other materials related to the trial.  In addition, this trial 
will be audited annually by the central clinical research office at Johns Hopkins.    
  
 
  
11.2   Data Safety Monitoring  
  
All SAE’s and major protocol deviations that occur at Johns Hopkins Hospital will be 
submitted to the Sidney Kimmel Comprehensive Cancer Center Data Monitoring 
Committee for review per Institutional guidelines.  In addition, the overall study 
safety and potential activation of the study’s early stopping rules will be assessed at 
the time of every SAE.  The Data Safety Monitoring Committee with review this trial 
for safety annually.   
  
 
11.3  
Data Reporting  
  
 
11.3.1  Method  
  
Data will be collected on Case Report Forms (CRF’s). These CRF’s will be 
completed by the Study Coordinator. The CRF’s for each subject will be kept 
in a separate research binder. Along with each completed CRF there will be 
corresponding source documentation filed for verification. The Principal 
Investigator, Research Nurse, and Study Coordinator will informally meet on 
a regular basis to make sure that the trial is progressing as mandated by the 
protocol. The Clinical Research Office (CRO) will audit this trial per their 
standards to ensure and verify that the protocol is being carried out according 
to plan as well as to verify that data included on subject CRF’s are accurate. 
Exit reports generated as a result of these CRO audits will be forwarded to 
both the Safety Monitoring Committee as well as to the IRB of record for 
review.  
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Appendix A:   
RTOG Neurological Function Class  
  
1 Able to work and perform normal activities. Neurological findings minor or absent.  
  
2 Able to carry out normal activities with minimal difficulty. Neurological impairment does 
not require nursing care or hospitalization  
  
3 Seriously limited in performing normal activities; requires nursing care or hospitalization. 
Patient confined to bed or wheelchair or with significant intellectual impairment.  
  
4 Unable to perform even minimal normal activities. Requires hospitalization and/or 
constant nursing care. Patient unable to communicate or in coma.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

27 J12127 Version: November 14, 2013  
  
  
  
Appendix B  
  
Performance Status Criteria  
  
  
ECOG/Zubrod Performance Status Scale  
  
  
Karnofsky Performance Scale  
Grade  
Descriptions  
Percent  
Description  
0  
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.  
100  
Normal, no complaints, no evidence 
of disease.  
90  
Able to carry on normal activity; 
minor signs or symptoms of disease.  
1  
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).  
80  
Normal activity with effort; some 
signs or symptoms of disease.  
70  
Cares for self, unable to carry on 
normal activity or to do active work.  
2  
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours.  
60  
Requires occasional assistance, but 
is able to care for most of his/her 
needs.  
50  
Requires considerable assistance and 
frequent medical care.  
3  
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.  
40  
Disabled, requires special care and 
assistance.  
30  
Severely disabled, hospitalization 
indicated.  Death not imminent.  
4  
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund, 
fatal 
processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
  
  
  
  

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Appendix C   
  
  
  

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Appendix D  
  
  

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