Phase II Trial of Hippocampal-Avoiding Whole Brain Irradiation With Simultaneous Integrated Boost for Treatment of Brain Metastases
Phase: PHASE2
Conditions: Brain Neoplasms, Adult, Malignant
Sponsor: University of Texas Southwestern Medical Center

Official title: Phase II Trial of Hippocampal-Avoiding Whole Brain Irradiation 
With Simultaneous Integrated Boost for Treatment of Brain Metastases 
 
NCT number: NCT01414738  
eIRB approval date: Version 8.0, 07/30/2014 

Phase II trial of Hippocampal-Avoiding Whole Brain Irradiation with Simultaneous 
Integrated Boost for Treatment of Brain Metastases 
 
University of Texas Southwestern Medical Center 
 
Principal Investigator (P.I.): 
Robert Timmerman, M.D. 
 
 
 
 
 
Department of Radiation Oncology 
 
Co Investigators: 
 
Hak Choy, M.D. 
Kevin Choe, M.D., Ph.D. 
Ramzi Abdulrahman, M.D. 
Dan Garwood, M.D. 
Puneeth Iyengar, M.D., Ph.D. 
Jeffrey Meyer, M.D. 
Lucien Nedzi, M.D. 
David Pistenmaa, M.D., Ph.D. 
Ann Spangler, M.D. 
Department of Radiation Oncology 
 
 
 
 
 
 
 
Jonathan Dowell, M.D. 
David Gerber, M.D. 
Randall Hughes, M.D. 
Joan Schiller, M.D. 
Department of Internal Medicine 
Division of Hematology-Oncology 
 
 
Tony Whitworth, M.D. 
Christopher Madden, M.D. 
Department of Neurosurgery 
 
C. Monro Cullum, Ph.D. 
Division of Clinical Psychology 
 
  
 
Version 
Date 
1 
4/28/2011 
2 
8/17/2011 
3 
1/16/2012 
4 
7/19/2012 
5 
8/20/2012 
6 
11/13/2012 
7 
05/06/2013 
8 
05/14/2014 

Page | 2  
 
 
INDEX 
 
 
Schema 
 
Eligibility Checklist  
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection 
 4.0 
Pretreatment Evaluations/Management 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy  
 7.0 
Drug Therapy 
 8.0 
Surgery 
 9.0 
Other Therapy 
10.0 
Tissue/Specimen Submission 
11.0 
Patient Assessments 
12.0 
Data Collection 
13.0 
Statistical Considerations 
 
References 
 
 
Appendix I  
Study Parameter Table/Study Calendar 
 
Appendix II  
Follow-up Radiographic Assessment Form 
 
Appendix III  
Neurocognitive Function Assessment 
 
Appendix IV  
Performance Status Scoring 
 
Appendix V  
RTOG RPA Classification System 
 

Page | 3  
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Population: (See Section 3.0 for Eligibility) 
 
1. Pathologically proven diagnosis of a non-hematopoietic malignancy other than small cell 
lung cancer and germ cell malignancy.   
 
2. Patients with less than 9 discrete metastases on MRI. 
 
3. Measurable brain metastasis outside a 5-mm margin around either hippocampus  
 
4. Have not been treated with SRS or surgical resection. 
 
5. Patients with progressive brain metastases beyond a brain lesion previously treated with 
radiosurgery are eligible so long as at least 3 months has transpired from the radiosurgery 
procedure prior to registration. 
 
6. RTOG RPA class I or II 
 
7. Life expectancy of at least 3 months 
 
8. Age ≥ 18 years 
 
9. Karnofsky performance status ≥ 70 
 
10. Two or fewer sites of uncontrolled or untreated sites of extracranial metastases 
 
11. No active pulmonary, gastrointestinal, genitourinary or other serious infection at time of 
enrollment 
 
 
 
 
 
 
 
Required sample size: 102 
Eligible 
patient 
WBRT-HA/SIB 
20 Gy in10 fractions – 
whole brain + 40 Gy in 10 
fractions – metastases  
Follow up for 
neurocognitive 
decline  

Page | 4  
 
ELIGIBILITY CHECKLIST 
(page 1 of 2) 
Patient Initials  
 
 
Case #  
 
 
 
 
 
 
(Y)   
1. Does the patient have a pathologically confirmed diagnosis of a non-
hematopoietic malignancy other than small cell lung or germ cell cancer? 
 
_______(Y) 
2. Does the patient have measurable brain metastases outside a 5-mm margin 
around either hippocampus? 
 
 
(N)    
3. Has the patient been treated with SRS or surgical resection? 
 
 
(Y)   
4. Has the patient had a history/physical examination within 28 prior to 
registration? 
 
 
(Y)   
5. Does the patient fall into RTOG RPA class I or II? 
 
________(Y) 
 6. Does the patient have a life expectancy of at least 3 months? 
 
 
(Y) 
 7. Is the patient 18 years or older? 
 
 
(Y) 
 8. Does the patient have a KPS of 70 or greater? 
 
 
(Y) 
 9. Did the patient provide study-specific informed consent prior to any 
protocol-specified procedure(s)? 
 
          (Y/NA)  
10.  If female, was there a negative serum or urine pregnancy test performed 
prior to treatment for women of childbearing potential? 
 
 
(N) 
12. Does the patient have more than 9 discrete metastases on the MRI? 
 
 
(N) 
13. Does the patient have leptomeningeal metastases? 
 
 
(N) 
 14. Is there a plan for chemotherapy or targeted therapies during WBRT or 
over the subsequent 7 days? 
 
  
(N)   
 15. Does the patient have a contraindication to MRI such as implanted metal 
devices or foreign bodies, severe claustrophobia and unable to receive 
gadolinium contrast agents? 
 
 
(N)  
 16. Does the patient have serum creatinine > 1.4 mg/dl ≤ 28 days prior to study 
entry? 
 
 
(N) 
17.  Is the patient planning to undergo radiosurgery to any CNS lesion or 
planning to have surgical resection of all of their CNS lesions? 
 
 
(Y)   
 18.   Does the patient have 2 or fewer sites of uncontrolled or untreated  
extracranial gross disease? 
 

Page | 5  
 
________(N) 
19.  Does the patient have an active pulmonary, gastrointestinal, genitourinary 
or other serious infection at time of enrollment?  
 
________(Y)    20.  For patients with progressive brain metastases beyond a brain lesion 
previously treated with radiosurgery, has at least 3 months transpired from the 
radiosurgery procedure? 
   
 
 
 
 
 
 
 
 
ELIGIBILITY CHECKLIST 
(page 2 of 2) 
 
Patient Initials  
 
 
Case #  
 
 
 
 
 
The following questions will be asked at Study Registration:  
 
 
 
 
1. Name of institutional person registering this case? 
 
 
(Y) 
2. Has the Eligibility Checklist (above) been completed? 
 
 
(Y) 
3. Is the patient eligible for this study? 
 
 
 
4. Date the study-specific Consent Form was signed 
 
 
 
5. Patient’s Initials (First Middle Last) [If no middle initial, use 
hyphen] 
 
 
 
6. Verifying Physician 
 
 
 
7. Date of Birth 
 
 
 
8. Race 
 
 
  
9. Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown) 
 
 
 
10. Gender 
 
 
 
 
17. Registration date 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
Investigator Signature  
 
 
 
 
 
Date 
 
 
 

Page | 6  
 
 
 
 
 
1.0 
INTRODUCTION 
1.1 
Neurocognitive Effects of Whole-Brain Radiotherapy (WBRT)  
Whole-brain radiotherapy (WBRT) is the most widely used treatment option for patients 
with multiple brain metastases (Sundstrom 1998).  In addition to providing rapid 
palliation of neurologic symptoms and improved local control as an adjuvant to resection 
or radiosurgery, WBRT also prolongs time to neurocognitive function (NCF) decline 
(Aoyama 2007).  As such, NCF and quality of life are correlated in patients with brain 
metastases receiving WBRT, with deterioration in NCF preceding self-reported quality of 
life decline by up to 153 days. (Li 2008).  Hence, there is a sequential association 
between NCF decline and deterioration in self-reported quality of life for patients with 
brain metastasis.  These results demonstrate that delaying NCF decline results in net 
clinical benefit important for preserving quality of life for patients with brain metastasis.   
 
However, NCF decline can also be a sequela of WBRT; the time course of this varies 
based on the specific domains being measured.  There is a component of early 
neurocognitive decline, within the first 1-3 months, which primarily reflects memory.  
Long-term serious and permanent adverse effects, including cognitive deterioration in 
other domains and cerebellar dysfunction, have also been described (Roman 1995).  
DeAngelis et al. (1989) suggested that as many as 11% of long-term brain metastases 
survivors (>12 months) treated with WBRT develop severe dementia, especially with the 
use of larger dose-per-fraction schedules.  The analysis of WBRT-induced NCF decline 
can be confounded by two effects: 1) patients with brain metastases tend to have reduced 
NCF at the time of presentation, and 2) disease progression will negatively skew 
population distributions of NCF scores.   
 
In an attempt to disentangle these confounding effects, a detailed analysis was published 
of the time course of NCF decline in eight prospectively measured domains in 208 brain 
metastases patients treated with 30 Gy of WBRT (Li 2007).  NCF, assessed by tests of 
memory, executive function, and fine motor coordination, was correlated with metastasis 
volume regression as measured by magnetic resonance imaging. NCF and survival were 
compared in 135 patients evaluable at 2 months with tumor shrinkage less than (poor 
responders) and greater than (good responders) the population median. The mean NCF 
scores and brain metastasis volume at 4 and 15 months were compared. Good responders 
experienced significantly improved survival (unidirectional p = 0.03).  For all tests, the 
median time to NCF deterioration was longer in the good than in the poor responders, 
with statistical significance seen for executive and fine motor functions. In long-term 
survivors, defined as patients surviving more than 15 months, tumor shrinkage was 
significantly correlated with preservation of executive function and fine motor 
coordination (r = 0.68-0.88).  These findings support two important possibilities.  First, 
achieving local control with WBRT was integral to both improving survival and 
preserving certain NCF domains.  Second, an intriguing exception to these findings was 
memory function, specifically recall and delayed recall as assessed with the Hopkins 
Verbal Learning Test (HVLT-R).  These NCF domains appeared to have a weaker 
association with tumor reduction and were the most susceptible to early decline, even in 
patients with non-progressing brain metastases, implying the selective effect of WBRT in 
preserving certain domains over others and the differential sensitivity of certain domains 
to radiation effects. 
 
Further evidence of the early susceptibility of memory function to WBRT 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 one to 

Page | 7  
 
three brain metastases, with the principal objective of comparing NCF decline between 
the two arms.  Utilizing HVLT-R as a neurocognitive metric for learning and memory, 
they defined NCF decline as a >5 point drop 3 months from baseline. Their study was 
halted early due to an interim observation of a two-fold increase in the mean probability 
of NCF decline (49%, SRS+WBRT, vs 23%, SRS alone).  Similar findings were reported 
by Welzel et al. (2008), who observed a decline in verbal memory function, as assessed 
by the Auditory Verbal Learning Test (AVLT) 6 to 8 weeks after the completion of 
WBRT for brain metastases.  The sum of these findings suggest that, although 
achievement of macroscopic lesion control is an important treatment aim, strategies 
meant to preserve memory-related NCF warrant further investigation.  
 
1.2 
Rationale for Hippocampal Avoidance During WBRT   
Emerging evidence suggests that the pathogenesis of radiation-induced NCF deficit may 
involve radiation-induced injury to proliferating neuronal progenitor cells in the 
subgranular zone of the hippocampi (Mizumatsu 2003; Raber 2004).   It has been found 
that relatively small doses of radiation cause apoptosis in the subgranular zone of young 
rats and mice (Mizumatsu 2003; Ferrer 1993; Nagai 2000).  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; Nagai 2000; Abayomi 1996; Madsen 2003; Monje 2002; 
Peissner 1999; Tada 2000).  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 WBRT 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).  
Preliminary results from a recent MD Anderson study of low-grade or anaplastic brain 
tumors treated with radiotherapy have observed a dose-response phenomenon, wherein 
the maximum radiation dose to the left hippocampus was correlated with subsequent 
decline in learning (p = 0.014) and delayed recall (p = 0.01) (Mahajan 2007). 
 
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 benefit in NCF, as well 
as the temporal sequence of events, following WBRT.   
 
We propose to use conformal avoidance of the hippocampal region during whole brain 
radiotherapy to reduce the dose to the hippocampi, 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 avoidance of 
the hippocampal region with WBRT may delay or reduce the onset, frequency, and/or 
severity of NCF decline, as measured with clinical neurocognitive tools. 
 
 
 
1.3 
Rationale for Integrated Boost During WBRT   
 
 

Page | 8  
 
Randomized trials involving WBRT with or without Stereotactic Radiosurgery (SRS) 
(Andrews 2004, Kondziolka 1999) in patients with multiple brain metastases have been 
published, and demonstrate improved local control for patients receiving SRS in addition 
to WBRT. Randomized trials involving SRS +/- WBRT in patients with multiple brain 
metastases show that the addition of WBRT reduces the risk of intracranial relapse 
(Aoyama 2007) at the expense of decreased neurocognition (Chang 2009). 
Intensity modulation can be utilized to deliver a dose of radiation to the whole brain to 
control microsopic disease while simultaneous delivering a boost of radiation all 
radiographically evident brain metastases. Additionally, intensity modulated radiation 
therapy (IMRT) can be utilized to spare the structures responsible for memory-related 
neurocognition. The technical feasibility of this approach has been reported for a variety 
of flavors of intensity modulation, including helical tomotherapy (Rodrigues 2010, 
Gutierrez 2007), as well as volumetric modulated arc therapy (Lagerwaard 2009, Hsu 
2010). Boost doses comparable to radiosurgery are generally achievable, with the 
possibility of delineation and avoidance of the hippocampal regions thought to be related 
to radiation-induced neurocognitive decline. There is a logistic advantage to the 
simultaneous integrated boost in that it can be administered in a single course of 
radiotherapy rather than a combination of conventionally fractionated radiotherapy and 
radiosurgery. Additionally, the treatment can be administered with linear accelerators that 
are common in most community-practice settings. There is a dosimetric advantage as 
well, in that the composite plan can be fully optimized to achieve a relatively 
homogenous whole brain dose, a steep gradient for the radiographically evident disease, 
and adequate hippocampal sparing, all at once. 
 
 
1.4 
Feasibility of Hippocampal Avoidance and Integrated Boost During WBRT  
 
In general, hippocampal avoidance 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.  In a recent dosimetric analyses of 30 
Gy in 10 fractions prescribed to the whole brain, intensity-modulated radiotherapy 
(IMRT) allowed for the delivery of highly conformal dose distributions, maintaining the 
hippocampal volume receiving 10 Gy or higher (V10) to less than 50% and the maximum 
dose to the hippocampus to less than 16 Gy (Gondi 2010a).  Coupling hippocampal 
avoidance with a more heterogenous plan than delivers a higher volume to 
radiographically evident disease has also been demonstrated in a single treatment plan 
(Gutierrez 2007).  Multiple institutions have also demonstrated the feasibility of WBRT 
with hippocampal avoidance utilizing LINAC-based IMRT delivery systems broadly 
available at multiple academic and community radiation oncology practices (Gondi 
2010a). Incorporating an integrated boost into a WBRT with hippocampal avoidance has 
been demonstrated as well (Hsu 2010). 
 
Avoiding the hippocampus poses the risk of attenuating the benefit of WBRT due to 
increased metastatic disease within the hippocampal conformal avoidance region.  The 
magnitude of this risk has been reported in a study reviewing the MR images of 100 
patients, 98 of whom received WBRT with or without SRS boost (Ghia 2007).  T1-
weighted, three-dimensional spoiled gradient, post-contrast axial MRI images with a 1.25 
mm slice thickness, obtained prior to radiotherapy, were reviewed.  In the 100 patients, 
272 metastases were identified and analyzed.  Out of the 272 metastases, 3.3% were 
within 5 mm of the hippocampi (n=9); 4.4% of metastases were between 5 to 10 mm 
from the hippocampi (n=11); and 6.3% of metastases lay between 10 and 15 mm from the 
hippocampi (n=17).  Of all metastases, 86.4% were greater than 15 mm from the 
hippocampi (n=235).  However, none of the metastases lay within the hippocampi.  The 
upper 95% confidence limit for the risk of finding a metastatic lesion within 5 mm of the 
hippocampi at the time of presentation was 15.2%.  An update of this study reported on 
an additional 271 patients with up to 10 brain metastases (Gondi 2010b).  Of these 

Page | 9  
 
patients, 1133 brain metastases were identified.  Thirty-two patients had at least one brain 
metastasis within 5 mm of the hippocampi at the time of presentation.  This yielded an 
incidence of 8.6%, allowing for the tightening of the estimated upper 95% confidence 
limit to 11.5%.  From this, it can be concluded that 91% of newly diagnosed patients will 
be eligible for the WBRT that avoids the hippocampus.  Patients who present with 
perihippocampal or hippocampal brain metastases will not be eligible for this protocol. 
 
Although response rates after WBRT without hippocampal avoidance vary, complete or 
partial responses have been documented in more than 60% of patients in randomized 
controlled studies conducted by the RTOG, with intracranial disease control observed in 
approximately 50% of patients at 6 months (Khuntia 2006).  It is currently not possible to 
provide a direct estimate of the risk of developing a metastasis after hippocampal 
avoidance WBRT, since such a comprehensive data set does not exist.  However, if we 
assume that the risk of developing subsequent brain metastasis in the hippocampal 
avoidance region scales in the same proportion as that at presentation, from our data on 
the distribution of brain metastases relative to the hippocampus at presentation, we can 
conclude that a patient treated with hippocampal WBRT will derive 91.4% of the relative 
benefit of WBRT in terms of radiographically evident intracranial lesions, with a lower 
95% confidence limit of 88.5% (Gondi 2010b).   As the overall aim is to improve the 
interval to NCF decline, we hypothesize that hippocampal avoidance WBRT will provide 
a net gain in this endpoint.  Furthermore, the modest increase in risk of intracranial 
progression with hippocampal avoidance may be partially compensated by the possibility 
of salvage with radiosurgery.  Should salvage SRS be indicated for a perihippocampal 
recurrence, we expect that, given the very steep radiation dose falloff with SRS, some but 
not all of the benefit of hippocampal avoidance will be lost.   
  
1.5 
Neurocognitive Function Assessment 
To assess our primary endpoint, we have chosen to use the Hopkins Verbal Learning Test 
(HVLT-R) test that has been used and validated in the phase III trial of motexafin 
gadolinium for patients with brain metastases.  In this trial, compliance with NCF testing 
was 87% to 98% at baseline and 77% to 87% at 6 months (Meyers 2004).  Our reasons 
for using this particular NCF test include: 1) its ease of use, 2) our institutional 
experience with its administration, and 3) its validation by RTOG for use in a prior multi-
institution study. In RTOG 0018, a phase II trial to evaluate the feasibility of 
neurocognitive testing of brain metastasis patients receiving WBRT in the cooperative 
group setting, compliance was >90% prior to WBRT, >84% at the completion of WBRT, 
and >78% at one month after WBRT.  Most non-compliance was attributed to patient-
related factors such as decline in performance status (Regine 2004). 
 
The version of the HVLT-R used in the phase III trial of motexafin gadolinium for 
patients with brain metastases, which for consistency and study comparability will be 
used in the present study, 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), identifying the 
12 targets from a list of semantically related or unrelated items (immediate recognition), 
and recalling the 12 targets after a 20-minute delay (delayed recall). Raw scores are 
derived for total recall, delayed recall, retention (percentage retained), and a recognition 
discrimination index.  Each patient will serve as his/her own control, as the difference in 
scores obtained at baseline and at pre-specified post-treatment intervals will be 
calculated.  
 
Prior to initiation of treatment, all patients will undergo baseline NCF testing using a test 
battery consisting of the HVLT-R, Trail Making Test (TMT), Controlled Word 
Association Test (COWAT), and Mini-Mental Status Examination (MMSE).  At that 
time, history regarding level of education reached will also be obtained.  After 

Page | 10  
 
completion of radiotherapy, all patients will undergo this neurocognitive test battery, 
conducted by trained and certified nurses or clinical research associates, at 3, 6, 9, 12, and 
24 months.  In the analysis of NCF decline, each patient will serve as his/her own control, 
as NCF for each test at each follow-up time point will be compared to baseline NCF. 
 
1.6 
Fatigue Assessment and Quality of Life Assessment 
 
Fatigue will be assessed using the Multidimensional Fatigue Inventory (MFI-20).   
 
The MFI-20 is a multidimensional, self-report instrument designed to measure fatigue. It 
covers the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, 
Reduced Motivation and Reduced Activity. A subscore from 4 to 20 is reported for each 
dimension, with 20 corresponding to maximal fatigue. 
 
Within 2 weeks prior to WBRT-HA/SIB, all patients will undergo a baseline fatigue 
assessment.  After completion of WBRT-HA/SIB, all patients will undergo fatigue 
assessments at 3, 6, 9, 12, and 24 months.   
 
Quality of life will be assessed using the Functional Assessment of Cancer Therapy with 
Brain Subscale (FACT-BR) and the Euroqol EQ-5D .The FACT-BR is a 
multidimensional, self-report quality of life instrument specifically designed and 
validated for use with brain malignancy patients. It is written at the 4th grade reading 
level and can be completed in 5-10 minutes with little or no assistance in patients who are 
not neurologically incapacitated. It measures quality of life related to symptoms or 
problems across 5 scales: physical well-being (7 items); social/family well-being (7 
items);emotional well-being (6 items); functional well-being (7 items); and concerns 
relevant to patients with brain tumors (23 items). Items are rated on a 5-point scale: 0-
“not at all”, 1- “a little bit”, 2-“somewhat”, 3-“quite a bit” and 4-“very much”. FACT-BR 
is self-administered and does not require pre-certification.  It has been translated into 26 
languages and is available free of charge to institutions with the completion of an 
agreement to share data, accessible at: 
http://www.facit.org/translation/licensure.aspx. 
 
 
 
Quality of Life Assessments 
 
 
 
 
Quality of Life Assesment 
Test 
Time to Administer 
Quality of Life (self reported) 
Functional Assesment of Cancer 
Therapy with Brain Subscale 
5 
Utility 
EQ-5DL (self reported) 
3 
 
Total Time 
8 
 
 
Within 2 weeks prior to HA-WBRT, all patients will undergo a baseline quality of life 
assessment.  After completion of HA-WBRT, all patients will undergo quality of life 
assessments every 3 months for 12 months and then at 24 months  until death. Quality of 
life assessments will be scored centrally by a blinded reviewer to avoid potential bias. 
 
1.7 
Summary and Historical Control 
In summary, preclinical and clinical evidence suggests that radiation dose received by the 
hippocampus during WBRT may play a role in radiation-induced neurocognitive decline. 
Although neurocognitive assessment in patients receiving WBRT can be confounded by 
intracranial metastatic disease, analyses suggest a differential sensitivity of various 
neurocognitive domains, such as delayed recall, to WBRT.  This provides the rationale to 
explore the clinical feasibility of hippocampal avoidance during WBRT.  The dosimetric 
capabilities of IMRT to conformally avoid the hippocampus without detriment to the 

Page | 11  
 
radiation dose the remaining brain receives has been demonstrated, as well. Through 
retrospective analyses, we have also estimated the theoretical risk of perihippocampal 
disease progression with hippocampal avoidance.  Given the overall aim of prolonging 
neurocognitive 
decline, 
and 
the 
possibility 
of 
salvaging 
hippocampal 
and 
perihippocampal recurrences with radiosurgery, we hypothesize that WBRT with HA and 
SIB (WBRT-HA/SIB) will provide a net gain in this endpoint. 
 
In this phase II study, we plan to treat patients with brain metastases with WBRT-
HA/SIB.  To assess the utility of WBRT-HA/SIB, a comparison of these endpoints with 
historical data of WBRT without hippocampal avoidance will be necessary to determine 
whether a phase III prospective randomized trial of WBRT with and without 
hippocampal avoidance would be warranted, and if so, what statistical considerations 
would be needed.  We plan to utilize data from the control arm (WBRT alone) of a recent 
phase III trial (PCI-P120-9801) of motexafin gadolinium and WBRT (30 Gy/10 
fractions) versus WBRT alone in 401 patients with brain metastasis (PI: Mehta) (Mehta 
2003; Mehta 2002).  These phase III data serve as a particularly useful control for our 
phase II study, given the similarities in inclusion criteria and study design.   
 

Page | 12  
 
 
 
 
 
2.0 
 OBJECTIVES 
2.1 
Primary Objective 
Evaluate delayed recall as assessed by the Hopkins Verbal Learning Test-Revised 
(HVTL-R) 3 months after whole-brain radiotherapy modified as outlined (WBRT-
HA/SIB) for brain metastases. 
 
2.2  
Secondary Objectives 
2.2.1 
Evaluate time to neurocognitive failure as measured by cognitive decline on a battery of 
tests: the HVLT-R for free recall, delayed recall, and delayed recognition; the Controlled 
Word Association Test (COWAT); the Trail Making Test Parts A and B (TMT); the 
Medical Outcomes Scale-Cognitive Functioning Subscale (MOS); and the Mini-Mental 
Status Examination (MMSE) after WBRT-HA/SIB for brain metastases 
2.2.2  
Evaluate fatigue, as assessed by the Multidimensional Fatigue Inventory (MFI-20) after 
WBRT-HA/SIB for brain metastases. 
2.2.3 
Evaluate local control within the brain 
2.2.3.1 Evaluate local control of brain metastases treated with integrated boost 
2.2.3.2 Evaluate local control within the region of brain within the CTV receiving 20 Gy. 
2.2.3.3 Evaluate local control within the hippocampal regions. 
2.2.4 
Evaluate time to radiographic progression after WBRT-HA/SIB for brain metastasis. 
2.2.5 
Evaluate overall survival after WBRT-HA/SIB for brain metastasis. 
2.2.6 
Evaluate adverse events according to CTCAE criteria. 
2.2.7 
Evaluate health-related quality of life [as assessed by the Functional Assessment of 
Cancer Therapy with Brain Subscale (FACT-BR) and the Euroqol EQ-5D before and 
after (WBRT-HA/SIB) 
 

Page | 13  
 
3.0 
PATIENT SELECTION  
 
3.1 
Conditions for Patient Eligibility 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of a non-hematopoietic 
malignancy other than small cell lung cancer and germ cell malignancy..  Direct biopsy 
of CNS lesions is not necessarily required although  could constitute an allowed site of 
tissue confirmation as medically prudent.  Patients who have been disease free for more 
than 5 years prior to the appearance of CNS metastases should undergo repeat biopsy of 
either a systemic metastasis or the CNS metastases to confirm the recurrent malignancy. 
3.1.2 
Patients with measurable brain metastasis outside a 5-mm margin around either 
hippocampus 
3.1.3 
Patients with measurable brain metastasis who have not been or will not be treated with 
SRS or surgical resection (Note: These treatment options are only permitted at relapse) 
3.1.4 
History/physical examination within 28 days prior to registration  
3.1.5 
Patients must fall into RTOG recursive partitioning analysis (RPA) class I or II 
3.1.6 
Patients must have a life expectancy of at least 3 months. 
3.1.7 
Age ≥ 18 years 
3.1.8 
Karnofsky performance status ≥ 70 
3.1.9 
Patients must provide study-specific informed consent prior to study entry 
3.1.10 
Women of childbearing potential and male participants must practice adequate 
contraception 
3.1.11 
Women of childbearing potential must have a negative, qualitative serum pregnancy test 
≤2 weeks prior to study entry 
3.1.12     Patients who had  radiosurgery > 3 months prior to registration are eligible 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Patients with greater than 9 discrete metastases on MRI. 
3.2.2 
Patients with leptomeningeal metastases 
3.2.3 
Patients with measurable brain metastasis not resulting from small cell lung cancer and 
germ cell malignancy 
3.2.4 
Plan for chemotherapy or targeted therapies during WBRT or over the subsequent 7 days 
3.2.5 
Contraindication to MR imaging such as implanted metal devices or foreign bodies, 
severe claustrophobia AND patients unable to receive gadolinium contrast agents 
3.2.6 
Serum creatinine > 1.4 mg/dl ≤ 28 days prior to study entry  
3.2.7 
Prior radiation therapy to the brain 
3.2.8 
Patients planning to undergo radiosurgery to any CNS lesion OR patients planning to 
have surgical resection of ALL of their CNS lesions 
3.2.9 
Patients with more than 2  (i.e., 3 or greater) uncontrolled or untreated extracranial sites 
of gross disease 
3.2.10 
Evidence of an active pulmonary, gastrointestinal, genitourinary, or other serious 
infection at time of enrollment. 
 

Page | 14  
 
 
 
 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT  
Note: This section lists baseline evaluations needed before the initiation of 
protocol treatment that do not affect eligibility.   
 
4.1 
Required Evaluations/Management 
4.1.1 
Neurocognitive assessments within 2 weeks before starting modified whole-brain 
radiotherapy (WBRT-HA/SIB): HVLT-R, COWAT, TMT, MOS, MMSE. 
 
4.1.2 
Fatigue assessment within 2 weeks before starting WBRT-HA/SIB: the Multidimensional 
Fatigue Inventory (MFI-20). 
 
4.1.3 
Scans Prior to WBRT-HA/SIB: See Section 6.0 for details.  
 
4.1.4       Subjects will be screened for renal impairment prior to administration of gadolinium-
based contrast agents (GBCA) as it is routinely done in the Radiology Department at 
UT Southwestern. A creatinine determination 28 days prior to the research MRI 
examination must be available to calculate an eGFR. An eGFR calculation may be 
repeated closer to the MRI appointment if the patient’s medical condition has changed. 
An eGFR ≥45 mL/min/1.73m2 is considered acceptable for administration of a 
standard weight-based dose of GBCA for research purposes. 
 
 
5.0 
REGISTRATION PROCEDURES 
5.1 
Procedures  
5.1.1 
Enrolling investigator must review eligibility checklist and sign/date at bottom that all 
criteria have been met. 
5.1.2 
FAX or carry the enrollment form to the Registrar 
5.1.3 
A unique patient participation ID will be assigned 
5.1.4 
Eligibility will be confirmed by CRO Personnel 
5.1.5 
Successful completion of preregistration activities will be confirmed by the CRO 
Personnel 
5.1.6 
Treatment assignments will be conveyed to the treating investigator  
 

Page | 15  
 
6.0 
RADIATION THERAPY  
Note: Intensity-Modulated RT (IMRT) is required.  Acceptable IMRT modalities include LINAC-
based IMRT involving static gantry angles or volumetric arc therapy (VMAT). 
 
6.1 
Dose Specifications (see target definitions below) 
6.1.1 
Prescription dose will be according to the following specifications: 
6.1.1.1 
The prescription for the whole brain planning target volume (PTVwb - whole brain 
clinical target volume excluding the hippocampal avoidance regions) is 20 Gy in 10 
fractions.  Treatment will be delivered once daily, 5 fractions per week, over 2 to 
2.5 weeks.  Breaks in treatment should be minimized. 
6.1.1.2 
The prescription dose for each metastasis planning target volume (PTV1, PTV2, 
etc.) is 40 Gy in 10 fractions as a simultaneous integrated boost. 
6.1.1.3 
Coverage is considered adequate when 95% of each of the PTVs is covered by the 
assigned prescription dose (D95% = prescription dose). 
6.1.1.4 
The minimum dose to 98% of each of the PTVs (D98%) is 80% of the assigned 
prescription dose. 
 
6.2 
Technical Factors 
6.2.1 
Megavoltage equipment capable of delivering static intensity modulation with a 
multileaf collimator or dynamic intensity modulation (using a multileaf collimator) is 
required.  The use of custom-made compensators or partial transmission blocks is also 
acceptable as long as dose specifications and constraints are satisfied. 
6.2.2 
A megavoltage beam of 4 MV or greater must be used, with a minimum source-axis 
distance of 80 cm.  
6.2.3 
MRI 
T1 contrast enhanced images should be used for targeting of gross lesions.  T2 images 
may also be used when they allow clear demarcation of the edge of the targeted 
tumor(s).  These imaging sequences should be obtained within two weeks of initiating 
treatment. 
 
6.3 
Localization, Simulation, and Immobilization 
6.3.1 
Patients will be immobilized in the supine position using an immobilization device 
such as an Aquaplast mask over the head.  A pituitary board may be utilized to 
maximze the number of available vertex beams. Patients will be treated in the 
immobilization device. 
6.3.2 
A non-contrast treatment-planning CT scan of the entire head region with a 1.25 mm 
slice thickness will be required to define clinical and planning target volumes and 
hippocampal avoidance regions.  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 2 weeks of initiating treatment. 
6.3.3 
The MRI (see Section 6.2.3) and treatment-planning CT should be fused semi-
automatically for hippocampal contouring. 
 
6.4 
Target Volumes 
6.4.1 
The Whole Brain Clinical Target Volume (CTVwb) is defined as the whole brain 
parenchyma to C1 (if no posterior fossa metastasis) or C2 (if MRI evidence of 
posterior fossa metastasis). 
6.4.2 
The Whole Brain Planning Target Volume (PTVwb) is defined as the CTV excluding 
the hippocampal avoidance regions (see Section 6.5.2). 
6.4.3 
Each brain metastasis identified on MRI will be assigned a unique Clinical Target 
Volume identified by number (CTV1, CTV2, etc.) 
6.4.4 
Each metastasis Planning Target Volume (PTV1, PTV2, etc.) is defined as the 
corresponding CTV with a uniform 2 mm margin. 
 
6.5 
Critical Structures 

Page | 16  
 
6.5.1 
Bilateral hippocampal contours will be manually generated on the fused 3D-SPGR 
MRI-planning CT image set by the treating physician according to contouring 
instructions.   
6.5.2 
Hippocampal avoidance regions will be generated by three-dimensionally expanding 
the hippocampal contours by 5 mm.   
6.5.3 
The lenses and orbits will be contoured as per the clinical experience of the treating 
physician. Care should be taken to minimize the dose to the lens and orbits. 
 
6.6 
Documentation Requirements 
6.6.1  
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. 
 
6.7 
Final Quality Assurance Analysis 
6.7.1 
All final treatment plans and contours will be reviewed after initiation of WBRT-
HA/SIB. 
6.7.2 
If unacceptable deviations of MRI/CT fusion, hippocampal contours, and/or 
WBRT-HA/SIB IMRT planning are found on final quality assurance analysis, that 
patient will be rendered inevaluable on final data analysis. 
6.7.3 
If a patient has an unscheduled break exceeding 3 normally scheduled treatment 
days, this unacceptable deviation must be reported to the Principle Investigator, and 
the patient will be considered inevaluable on final data analysis. 
 
6.8  
Compliance Criteria and Critical Structure Constraints 
 
Treatment 
Component 
Parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Contouring 
Hippocampal 
Contouring 
≤ 2 mm deviation 
using the Hausdorff 
distance* 
> 2, ≤ 7 mm 
deviation 
using the 
Hausdorff 
distance* 
Neither per 
protocol or 
variation 
acceptable 
Planning 
PTVwb 
D95 ≥ 20 Gy; D98 ≥ 
16 Gy 
D95 ≥ 18 Gy; D98 ≥ 
15 Gy 
Neither per 
protocol or 
variation 
acceptable 
PTV1, PTV2, 
etc 
D95 ≥ 40 Gy; D98 ≥ 
30 Gy 
D95 ≥ 37.5 Gy; D98 
≥ 28 Gy 
Neither per 
protocol or 
variation 
acceptable 
Hippocampus 
Maximum Dose ≤ 16 
Gy 
Maximum Dose 
≤17 Gy 
Maximum dose > 
17 Gy 
Unscheduled 
Break Days 
 
0 break days 
1-3 break days 
> 3 break days 
 
 
 
 
 
* To assess the Hausdorff distance, the Principal Investigator will remotely contour the “true” hippocampus 
on the submitted MRI/CT fusion, and a comparison will be made to the submitted contours. 
 
6.9 
Radiation Therapy Interruptions 
6.9.1 
Radiotherapy will be continued without interruption if at all possible.   

Page | 17  
 
6.9.2 
If the sum total of radiotherapy interruptions exceeds -7 normally scheduled treatment 
days, the treatment will be considered an unacceptable deviation from the protocol. 
This should be reported to the Principal Investigator, and the patient will be considered 
inevaluable on final data analysis.   
 
6.10 
Radiation Therapy Adverse Events 
6.10.1 
Definition of an Adverse Event (AE) 
6.10.1.1 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or 
procedure (attribution of unrelated, unlikely, possible, probable, or definite). 
6.10.2 
Definition of a Serious Adverse Event (SAE) 
6.10.2.1 
Any adverse experience occurring during any part of protocol treatment and 30 
days after that results in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect. 
6.10.3 
Expected Adverse Events 
6.10.3.1 Acute, ≤ 90 days from treatment start: Expected adverse events include hair loss, 
erythema of the scalp, head ache, nausea and vomiting, lethargy, and transient 
worsening of neurologic deficits.  Reactions in the ear canals and on the ear should 
be observed and treated symptomatically. 
6.10.3.2 Late, > 90 days from treatment start: Possible adverse events include radiation 
necrosis, cognitive dysfunction, visual difficulties, accelerated atherosclerosis, and 
radiation-induced neoplasms. 
6.10.4 
Any adverse event equivalent to CTC V.4 grade 3, 4, or 5 or which precipitates 
hospitalization or prolongs an existing hospitalization must be reported regardless of 
designation (expected or unexpected) along with the attribution. This includes all 
deaths that occur within 30 days after the patient was discontinued from the study 
regardless of attribution AND any events that occur beyond 30 days and are considered 
probably related to treatment. 
6.10.5 
SAE reports must be completed (the CRF plus information describing the event, the 
grade, and the attribution) within 48 hours of the investigator’s awareness of the 
occurrence of the event. 
6.10.6 
Attribution of an event can be categorized as:  
 
Not Related 
 
Possibly Related 
 
Probably Related 
 
Definitely Related 
6.10.7 
Adverse events (below grade 3) do not need to be submitted immediately.  Rather, they 
should be documented in the Adverse Events Clinical Report Form (CRF) along with a 
brief description of the event, grade, and attribution).   
 
7.0 
DRUG THERAPY 
 
Not applicable to this study. 
 
8.0 
SURGERY 
 
Not applicable to this study. 
 
9.0 
OTHER THERAPY 
 
Not applicable to this study. 
 

Page | 18  
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
 
Not applicable to this study. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters: See Appendix I. 
11.2 
Neurocognitive Evaluation 
11.2.1 
Summary of Required Neurocognitive Tests for All Patients 
 
The tests will be used to assess neurocognitive function.  These tests are to be 
administered by a certified examiner (a health care professional such as a physician, 
nurse or data manager certified to administer the tests)Certification from other 
RTOG/ECOG studies is acceptable,  
 
11.2.2.1 
Hopkins Verbal Learning Test (HVLT-R) 
The 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 version 
used in RTOG 0933 involves memorizing a list of 12 targets for 3 consecutive trials 
(immediate recall), identifying the 12 targets from a list of semantically related or 
unrelated items (immediate recognition), and recalling the 12 targets after a 20-
minute delay (delayed recall). Raw scores are derived for total recall, delayed recall, 
retention (percentage retained), and a recognition discrimination index.  Each 
patient will serve as his/her own control, as the difference in scores obtained at 
baseline and at pre-specified post-treatment intervals will be calculated.  
11.2.2.2 
Trail Making Test (TMT) 
This is a measure of visuospatial scanning, attention, sequencing, and speed Part A 
and executive function in Part B. Patients must “connect the dots” either in a 
numbered sequence or alternating letters and numbers. Generally Part A and Part B 
require less than 5 minutes, and Part A is discontinued at 3 minutes, Part B at 5 
minutes, to reduce burden on patients with significant cognitive impairment. 
11.2.2.3 
Controlled Word Association Test (COWAT) 
The patient produces as many words as possible in 1 min. (each) for a specific letter 
(C, F, L or P, R, W). Requires about 5 min to complete. Assesses language and 
executive/frontal skills. 
11.2.2.4 
Mini-Mental Status Examination (MMSE) 
This is a brief, standardized tool to grade patients’ global cognitive function.61 The MMSE begins 
with an assessment of orientation to place and time. Next is a test of memory 
(immediate recall) by having the subject immediately repeat the names of 3 objects 
presented orally. Following this the patient subtracts sevens serially from 100. The 
subject is then asked to recall the three items previously repeated (delayed recall). The 
final section evaluates aphasia and apraxia by testing naming, repetition, compliance 
with a 3-step command, comprehension of written words, writing, and copying a 
drawing. The maximum score that can be obtained for the entire MMSE is 30 points. 
There is no specific training to perform MMSE as the questions and conduct are 
straightforward and this is not a validated metric like the others. 
 
 
11.3 
Fatigue Evaluation  
Fatigue will be assessed using the Multidimensional Fatigue Inventory (MFI-20). 
11.3.1 
Summary of Required Fatigue Evaluations For All Patients 
11.3.1.1 
Multidimensional Fatigue Inventory (MFI-20) 
The MFI-20 is a multidimensional, self-report instrument designed to measure 
fatigue. It covers the following dimensions: General Fatigue, Physical Fatigue, 
Mental Fatigue, Reduced Motivation and Reduced Activity. A subscore from 4 to 
20 is reported for each dimension, with 20 corresponding to maximal fatigue. 
 

Page | 19  
 
11.4 
Quality of Life Assessments 
11.4.1 
Summary of Quality of Life Assessments 
 
      11.4.1.1    
FACT-BR (Appendix VI) 
The FACT-BR is a multidimensional, self-report QOL instrument specifically 
designed and validated for use with brain malignancy patients. It is written at the 
4th grade reading level and can be completed in 5-10 minutes with little or no 
assistance in patients who are not neurologically incapacitated. It measures 
quality of life related to symptoms or problems across 5 scales: physical well-
being (7 items); social/family well-being (7 items); emotional well-being (6 
items); functional well-being (7 items); and concerns relevant to patients with 
brain tumors (23 items). Items are rated on a five-point scale: 0-“not at all”, 1- 
“a little bit”, 2-“somewhat”, 3- “quite a bit” and 4-“very much”. FACT-BR is 
self-administered and does not require precertification. It has been translated 
into 26 languages and is available free of charge to institutions with the 
completion of an agreement. Form is available in English and Spanish.  
 
     11.4.1.2 
EQ-5D (Appendix VII) 
The EQ-5D health related quality of life questionnaire will be used as well.  EQ-
5D is a standardized instrument for use as a measure of health outcome. 
Applicable to a wide range of health conditions and treatments, it provides a 
simple descriptive profile and a single index value for health status. .  The US 
version of the EQ-5D will be used, to enable mapping of general HR-QoL 
scores from EQ-5D scores into health state utility scores (ranging from 0 to 1) 
for the US population.  These utility scores are needed for cost-utility analysis 
(estimates of costs per “quality adjusted” life-year gained). Form is available in 
English and Spanish.  This form can be completed in less than 5 minutes and is a 
two page questionnaire.  
 
         
11.5 
Administration of Neurocognitive, Fatigue, and Quality of Life Assessments 
11.5.1 
Timing 
11.5.1.1 
Prior to initiation of treatment, all patients will undergo baseline neurocognitive, 
fatigue, and quality of life testing using this test battery.  At that time, history regarding level 
of education reached will also be obtained.  After completion of radiotherapy, all patients will 
undergo neurocognitive and fatigue evaluation at 3, 6, 9, 12, and 24 months after WBRT-
HA/SIB. 
11.5.1.2 
Examiners will give patients a short break if the patient appears fatigued or 
otherwise in need of a few-minutes break. 
 
 
11.6 
Measurement of Response 
Patients will undergo brain MRI prior to study entry (the MRI obtained for hippocampal 
contouring can be used for this purpose) and every 3 months until death or until 2 years 
after WBRT-HA/SIB, whichever comes first. 
11.6.1 
Criteria for CNS Progression 
11.6.1.1 
Assessment 
The the bidimensional product for each of the 1-3 largest brain metastases identified 
at baseline will be recorded.  The bidimensional product is defined as the largest 
dimension multiplied by the second largest dimension that is perpendicular to it (the 
largest dimension).  This value will be recorded on the baseline form and every 
subsequent follow-up form.  The appearance (yes/no and number) of any new brain 
metastases within the whole brain minus the hipposcampal region will be recorded 
on all follow-up forms.  The appearance (yes/no and number) of any new brain 
metastases within the hippocampal avoidance region (the hippocampus plus 5 mm) 
will be recorded on all follow-up forms. 
 
Recurrences will be categorized as either within the hippocampal avoidance region 
or elsewhere within the brain. Therefore, there will be 3 kinds of local recurrences 

Page | 20  
 
reported: a) in the brain, b) in the hippocampal avoidance region, and c) elsewhere 
in the brain. 
11.6.1.2 
Definition of CNS Progression 
CNS progression will be defined as a defined increase (see below) in perpendicular 
bidimensional tumor area for any of the tracked brain metastases, or the appearance 
of any new brain metastasis on a follow-up MRI.   
 
For lesions < 1cm in maximum diameter, a minimum increase of 50% of 
perpendicular bi-dimensional treatment area will be necessary to score as 
progression.  This caveat is included to account for potential variability in 
measurement, which will be most susceptible to proportionate errors at smaller 
sizes. 
 
For lesions > 1cm in maximum diameter, the definition will use a 25% rule for 
change. 
 
11.7 
Criteria for Discontinuation of Protocol Treatment 
11.7.1 
Unacceptable adverse event to the patient (at the discretion of the treating physician)—
Reasons for removal must be clearly documented on the appropriate case report 
form/flowsheet. 
11.7.2 
Interruption of treatment of >3 days 
 
 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol but the patient will be considered inevaluable. 
 

Page | 21  
 
12.0 
DATA COLLECTION 
 
 
Summary of Data Submission 
 
 
 
Item 
Due 
Demographic Form 
Within 2 weeks of registration 
Initial Evaluation Form 
 
Mini-Mental Status Exam 
 
Neurocognitive 
Evaluation 
Summary 
Form 
(HVLT-R, TMT, COWAT) 
Before the first treatment 
Fatigue Evaluation Summary, FACT-BR, EQ-5D 
 
 
 
Follow-up Forms 
3, 6, 9, 12, and 24 months after radiotherapy 
is completed 
Mini-Mental Status Exam 
 
Neurocognitive 
Evaluation 
Summary 
Form 
(HVLT-R, TMT, COWAT) 
 
Fatigue Evaluation Summary 
 
Quality if life Assessments (FACT-BR, EQ-5D) 
As above 
Progression MRI Scan & Report 
Within 1 week of scan date 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Endpoints 
13.1.1 
Primary Endpoint 
Delayed recall, 3 months from the start of treatment as measured by the Hopkins 
Verbal Learning Test-Revised for delayed recall (HVLT-R delayed recall)  
13.1.2 
Secondary Endpoint 
13.1.2.1 
Cognitive function includes the HVLT-R for free recall, and delayed recognition; the 
Controlled Word Association Test (COWAT); the Trail Making Test Parts A and B 
(TMT); the Medical Outcomes Scale-Cognitive Functioning Subscale (MOS); the 
Mini-Mental Status Examination (MMSE) after WBRT-HA/SIB for brain metastasis 
13.1.2.2 
Fatigue as measured by the Multidimensional Fatigue Inventory (MFI-20) 
13.1.2.3 
Time to radiographic progression 
13.1.2.3 
Overall survival 
13.1.2.5 
Adverse events based on CTCAE criteria 
 
13.2 Sample Size  
The primary endpoint will be delayed recall, as measured by the relative (percent) change 
in HVLT-R delayed recall score from the start of treatment to 3 months after the start of 
treatment. 
 
The sample size calculation will address the specific primary hypothesis that WBRT-
HA/SIB reduces decline in delayed recall (from baseline to 3 months). We do not expect 
improvement in delayed recall; at best, we anticipate a preservation of delayed recall. 
Data from a randomized trial showed that the decline in HVLT-R delayed recall score 
was 64% at 4 months for those getting whole brain radiation for brain metastases (Chang 
et al., 2009). We anticipate that WBRT-HA/SIB will have better delayed recall 
functioning at 3 months than WBRT alone. Detecting a 30% average relative loss due to 
WBRT-HA/SIB suggests a 50% relative improvement over previous results. The null and 
alterative hypotheses are:  
 
H0: ΔHVLT-R = 0.60 vs. HA: ΔHVLT-R ≤  0.30  

Page | 22  
 
 
 
ΔHVLT-R is the mean of relative decline between baseline and 3 month after treatment 
in this patient population. For patient individual i, the relative decline is calculated as 
follows: ΔHVLT-Ri =( HVLT-Ri0 – HVLT-Ri3 ) / HVLT-Ri0 , where HVLT-R i0 and 
HVLT-R i3  denote individual patient scores at baseline and 3 months after treatment, 
respectively.  
 
                          Initial sample size calculation: 
Based on the one-sided one sample t-test, assuming a standard deviation of 41%, 
with alpha=0.05 (one-sided), a total of 9 analyzable patients would ensure 80% 
statistical power to detect a 30% average relative loss in delayed recall at 3 
months. Assuming a death rate of 60% prior to 3 months and a 10% in-evaluable 
rate, the target sample size will be 34 registered patients. 
 
Sample size re-estimation based on internal pilot study: 
The internal pilot consists of 32 patients enrolled at baseline, among which 9 
patients have complete information on HVLT-R delayed recall score at the start 
of treatment and 3 months after the start of treatment.  For the 9 patients, the 
mean and standard error of relative (percent) change (decline) in HVLT-R 
delayed recall score is 31% and 51%. We re-estimate the required sample size 
using the updated standard error. 
 
Based on the one-sided one sample t-test, assuming a standard deviation of 51%, 
with alpha=0.05 (one-sided), a total of 18 analyzable patients would ensure 80% 
statistical power to detect a 30% average relative loss in delayed recall at 3 
months. Assuming a death rate of 60% prior to 3 months and a 10% in-evaluable 
rate, the target sample size will be 50 registered patients. Therefore, additional 18 
patients need to be recruited at the second stage. 
 
13.3 
Analysis Plan 
13.3.1  
Primary Endpoint 
The primary endpoint is delayed recall, as determined by the relative change in HVLT-
R delayed recall score from the start of treatment to 3 months after the start of 
treatment.  To test the null hypothesis H0, the primary endpoint will be analyzed using 
the one-sided one sample t-Test with a significance level of 0.05.  
 
 
 
13.3.2 
Secondary Endpoints 
13.3.2.1 
Cognitive Function and Fatigue 
All the secondary cognitive and fatigue endpoints will by analyzed similar to the 
primary endpoint.  Additionally, the relationship between the change from baseline 
through 12 months in cognitive and fatigue endpoints will be evaluated using 
Spearman correlation coefficients. 
13.3.2.2 
MFI 
Change in MFI domain scores from baseline to each post-baseline assessment point 
will be analyzed using mixed models for repeated measures. 
13.3.2.3 
Radiographic Progression  
The Kaplan-Meier estimator will be used to determine the median time to 
radiographic progression for this patient population (along with 95% confidence 
intervals). The Cox proportional hazards regression model will be used to evaluate 
the effects of covariates of interest on time to radiographic progression. 
 
Overall Survival   

Page | 23  
 
The Kaplan-Meier estimator will be used to determine the median time to death for 
this patient population (along with 95% confidence intervals). The Cox proportional 
hazards model will be used to evaluate the effects of covariates of interest on 
survival.  
13.3.2.5          Adverse Events   
 
Adverse events will be reported according the CTCAE criteria. 
 
13.0 
DATA SAFETY MONITORING PLAN 
13.1 Purpose and Scope 
13.1.1 
The purpose of the Radiation Oncology Data and Safety Monitoring Plan is to ensure that 
clinical trial data is accurate and valid and to ensure the safety of trial participants.   
13.1.2  
The Radiation Oncology DSMC is charged with developing, implementing, and 
maintaining the Data and Safety Monitoring Plan. The membership consists of a Medical 
Director of Clinical Research as well as representation from the following groups:  
clinical research, nursing, regulatory, pharmacy, physicists, radiation therapists, and 
faculty. Ad hoc members are contacted to participate as needed 
13.2 Procedures 
13.2.1 
Clinical trials are assessed for safety on a continual basis throughout the life of the trial.  
All SAE’s and any AEs that are unexpected and possibly/likely related to study 
participation are reported to UTSW IRB through an electronic research system per 
UTSW IRB guidelines.   
All clinical trials are reviewed on monthly basis for enrollment.  All local SAEs are reviewed by 
Radiation Oncology DSMC monthly for severity and attribution. For investigator-initiated trials, 
all SAEs at affiliated institutions are monitored as local SAEs.  The principle investigator and 
study coordinator will present a study treatment summary and SAEs for review.  Source 
documents will be available for the DSMC members during the review. NCI Common Toxicity 
Criteria Version 4 will be used for grading and attributing adverse events.   
 
If the SAE occurs on a multi-institutional clinical trial coordinated by the Radiation Oncology 
Clinical Research Office, the Clinical Research Manager or primary coordinator ensures that all 
participating sites are notified of the event and resulting action, within one (1) working day of the 
determination. 
 
 

Page | 24  
 
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Lee PW, Hung BK, Woo EK, et al. Effects of radiation therapy on 
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Li J, Bentzen SM, Renschler M, et al. Regression after whole-brain radiation 
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Li J, Bentzen SM, Renschler M, et al. Relationship between neurocognitive function 
and quality of life after whole-brain radiotherapy in patients with brain metastasis. 
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Madsen TM, Kristjansen PE, Bolwig TG, et al. Arrested neuronal proliferation and 
impaired hippocampal function following fractionated brain irradiation in the adult 
rat. Neuroscience 2003;119:635-642. 
 
Mahajan A, Dong L, Prabhu S, et al. Application of deformable image registration 
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Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a 
randomized trial of motexafin gadolinium and whole-brain radiation therapy in 
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Mehta MP, Shapiro WR, Glantz MJ, et al. Lead-in phase to randomized trial of 
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Page | 29  
 
APPENDIX I: 
STUDY 
PARAMETER 
TABLE 
Pre-Treatment 
 
Follow-Up 
 
Within 5 yrs 
prior to 
registration 
Within 28 
days prior to 
registration 
Within 2 wks 
prior to 
registration 
Before 1st  
treatment 
3 mos after 
RT 
4-6 mos after 
RT 
9 mos after 
RT 
12 mos 
after RT 
24 mos after RT 
Histo/cyto eval 
X 
 
History/physical 
X 
 
X 
X 
X 
X 
X 
Performance 
status 
X 
 
X 
X 
X 
X 
X 
Serum creatinine 
X 
 
Serum pregnancy 
test (if applicable) 
X 
 
Adverse event 
eval 
 
X 
X 
X 
X 
X 
MRI with 
contrast and 
assessment 
X 
 
 
 
X 
X 
X 
X 
X 
Head CT 
simulation scan 
 
X 
HA/SIB-WBRT 
treatment 
planning 
 
 
X 
Neurocognitive 
assessment 
 
X 
X 
X 
X 
X 
X 
Fatigue 
assessment 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Quality of Life 
Assessments 
 
X 
X 
X 
X 
X 
X 

 
 
 
 
 
Appendix II: 
Follow-up Radiographic Assessment 
 
  
 
 
 
 
Date of MRI: 
 
Patient Name: 
 
 
 
Treated metastases 
Lesion 
Number 
Side 
(L,R,ML) & 
Location 
 
dAP (cm) 
(Ant-
Pos) 
dML (cm) 
(Med-
Lat) 
dSI (cm) 
(Sup-
Inf) 
Bidimensional 
product1 
First set of treated metastases 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
1 Bidimensional product = largest dimension x second-largest dimension 
 
New Brain Metastases outside the hippocampus? (yes/no)  
 
Number 
 
New Brain Metastases within the hippocampus? (yes/no) 
 
Number 

 
 
 
 
 
Appendix III: 
Neurocognitive Function Assessments 
Background Information and Test Instructions 
 
There are three immediate recall responses, one delayed recall response, and one delayed recognition 
response in the HVLT-R. The response is the number of words the patient can recall out of 12 words for 
recall responses and the difference of the listed words correctly and incorrectly recalled for recognition 
response. The response from Trail Making Test, parts A & B is the time takes to finish each test less than 3 
and 5 minutes, respectively. There are three responses for the COWAT, and each response is the number of 
words starting with a provided letter of the alphabet that the patient can produce in one minute. 
 
Testing: General Information 
 
1. Testing should be completed in one session. Test instructions must be followed verbatim with 
every patient at every assessment visit. 
2. Tests should be administered in the following order to every patient and at each assessment visit: 
HVLTR Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWAT; 
HVLT-R Part B (Delayed Recall); and the HVLT-R Part C (Delayed Recognition). 
3. Follow the instructions on the Forms Packet Index before submitting the forms. 
4. All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is 
found in the Forms Packet. Study/case-specific labels must be applied to all forms. 
5. Note: Sites should keep all original test records, and test results must remain on file at the 
institution as source documentation pending request for submission by a Study Chair.  
6. Patients should not be given copies of their tests to avoid learning the material between test 
administrations. 
7. The HVLT-R and the COWAT have alternate forms or versions in order to reduce the effects of 
practice. See the test instructions below for the versions to be administered at pre-treatment and 
subsequent sessions. The forms should continue to be alternated in this order for the duration of 
the study. The forms packet will contain alternate versions of these neuropsychological tests. 
 
Before dismissing the patient, thank him/her for their cooperation. Remind the patient of their next 
appointment and that these tests will be repeated. 
 
In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the 
data summary form. 
 
Testing: Specific Instructions 
Note: Administer the tests in the following order to every patient at each assessment visit. 
 
1. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
 
This test has three parts and six alternate forms (only the first 4 forms will be used in this study): 
Part A - Free Recall: Complete the three learning trials first 
Part B - Delayed Recall: Complete after Trail Making Tests and COWAT 
Part C - Delayed Recognition: Complete after Delayed Recall 
 
Part A – Free Recall: Trial 1 
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, I’d 
like you to tell me as many of the words as you can remember. You can tell them to me in any order. Are 
you ready?” 
• Read the words at the rate of one word every 2 seconds. 
 
Examiner: “OK. Now tell me as many of those words as you can remember.” 

 
 
 
 
 
• Check off the words the patient recalls on the form. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list. 
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any 
more words. 
• If not, move on to trial 2. Later, you can record the number of words that were correctly repeated on the 
summary form. 
 
Part A – Free Recall: Trial 2 
Examiner: “Now we are going to try it again. I am going to read the same list of words to you. Listen 
carefully, and tell me as many of the words as you can remember, in any order, including the words you 
told me the first time.” 
• Read the words at the rate of one word every 2 seconds. 
• Check off the words the patient recalls on the form. 
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say 
nothing to the patient about the word not being on the list. 
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any 
more words. 
• If not, move on to trial 3. Later, you can record the number of words that were correctly repeated on the 
summary form. 
 
Part A – Free Recall: Trial 3 
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of the 
words as you can remember, in any order, including all the words you’ve already told me.” 
• Read the words at the rate of one word every 2 seconds. 
• Check off the words the patient recalls on the form. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list. 
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any 
more words. 
• Do not tell the respondent that recall of the words will be tested later. 
• Record the time on the clock that you complete ‘Part A – Free Recall’ (for example, 1:00 p.m.) on the 
designated space on the HVLT-R form. 
 
2. TRAIL MAKING TEST [Timed Test] 
 
Part A – Sample: Place the Sample A worksheet flat on the table, directly in front of the patient (the 
bottom of the worksheet should be approximately six inches from the edge of the table). Give the patient a 
black pen and say: 
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line 
from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the 
end (point to the circle marked END). Draw the lines as fast as you can. Ready, begin.” 
 
If the patient completes Sample A correctly, and in a manner demonstrating that s/he understands what to 
do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and 
explain it. 
The following explanations of mistakes serve as illustrations: 
• This is where you start (point to number 1). 
• You skipped this circle (point to the circle omitted). 
• You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END. 
 
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind 
the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample A, take 

 
 
 
 
 
his/her hand and guide him/her through the trail using the opposite end of the pen, lightly touching the 
worksheet to avoid making marks on he copy. Then say: 
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3 
(point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do 
not skip around, but go from one number to the next in proper order. Remember to work as fast as you 
can. Ready, begin.” 
 
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A 
correctly and appears to understand what to do, proceed immediately to Part A. 
 
Part A – Test: After the patient has completed Sample A, place the Part A test worksheet directly in front 
of the patient and say: 
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same way. 
Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4) 
and so on, in order, until you reach the circle marked END (point). Do not skip around, but go from one 
number to the next in proper order. Remember to work as fast as you can. Ready, begin.” 
• Start timing as soon as the instruction is given to “begin” 
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to 
his/her attention immediately and have him/her proceed from the point the mistake occurred 
• The patient must complete the test in 3 minutes or less. 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”. 
• Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and 
seconds 
• If the patient does not complete the test within 3 minutes terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet 
and complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct 
number reached on the test. 
 
Part B – Sample: Place the Sample B worksheet flat on the table, directly in front of the patient (the 
bottom of the worksheet should be approximately six inches from the edge of the table) and say: 
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point to 1) and 
draw a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point 
to C) and so on, in order, until you reach the end (point to the circle marked END). Remember, first 
you have a number (point to 1), then a letter (point to A), then a number (point to 2), then a letter (point 
to B), and so on. Draw the lines as fast as you can. Ready, begin.” 
 
If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what to 
do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and 
explain it. 
The following explanations of mistakes serve as illustrations: 
• You started with the wrong circle. This is where you start (point to number 1) 
• You skipped this circle (point to the circle omitted) 
• You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point 
to 3) and so on, until you reach the circle marked END (point). 
 
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the 
patient, however, to be sure to touch the circles. If the patient still cannot complete Sample B, take their 
hand and guide them through the trail using the opposite end of the pen, lightly touching the worksheet to 
avoid making marks on the copy. Then say: 
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 to A 
(point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in order, until you 
reach the circle marked END (point). Ready, begin.” 
 

 
 
 
 
 
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A 
correctly and appears to understand what to do, proceed immediately to Part A. 
 
Part B – Test: 
After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and 
say: 
Examiner: “Good! Let’s try the next one. On this page are both numbers and letters. Do this the same 
way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 (point to 2), 2 to B 
(point to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, until you reach the circle marked 
END (point). Remember, first you have a number (point to 1), then a letter (point to A), then a number 
(point to 2), then a letter (point to B), and so on. Do not skip around, but go from one circle to the next 
in the proper order. Draw the lines as fast as you can. Ready, begin.” 
• Start timing as soon as the instruction is given to “begin”. 
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it 
to his/her attention immediately and have him/her proceed from the point the mistake occurred 
• The patient must complete the test in 5 minutes or less. 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”. 
• Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and 
seconds. 
• If the patient does not complete the test within 5 minutes terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet and 
complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct number 
or letter reached on the test. 
 
3. CONTROLLED ORAL WORD ASSOCIATION TEST (COWAT) [Timed Test] 
 
This test has three parts (letters) and two alternate forms. 
 
Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can all of 
the words that you can think of that begin with that letter. You may say any words at all, except proper 
names such as the names of people or places. So you would not say ‘Rochester’ or ‘Robert’. Also, do not 
use the same word again with a different ending, such as ‘Eat,’ ‘Eats,’ and ‘Eating.’ 
 
“For example, if I say ‘s,’ you could say ‘sit,’ ‘shoe,’ or ‘show.’ Can you think of other words beginning 
with the letter ‘s’?” 
 
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word 
beginning with the letter “s”. If a second appropriate word is given, proceed to the test itself. 
 
If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the instructions. 
If the patient then succeeds, proceed to the test. 
 
If the patient fails to respond, repeat the instructions. If it becomes clear that the patient does not 
understand the instructions or cannot associate, stop the procedure, and indicate the reason(s) on the scoring 
sheet. 
 
If the patient has succeeded in giving two appropriate words beginning with the demonstration letter, say: 
 
Examiner: “That is fine. Now I am going to give you another letter. Again, say all of the words 
beginning with that letter that you can think of. Remember, no names of people or places, just ordinary 
words. Also, if you should draw a blank, I want you to keep on trying until the time limit is up and I say 
STOP.” 
 

 
 
 
 
 
“You will have a minute for each letter. The first letter is ‘___’” (see scoring sheet). 
 
**Allow exactly one minute for each letter.** 
• If the patient discontinues before the end of the time period, encourage him/her to try to think of more 
words. 
• If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the words 
you can think of that begin with a “c”). 
• No extension on the time limit is made in the event that instructions are repeated. 
• Continue the evaluation with the remaining two letters, allowing one minute for each. 
 
Recording and Scoring: 
• The record sheet provides lines on which the patient’s responses can be entered (e.g., write in the word 
that is said by the patient). If his/her speed of word production is too fast to permit verbatim recording, a 
“+” should be entered to indicate a correct response. 
• Incorrect responses either should not be recorded or, if recorded, should be struck through with a line. 
• If the patient provides more responses than there are lines on the record sheet, keep writing the responses 
(or a “+”) elsewhere on the record sheet. 
• Count all the correct responses. The number of correct words should be indicated below each column 
on the recording sheet and on the summary data form. 
 
Comments on scoring: 
• Note: It can be helpful for the first several patients and for patients known to be fast with their word 
production to tape record the session for transcription at a later time. 
• The instructions include a specific prohibition against giving proper names or different forms of the same 
word. Therefore, inflections of the same word (e.g., eat-eating; mouse-mice; loose-loosely; ran-run-runs) 
are not considered correct responses. 
• Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-funny; 
sadsadness). These are not considered correct responses. On the other hand, if the word refers to a specific 
object (e.g., foot-footstool; hang-hanger), it would be counted as a correct answer. 
• Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the word is 
acceptable IF the patient definitely indicates the alternative meaning to you. 
• Slang terms are OK if they are in general use. 
• Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be considered 
part of English vocabulary (for example, in general use or found in the dictionary). 
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the 
reason on the Tests Discontinued/Not Done CRF 
 
4. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
 
Part B – Delayed Recall 
• DO NOT READ THE WORD LIST AGAIN. 
• Record the time on the clock that you start ‘Part B – Delayed Recall’ (for example, 1:20 p.m.) on the 
designated space on the HVLT-R form. 
• Administer ‘Part B – Delayed Recall’ after completing all Trail Making Tests and the COWAT. There 
should be at least 15 minutes between ‘Part A’ and ‘Part B’. If the time is too short, allow the patients to 
complete a questionnaire. 
 
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those 
words as you can remember.” 
• Check the box on the corresponding line of the HVLT-R worksheet for each word the patient accurately 
recalls. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list. 

 
 
 
 
 
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any 
more words. 
• If not, record the number of words that were correctly recalled on the summary form. 
 
Part C – Delayed Recognition 
Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the 
original list, and some are not. After I read each word, I’d like you to say “Yes” if it was on the original 
list or “No” if it was not. Was [word] on the list?” 
• Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response. 
• Guessing is allowed. 
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the 
reason on the Tests Discontinued/Not Done CRF. 
The score for this portion of the HVLT-R is the number of list words (i.e., words that in CAPS) correctly 
identified (“yes” response) minus the number of non-list words (i.e., words in lower case) incorrectly 
identified (“yes” response). Therefore, the actual score can range from –12 (no list words identified and all 
non-list words identified) to +12 (all list words identified and no non-list words identified). 
 

 
 
 
 
 
APPENDIX IV: 
Performance Status Scoring 
 
ZUBROD PERFORMANCE SCALE 
0 
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90-100). 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work (Karnofsky 70-80). 
 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours 
(Karnofsky 50-60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours (Karnofsky 30-40). 
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed 
or (Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 

 
 
 
 
 
APPENDIX V 
 
RTOG RPA Classification System 
 
 
Class I:  
KPS ≥ 70 (Zubrod 0-1);  
Age < 65 years;  
No extra-cranial metastases; and  
Controlled primary malignancy* 
 
 
Class II:  
KPS ≥ 70  
Age ≥ 65;  
Extra-cranial metastases  
Controlled primary malignancy  
 
 
Class III:  
KPS < 70 
 
 
 
*Controlled primary malignancy is defined clinically, radiographically, and/or serologically, as 
appropriate for the underlying malignancy during the previous 3 months or longer). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
APPENDIX VI  
FACT-BR (VERSION 4) – form is available in English and Spanish 
 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 

 
 
 
 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad .............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...........................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) .........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .....................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
 
 
GS7 
I am satisfied with my sex life .............................................
0 
1 
2 
3 
4 

 
 
 
 
 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
Br1 
I am able to concentrate ......................................................
0 
1 
2 
3 
4 
Br2 
I have had seizures (convulsions) .......................................
0 
1 
2 
3 
4 
Br3 
I can remember new things ................................................
0 
1 
2 
3 
4 
Br4 
I get frustrated that I cannot do things I used to .................
0 
1 
2 
3 
4 
Br5 
I am afraid of having a seizure (convulsion) ......................
0 
1 
2 
3 
4 
Br6 
I have trouble with my eyesight .........................................
0 
1 
2 
3 
4 
Br7 
I feel independent ...............................................................
0 
1 
2 
3 
4 
NTX6 
I have trouble hearing .........................................................
0 
1 
2 
3 
4 
Br8 
I am able to find the right word(s) to say what I mean.......
0 
1 
2 
3 
4 
Br9 
I have difficulty expressing my thoughts ........................... 
0 
1 
2 
3 
4 
Br10 
I am bothered by the change in my personality ..................
0 
1 
2 
3 
4 
Br11 
I am able to make decisions and take responsibility .......... 
0 
1 
2 
3 
4 
Br12 
I am bothered by the drop in my contribution to the 
family .................................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
Br13 
I am able to put my thoughts together ................................
0 
1 
2 
3 
4 
Br14 
I need help in caring for myself (bathing, dressing, 
eating, etc.) ......................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Br15 
I am able to put my thoughts into action ............................
0 
1 
2 
3 
4 
Br16 
I am able to read like I used to ...........................................
0 
1 
2 
3 
4 
Br17 
I am able to write like I used to ..........................................
0 
1 
2 
3 
4 
Br18 
I am able to drive a vehicle (my car, truck, etc.) ................
0 
1 
2 
3 
4 
Br19 
I have trouble feeling sensations in my arms, hands, or 
legs ......................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 

 
 
 
 
 
Br20 
I have weakness in my arms or legs ...................................
0 
1 
2 
3 
4 
Br21 
I have trouble with coordination ........................................
0 
1 
2 
3 
4 
An10 
I get headaches ................................................................... 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
APPENDIX VII – EQ-5D – form is available in English and Spanish 
Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 

I have slight problems walking  
 
 
 
 
I have moderate problems walking 
  
 
 
 
I have severe problems walking 
  
 
 
 
I am unable to walk 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 

I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself   
 
I am unable to wash or dress myself   
 
 

 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 

I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
I am moderately anxious or depressed  
 
 

I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 

 
 
 
 
 
 
 We would like to know how good or bad your health is  
TODAY. 
 This scale is numbered from 0 to 100. 
 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 Mark an X on the scale to indicate how your health is TODAY. 
 Now, please write the number you marked on the scale in the box 
below.  
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
 
 
 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health      
 you can imagine 
The worst health    
 you can imagine