notification of full committee approval · university of virginia hospital, ... the only exception...

Human Research Protection Program Committee on Human Research

Notification of Full Committee Approval

Principal Investigator Igor J Barani, MD Type of Submission: Initial Review Submission Packet Study Title: RANDOMIZED CONTROLLED STUDY OF NEUROCOGNITIVE OUTCOMES IN

PATIENTS WITH FIVE OR MORE BRAIN METASTASES TREATED WITH RADIOSURGERY OR WHOLE-BRAIN RADIOTHERAPY-CC121010/NAGKC12-01

IRB #: 12-09475 Reference #: 054620 Reviewing Committee: Mount Zion Panel Study Risk Assignment: Greater than minimal Approval Date: 12/21/2012 Expiration Date: 12/20/2013 Regulatory Determinations Pertaining to This Approval (if applicable): Individual HIPAA authorization is required of all subjects. A waiver of HIPAA Authorization is acceptable for the recruitment procedures to identify potential subjects. The recruitment procedures involve routine review of medical or other records, do not adversely affect the rights and welfare of the individuals, and pose minimal risk to their privacy, based on, at least, the presence of the following elements:(1) an adequate plan to protect the identifiers from improper use and disclosure; (2) an adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the research, or a health or research justification for retaining the identifiers was provided or such retention is otherwise required by law;(3) adequate written assurances that the requested information will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of the requested information would be permitted by the Privacy Rule; (4) the research could not practicably be conducted without the waiver; and (5) the research could not practicably be conducted without access to and use of the requested information. IRB Comments (if applicable): 1. Please submit copies of the IRB approval letters from the collaborating sites (University of Pittsburgh, University of Virginia Hospital, University of Manitoba, New York University, Yale University, and the University of Pennsylvania) when received to the CHR for acknowledgement. The letters can be submitted to the CHR as an administrative modification.

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A RANDOMIZED CONTROLLED STUDY OF NEUROCOGNITIVE OUTCOMES IN PATIENTSWITH FIVE OR MORE BRAIN METASTASES TREATED WITH RADIOSURGERY OR

WHOLE-BRAIN RADIOTHERAPY (CC121010/NAGKC 12-01)1

Principal Investigator:

Igor J. Barani, M.D.Assistant ProfessorDepartment of Radiation OncologyUniversity of California, San Francisco505 Parnassus Ave., Room L-08, Box 0226San Francisco, CA 94143-0226Tel: 415-353-1195 Fax: 415-680-2440Email: [email protected]

Co-Investigators:

David Larson, M.D., Ph.D.ProfessorDept. of Radiation OncologyUniversity of California, San FranciscoTel: 415-353-8950Email: [email protected]

Washington Hospital Gamma Knife Center2500 Mowry Avenue, Fremont, CA 94538-1716Phone: (510) 745-6480

Michael W. McDermott, M.D.ProfessorDept. of Neurological SurgeryUniversity of California, San FranciscoTel: 415-353-2243Email: [email protected]

Gelareh Zadeh, M.D., Ph.D.Assistant ProfessorDepartment of SurgeryUniversity of TorontoTel: 461-603-5679Email: [email protected]

Veronica Chiang, M.D.Associate ProfessorDepartment of NeurosurgeryYale School of MedicineTel: 203-785-2808Email: [email protected]

Caroline Racine, Ph.D.Study NeuropsychologistAssistant Adjunct ProfessorDepts. of Radiation Oncology & NeurosurgeryUniversity of California, San FranciscoTel: 415-353-7130Email: [email protected]

Soonmee Cha, M.D.Study NeuroradiologistProfessorDepts. of Radiology & NeurosurgeryUniversity of California, San FranciscoTel: 415-353-1537Email: [email protected]

Lijun Ma, Ph.D.Study Medical PhysicistProfessorDepartment of Radiation OncologyUniversity of California, San FranciscoTel: 415-353-8932Email: [email protected]

Angelica A. Perez-Andujar, Ph.D.Study Cost-E↵ectiveness Research LeadClinical InstructorDepartment of Radiation OncologyUniversity of California, San FranciscoTel: 415-514-8536Email: [email protected]

Annette Molinaro, M.A., Ph.D.Study BiostatisticianAssociate Adjunct ProfessorDept. of Neurological SurgeryUniversity of California, San FranciscoEmail: [email protected]

Protocol Information:

Revision: 1.2 Date: November 1, 2012

1Disclaimer: This clinical protocol was developed by UCSF investigators for the North American Gamma Knife

Consortium (NAGKC) use only. No other use or reproduction is authorized.

A RANDOMIZED CONTROLLED STUDY OF NEUROCOGNITIVE OUTCOMES IN PATIENTS WITH FIVE OR MORE BRAIN METASTASESTREATED WITH RADIOSURGERY OR WHOLE-BRAIN RADIOTHERAPY (CC121010/NAGKC 12-01)

Contents

List of Abbreviations 5

1 Study Schema 7

2 Objectives 82.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.2 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2.2.1 Primary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.2.3 Exploratory Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3 Background 103.1 Clinical Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.2 Whole-Brain Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.3 Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.4 Neurocognitive Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4 Participant Selection 184.1 Conditions for Patient Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184.2 Conditions for Patient Ineligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194.3 Pre-Treatment Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.3.1 Required Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204.3.2 Recommended Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5 Recruitment Plan 20

6 Registration 216.1 Online Registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

7 Stereotactic Radiosurgery 217.1 It is possible at the time of radiosurgery that one of the following scenarios occurs: . 227.2 Timing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227.3 Localization and immobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227.4 Target volume determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227.5 Critical structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237.6 Dose & prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237.7 Radiosurgical (SRS) technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237.8 Radiosurgery (SRS) treatment planning data . . . . . . . . . . . . . . . . . . . . . . 23

8 Whole-brain Radiation Therapy 248.0.1 Timing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248.0.2 Localization, simulation, immobilization, and target volume . . . . . . . . . . 248.0.3 Critical Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248.0.4 Dose & prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258.0.5 WBRT technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258.0.6 Documentation requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2


8.0.7 Radiation therapy interruptions . . . . . . . . . . . . . . . . . . . . . . . . . . 25

9 Salvage Therapy for Progression within the Brain 259.1 Salvage Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259.2 Salvage Whole-brain Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 269.3 Other Salvage Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

10 Central Dosimetry Review 26

11 Criteria for Response Assessment 2611.1 Response Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

11.1.1 “New” Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

12 Radiation Necrosis 2712.0.2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2712.0.3 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2812.0.4 Recommended Radiation Necrosis Management . . . . . . . . . . . . . . . . . 28

13 Comprehensive Quality Assurance Review 29

14 Radiation Adverse Events 2914.1 Acute, 90 days from treatment start . . . . . . . . . . . . . . . . . . . . . . . . . . 2914.2 Late, >90 days from treatment start . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014.3 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

15 Radiation Adverse Event Reporting 3015.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Requirements 3015.2 NCI Common Terminology Criteria for Adverse Events (CTCAE) . . . . . . . . . . 31

16 Criteria for Removal from Study 31

17 Surgery 31

18 Drug Therapy 31

19 Other Therapy 31

20 Patient Assessments 3420.1 Study Schema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420.2 Assessments Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420.3 Clinical Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420.4 Neurocognitive Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

20.4.1 Online Neurocognitive Function (oNCF) Assessments . . . . . . . . . . . . . 3420.4.2 Quality of Life (QoL) Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . 3620.4.3 Patient “Self-Reported” Measures . . . . . . . . . . . . . . . . . . . . . . . . 3820.4.4 Caregiver Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

20.5 Cost Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3820.6 Anatomic Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 3820.7 OPTIONAL: Perfusion MR Imaging (pMRI) . . . . . . . . . . . . . . . . . . . . . . 38

3


21 Biostatistics 3821.1 Study Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

21.1.1 Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3821.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

21.2 Exploratory Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3921.2.1 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3921.2.2 Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3921.2.3 Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4021.2.4 Surviving Fraction Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

22 Data Safety Monitoring Plan 4222.0.5 Interim Analysis to Monitor Study Progress . . . . . . . . . . . . . . . . . . . 42

22.1 Data and Safety Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4222.2 Data Management Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

22.2.1 Study Manager Contact Information . . . . . . . . . . . . . . . . . . . . . . . 4322.3 Study Principal Investigator Contact Information . . . . . . . . . . . . . . . . . . . . 43

23 Protection of Human Subjects 4323.0.1 Consent Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

24 References 44

A Patient Informed Consent Form 50

B Caregiver Informed Consent Form 62

C Experimental Subject’s Bill of Rights 66

D Karnofsky Performance Status Scale 67

E Radiosurgery Single-Fraction Prescription Guidelines 68

F Target Volume Screening Diagram 69

4


List of Abbreviations

11C-met 11C-methionine.

oNCF online neurocognitive function.

AEs Adverse Events.

BCM20 Brain Cancer Module - 20.

BPT Brain Power TestTM.

CBCT cone-beam CT.

CR Complete Response.

CRF case report form.

CTCAE NCI Common Terminology Criteria for Adverse Events.

CTEP Cancer Therapy Evaluation Program.

CTV Clinical Target Volume.

DS-GPA diagnosis-specific GPA.

DSMC Data and Safety Monitoring Committee.

E-Cog Everyday Cognition.

eGFR Estimated glomerular filtration rate.

EQ-5D EuroQol Group Questionnaire - 5D.

FrSBE Frontal Systems Behavior Scale.

GK Gamma Knife.

IDL isodose line.

IDV isodose volume.

IRB Institutional Review Board.

KPS Karnofsky performance status.

MLC multi-leaf collimator.

MMSE mini-mental status examination.

MR Magnetic Resonance.

NAGKC North American Gamma Knife Consortium.

5


NCF neurocognitive function.

NPI Neuropsychiatric Inventory.

NR No Response.

PD Progressive Disease.

PET positron emission tomography.

PI Principal Investigator.

PR Partial Response.

PTV Planning Target Volume.

QoL quality of life.

QOL-30 EORTC Quality of Life Questionnaire - Core 30.

RCI Reliable Change Index.

RT radiation therapy.

RT-PACS Radiation Therapy - Picture Archiving and Communication System.

RTOG Radiation Therapy Oncology Group.

SAEs Serious Adverse Events.

SEM standard error of measurement.

SF Surviving Fraction.

SRS stereotactic radiosurgery.

UD Untreated Disease.

VAS Visual Analog Scale.

WBRT whole-brain radiation therapy.

WHO PS World Health Organization performance scale.

6


1 Study Schema

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e NC

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ly

(2

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Hom

e Se

tting

•O

ptio

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estin

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ine

NCF

Asse

ssm

ent

Ever

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wee

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e NC

F te

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es

tabl

ish p

re-tr

eatm

ent

func

tion

(two

test

s, 7

day

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art;

20-3

0 m

ins

each

)

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line

NCF

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ssm

ent

≤14

days

prio

r to

SRS

NCF

ASSE

SSM

ENT

SCHE

DULE

Glo

ssar

y:CR

: com

plet

e re

spon

sePR

: par

tial r

espo

nse

NR: n

o re

spon

sePD

: pro

gres

sive

dise

ase

UD: u

ntre

ated

dise

ase

120

Parti

cipan

ts:

•ne

wly-

diag

nose

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ain

met

asta

ses

•≥5

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ns o

n di

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MRI

•≤1

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larg

est t

umor

vol

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5 cc

tota

l tum

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no le

ptom

enin

geal

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ase

•KP

S ≥7

0, u

nles

s du

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ania

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ase

Recr

uit

Pre-

SRS

Eval

uatio

ns:

•O

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e NC

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2•

Clin

ical/n

euro

logi

c ex

am•

Perfo

rman

ce s

tatu

s•

Syst

emic

dise

ase

exte

nt (P

ET/

CT o

r sim

ilar)

•Re

cord

act

ive s

yste

mic

tx•

MRI

Base

line

Eval

uatio

ns

Asse

ss R

espo

nse:

CR PR NR

•Cl

inica

l/neu

rolo

gic

exam

•Pe

rform

ance

sta

tus

•Sy

stem

ic di

seas

e ex

tent

•Re

cord

act

ive s

yste

mic

tx•

MRI

PD UD

Resp

onse

Ass

essm

ent

Post

-SRS

Eva

luat

ions

:•

Clin

ical/n

euro

logi

c ex

am•

Perfo

rman

ce s

tatu

s•

Syst

emic

dise

ase

exte

nt (P

ET/

CT o

r sim

ilar)

•Re

cord

act

ive s

yste

mic

tx•

MRI

Clin

ical

Fol

low

-up

Choi

ce o

f Sal

vage

The

rapy

:•

SRS

or•

Who

le-b

rain

RT

(WBR

T)•

Best

sup

porti

ve c

are

(ste

roid

s)

Mng

mt.

at th

e di

scre

tion

of p

hysic

ian

Salv

age

Ther

apy

Ever

y 10

-12

wee

ksEv

ery

10-1

2 w

eeks

Toxi

city

Ass

essm

ent

If su

spec

ted

radi

onec

rosis

:•

Clin

ical/n

euro

logi

c ex

am•

Perfo

rman

ce s

tatu

s•

Perfu

sion

MRI

(if a

vaila

ble)

Radi

onec

rosis

man

agem

ent o

ptio

ns:

•G

luco

corti

coid

s•

Surg

ical r

esec

tion

•Pe

ntox

ifillin

e, a

nti-o

xidan

ts•

Hype

rbar

ic ox

ygen

•O

ther

Mng

mt.

at th

e di

scre

tion

of p

hysic

ian

Radi

onec

rosi

s M

ngm

t.

Rand

omiz

e(if

NCF

sc

ore ≥7

0)

Gam

ma

Knife

Per

fexio

n SR

S:•

Dose

(s),

per A

ppen

dix

D

SRS

Who

le-B

rain

RT:

•Do

se: 3

0 G

y/10

dai

ly fra

ctio

ns

Who

le-B

rain

RT

CLIN

ICAL

SCH

EDUL

E

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(2

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/Clin

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10-1

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7


2 Objectives

2.1 Study Design

This is randomized controlled study of neurocognitive outcomes in patients with five or more brainmetastases treated with stereotactic radiosurgery (SRS), specifically the Gamma Knife (GK) system,or whole-brain radiation therapy (WBRT). The goal of the study is to enroll 120 patients with atleast five (�5) newly-diagnosed brain metastases from non-melanoma (except melanoma patientswith BRAF V600E mutation) primary cancers with the largest intracranial tumor volume 10 cc,15 cc total tumor volume, absence of leptomeningeal disease on MRI, and Karnofsky performancestatus (KPS) score �70 (unless due to intracranial disease), and KPS expected to improve to �70with treatment.

All study participants will undergo standard, pre-treatment clinical evaluations that include:complete clinical/neurologic exam, performance status assessment, systemic staging, and diagnos-tic MRI of the brain. The baseline neurocognitive function (NCF) will be assessed by a short(20-30 minute) online test battery that can be completed by patients at home. All study partici-pants will be randomized to receive radiosurgical or whole-brain radiation treatment for their brainmetastases. All patients will have treatment response assessments every 10-12 weeks consistingof a clinical/neurologic exam, performance status evaluation, disease re-staging (if indicated), anddiagnostic MRI of the brain. If progressive disease is identified (radiographic progression of treatedlesions or new brain lesions), the patients will be considered for “salvage” therapy which will pri-marily consiste of SRS, WBRT, surgery±brachytherapy or best supportive care (e.g. steroids only).The preferred salvage therapy will be SRS provided that the re-treatment criteria are met. TheNCF follow-up will start 2 weeks after completion of the initial SRS treatment and will repeat at2-week intervals, irrespective of any salvage therapy that may be indicated. All study participantswill be followed until death or withdrawal from the study.

The primary aim of this study is to compare the change in neurocognitive outcome betweenbaseline and 6 months for surviving patients in upfront WBRT versus SRS treatment groups. Theprimary study endpoint is neurocognitive function as measured by a significant change in onlineneurocognitive function (oNCF) z-score from baseline to 6 months. The outcomes will be comparedafter initial treatment and then repeatedly in follow-up, and will include the impact of salvage SRStreatments. This approach will allow us to assess the relative impact on neurocognitive outcomesof repeat SRS treatments to sites of new brain metastases.

Since SRS and WBRT are two very di↵erent forms of treatment (single high-dose treatmentvs. multiple low-dose treatments) with markedly di↵erent target volumes, it is expected that localcontrol rates will also be markedly di↵erent. This, in turn, will impact salvage therapies andassociated costs. This study will evaluate local control rates and overall intracranial disease controlat 3, 6, 9, and 12 months as a function of initial treatment cohort (SRS vs. WBRT). We also expectsignificant di↵erences between the treatment groups in patient- and caregiver-reported quality oflife (QoL) measures.

It is also expected that the SRS cohort will require multiple SRS treatments over the courseof the study since, unlike WBRT, the treatments target only gross brain metastases and do notaddress microscopic (clinically undetectable) disease. Conversely, WBRT is expected to result ininferior control rates of gross metastatic disease, increasing the likelihood of subsequent SRS orother salvage therapy. For these reasons, we will track the actual costs of treatments over thecourse of the study, including the need for supportive care and the ability of patients to continueto work in their previous occupation.

The structure of the current study provides a unique opportunity to explore various dosimetric

8


SRS parameters in the setting of multiple brain metastases. Dose-volume criteria for SRS havebeen established in a prospective RTOG 90-05[1] dose-finding study and subsequently validated inRTOG 95-08, a randomized controlled trial of WBRT±SRS in patients with 1-3 brain metastases[2].Several single-institution series as well as multi-institutional retrospective analyses support the useof single-dose SRS for treatment of brain metastases[3]; however, the dose-volume criteria andprescription guidelines are not known in the setting of �5 brain metastases where dose interactionamong di↵erent lesion targets are much more likely. These interactions can potentially lead toincreased rates of radiation necrosis, and if the SRS doses are arbitrarily reduced because of suchconcerns, then to a potentially decreased local control rates. These parameters will be closely trackedin this study with the aim of establishing an evidence-based dosimetric guidelines for radiosurgicaltreatment of multiple (�5) brain metastases.

The data gained from this study could help define patient selection and treatment criteria for SRSof multiple brain metastases as a potential alternative to WBRT in a select group of patients. Thiswill also be a first study of its kind to use online neurocognitive assessments for its primary endpointsto demonstrate feasibility and cost-e↵ectiveness of such an approach in a multi-institutional setting.

2.2 Objectives

2.2.1 Primary Objectives

• To compare the relative change in neurocognitive outcomes (change in oNCF z-score) betweenbaseline and 6 months for surviving patients in upfront WBRT vs. SRS treatment groups.

2.2.2 Secondary Objectives


• To estimate consistency and change in z-scores for oNCF assessments over all study endpointsin surviving patients treated with upfront WBRT vs. SRS.

• To compare the relative impact of initial therapy (upfront WBRT or SRS) on patients’ qualityof life (patient-reported measures) as measured by Beck Depression Inventory, Beck AnxietyInventory, FACT-Br, FACT-Cog, and Fatigue Severity Scale over all study timepoints.

• To compare the relative impact of initial therapy (upfront WBRT or SRS) on patients’ QoLas measured by caregiver assessments (Frontal Systems Behavior Scale, Neuropsychiatric In-ventory, Functional Activities Questionnaire, and Everyday Cognition Questionnaire) over allstudy timepoints.

• To compare proportions of patients in the two treatment groups (upfront WBRT vs. SRS)that require salvage therapy at 3, 6, 9, and 12 months as a function of systemic disease control(controlled vs. uncontrolled).

• To compare the overall survival between patients in upfront WBRT vs. SRS treatment groups.

2.2.3 Exploratory Objective

• To determine what healthcare cost data can be collected in patients with metastatic diseasewithin a context of a multi-institutional clinical trial.

9


3 Background

3.1 Clinical Problem

Brain metastases a↵ect up to 30% of patients with cancer.[4] A 2002 population-based study in theNetherlands found that 8.5% of cancer patients developed brain metastases.[5] This latter studyshowed that the 5-year cumulative incidence of brain metastases was approximately 16%, 10%,7%, 5%, and 1% for patients with lung cancer, renal cell cancer, melanoma, breast cancer, andcolorectal carcinoma, respectively. These incidence estimates for specific pathologies can be appliedto estimates of new cancer cases in the United States for 2010 to yield an estimate of approximately60,000-70,000 yearly cases of brain metastases.[6] However, if autopsy-based incidence figures areused, the expected number of cases of brain metastases may be as high as 170,000 per year.[7]Barnholz-Sloan et al.[8] calculated the population-based incidence of brain metastases within theMetropolitan Detroit Cancer Surveillance System. In this cohort, 16,210 patients were found tohave brain metastases, representing 9.6% of all lung, melanoma, breast, renal, and colorectal cancerpatients diagnosed from 1973 to 2001.[8]

More than 80% of brain metastases are detected after the primary tumor has been diagnosed(metachronous metastases) and less frequently, they are the first manifestation of disease or arediagnosed at the same time as the primary tumor (synchronous metastases). The median time fromdiagnosis of the primary tumor to the onset of neurologic symptoms is approximately 12 months,ranging from 3 months in the setting of lung adenocarcinoma to 53 months in breast cancer.[9]Brain metastases are symptomatic at some point in 67% of patients.[10]

Some types of primary cancer have a predilection for spread to the central nervous system.However, the reported percentage of cases of each primary type that metastasizes to the brain variesconsiderably. Lassman and De Angelis[11] reviewed nine studies and found the following variationin reported percentages of patients developing brain metastases for specific primary histologies:18% to 64% (lung cancer), 2% to 21% (breast cancer), 2% to 12% (colorectal cancer), 4% to 16%(melanoma), 1% to 8% (kidney), 1% to 10% (thyroid), and 1% to 18% (unknown primary). Theoverall rate of brain metastases was 6% to 24% in five cited studies.

Cancer patients with brain metastases present with significant neurologic, cognitive, and emo-tional di�culties. Diagnosis of brain metastases was traditionally considered to represent end-stagedisease and indicative of a turning point from curative treatment to palliative management. Fortu-nately, progress in systemic therapy is enabling patients with cancer to live longer after diagnosisof brain metastases, which has focused attention on the long-term sequelae of treatment of CNSdisease, such as somnolence, fatigue, depression, and complaints of “mental slowness” and “mem-ory problems”. Secondary e↵ects related to neurocognition have come under scrutiny because ofphysician and patient desires to enhance quality of life during and after cancer therapy.[12]

3.2 Whole-Brain Radiation Therapy

Almost half a century ago, in the absence of any e↵ective therapy or brain imaging tools, the majorityof patients with brain metastases presented with significant neurologic symptoms or increase inintracranial pressure and symptoms consequential to this. Although no contemporary studies ofobservation alone exist, older data suggest that these patients in general could be expected to liveapproximately a month, and the use of steroids to relieve edema and mass e↵ect could lengthensurvival to about 2 months.[13] A series of clinical trials, primarily led by Radiation TherapyOncology Group (RTOG) in the 1960s, suggested that the use of WBRT could lengthen mediansurvival to about 4 months, and a considerable amount of clinical research e↵ort was directedtoward testing various dose-fractionation schemes, none of which was found to be superior to any

10


other scheme. This lack of a dose-e↵ect relationship was explained on the basis of two factors: thedose of whole brain radiotherapy was always subtherapeutic, given the inherent sensitivity of thebrain to late radiation toxicity, and therefore, almost half of all patients continued to succumb tointracranial disease progression; and ine↵ective systemic therapies resulted in absence of extracranialdisease control, which resulted in the demise of the other half of this group of patients. Thisobservation was not surprising, given that almost half of all patients with brain metastases havelung cancer as the underlying disease, which was e↵ectively untreatable with chemotherapy untilthe advent of the platinoids. Consequently, WBRT became the modality of choice, and althoughvarious schedules are in use, the schedules of 30 Gy in 10 fractions and 37.5 Gy in 15 fractionsare most commonly used and balance the need to deliver modest dose of radiotherapy in a shortperiod of time(Figure 1(b)).[2, 13, 14] However, no modern trial compared the best supportivecare with WBRT. The Medical Research Council has recently initiated a large randomized trialof corticosteroids/best supportive care alone compared with the same treatment plus WBRT inpatients with primary non-small cell lung cancer and brain metastases.[15]

WBRT provides e↵ective symptom relief in the majority of cases (Figure 1(b)).[16] Althoughsymptom response rates after WBRT vary, complete or partial responses have been documentedin 43% to 64% of patients as early as week 2 in randomized controlled studies conducted byRTOG.[13, 14, 17, 18, 19] Recently, various groups have reported responses in the same range– in 38% of patients after 30 Gy WBRT[20]; symptomatic relief after �25 Gy in 66%, allowing cor-ticosteroid dose reduction[21]; and radiographic responses in comparable proportions of patients.[22]WBRT-induced tumor reductions correlated with better survival and cognitive function preserva-tion in a cohort of 135 patients from a phase III trial of WBRT with a sensitizing agent motexafin-gadolinium.[23] Previous RTOG data suggest that patients with controlled brain metastases afterWBRT tend to experience stable mini-mental status examination (MMSE) scores, whereas thosewith uncontrolled lesions experienced an average decrease of 6 point at 3 months.[24] Of the survivorsat 6 months from the WBRT arm of the randomized RTOG radiosurgery trial, 40% experiencedimprovement in mental status, and 45% experienced a decreased need for corticosteroids.[2]

Although the median survival of 4 months has become a widely quoted statistic, and for the mostpart remains true even today, there is clear recognition that not all patients with brain metastaseshave equivalently poor survival outcome, and a small but significant minority live for a longerperiod of time. The most commonly used prognostic system is the RTOG RPA classification.[26]Gaspar et al.[26] performed recursive partitioning analysis to generate regression prognostic treesof 1,200 patients from three consecutive RTOG trials conducted between 1979 and 1993, whichtested several di↵erent WBRT fractionation schemes and radiation sensitizers. This classificationscheme stratifies patients on the basis of three prognostic categories (RPA classes 1, 2, and 3, witha higher class indicating a worse prognosis) according to age at diagnosis, absence or presence ofextracranial metastases, KPS score, and status of the primary cancer. On the basis of this analysis,the median survival of patients with brain metastases ranges from 2.3 to 7.1 months, promptingthe debate regarding whether the patients in at least the best-prognosis category should or shouldnot be treated with more aggressive therapies to control intracranial disease.[26] At the core of thedebate was the recognition that WBRT produced only a modest rate of intracranial disease controland that, too, for a limited duration. For example, Nieder et al.[22] have shown that, with WBRTto 30 Gy, few lesions larger than 1cm3 are locally controlled after one year. In 1990, Patchell etal.[27] reported on a seminal trial, randomly assigning patients with a single brain metastasis andKPS �70 to WBRT with biopsy versus surgical resection, and although relatively small (N=48),this trial changed practice because patients with a single brain metastasis experienced improvedsurvival (median survival, 40 vs. 15 weeks for resection vs. biopsy), superior local control (80% vs.48%), and lengthening of functional independence as defined by the maintenance of KPS greater

11


(a)

(b) (c)

Figure 1: (a) Leksell Perfexion Gamma Knife radiosurgery system uses 192 converging, shaped beams todeliver high-doses of focused radiation safely to small intracranial targets. The patient is immobilized usinga rigid, titanium alloy headframe that is afixed to the patient’s skull with four pins (inset).[25], (b) WBRTdelivers uniform dose to all cranial contents; a dose of 30 Gy was delivered in this example over 10 fractions.and (c) Patient treated with SRS to multiple brain metastases; each metastasis was treated to 18 Gy in asingle treatment session. Please note the markedly reduced dose to surrounding normal brain structures.

than 70 (38 vs. 8 weeks). The clear lesson from this trial was that there are indeed some patientswith brain metastases for whom enhanced intracranial disease control translates into a survivaland QoL advantage. In part to better identify the cohort with improved prognosis, a more recentanalysis (and more relevant to contemporary clinical practice) of the RTOG database of brainmetastases led to the development of a revised prognostic scale — GPA.[28] Although analysis ofthe RTOG RPA database showed the status of the primary cancer to be prognostic, the RTOGGPA analysis showed the number of metastatic lesions (one, two, or three, or more than three) to beprognostic. Neither system suggested that the type of primary tumor influences outcomes when allbrain metastases patients were analyzed in aggregate, however, when stratified by primary histology,marked survival di↵erences emerged leading to the creation of diagnosis-specific GPA (DS-GPA)

12


(Table 1).[29] Unfortunately, even the DS-GPA (and other prognostic indeces) do not considerthe specific molecular biology of various tumors (e.g. patients with melanoma tumors bearing theBRAF V600E mutation tend to respond to therapy better and live longer than those without themutation).[30] In general, patients with KPS�70 and limited (or stable) systemic disease tend tolive longer with up to 30% survival being reported at one year.[31]

Table 1: Median survival stratified by primary tumor diagnosis for patients with newly-diagnosed brainmetastases, according to DS-GPA database.[29]

Primary Diagnosis Median Survival (mo.) 95% CI

NSCLC 7.00 6.53-7.50

SCLC 4.90 4.30-6.20

Melanoma 6.74 5.90-7.57

Renal cell carcinoma 9.63 7.66-10.91

Breast cancer (all) 11.93 9.69-12.85

Gastrointestinal cancer 5.36 4.30-6.30

Not-specified 6.37 5.22-7.49

Those who favor inclusion of initial WBRT highlight the evidence that demonstrates improvedlocal control and distant tumor control with concurrent administration of WBRT (Table 2). Theyalso argue that increased CNS tumor burden and failure of local and regional control contributeto cognitive decline and that the increased need for salvage therapy in patients not treated withupfront WBRT adversely a↵ects QoL. Conversely, opponents of this strategy argue that improvedCNS tumor control does not appear to increase overall survival time, and that routine use of initialWBRT limits therapeutic options at the time of recurrence. Additionally, the limited availableevidence suggests that upfront WBRT might adversely a↵ect neurocognition, late toxicity thatpatients wish to avoid. There remains considerable interest but scant data regarding neurocognitivee↵ects. Acute side e↵ects of WBRT include common e↵ects (occurring in >50% of patients) suchas alopecia, fatigue, and scalp erythema and less common e↵ects (occurring in <20% of patients)such as otitis externa, impaired sense of taste, nausea, and headache. Early delayed and late sidee↵ects from WBRT may include tanning of the scalp, alopecia, hearing loss, neurocognitive decline,behavioral changes, somnolence syndrome, and radiation necrosis.

3.3 Stereotactic Radiosurgery

SRS techniques can safely deliver high doses of radiation to a precisely defined target by exploitingmultiple beamlets, each of which does not transport much energy, that converge on the target(Figure 1(a), 1(c)). With this approach, the dose within tumor is much higher than the dose in thesurrounding normal brain tissue, as a result of a sharp dose gradient (“dose fallo↵”) achieved bythe multiple intersecting beams of radiation. Since the normal tissue interface is larger and dosefallo↵ is less rapid for larger lesions, increasing the exposure of the surrounding normal brain tissue,the prescribed dose for brain metastases is inversely proportional to the maximum tumor diameter,

13


Tab

le2:

StudiescomparingSRSplusW

BRT

withSRSalon

e.Note:

Asign

ificance

valueof

p<0.05

was

usedunless

otherwisespecified.

Stu

dy

Modality

nM

edian

surv

ival

(mo.)

1-yr.

surv

ival

(%)

1-yr.

free

dom

from

CNS

re-

curren

ce(%

)

1-yr.

loca

lco

ntrol

(%)

1-yr.

dis-

tantco

ntrol

(%)

Neu

roco

gnitive

assessm

ent

Chan

get

al.

[32]

SRSon

lySRS+W

BRT

30 2815.2

5.7

63.0

21.0

27.0

73.0

67.0

100

45.0

73.0

HVLT-R

(+others)

Aoyam

aet

al.

[33,

34]

SRSon

lySRS+W

BRT

67 658.0

7.5

28.4

38.5

23.6

53.2

72.5

88.7

36.3

58.5

MMSE

Sneedet

al.

[35]

SRSon

lySRS+W

BRT

268

301

8.2

8.6

38.0

35.0

NR

NR

NR

NR

NR

NR

Non

e

Andrewset

al.

[2]

WBRT

WBRT+SRS

164

167

6.5

5.7

NR

NR

NR

NR

71.0

82.0

NR

NR

Non

e

Regineet

al.

[24]

SRSon

ly36

9.0

36.0

53.0

61.1

75.0

Non

e

Kocher

etal.

[36]

SRSon

lySRS+W

BRT

100

9910.7

10.9

41.8

44.4

16.0

26.2

84.0

73.7

22.0

52.0

Non

e

Serizaw

aet

al.

[31]

SRSon

ly77

88.6

NR

NR

89.5

54.3

Non

e

14


generally resulting in better control rates of smaller lesions. This physical phenomena largely limitsthe application of SRS to lesions 3 cm in diameter. Acute e↵ects from SRS include commoncomplications such as pin-site soreness and headache after frame removal in the case of GammaKnife, as well as less frequent complications (in <5%) of patients such as pin-site infection, short-term exacerbation of neurologic symptoms, and seizures. Later side e↵ects, either early delayedor late, are uncommon (occurring in <5%) and include brain edema, radiation necrosis, and theworsening of preexisting neurologic deficits or development of new ones.[33]

When SRS techniques to enhance intracranial control to rates similar to that achieved withsurgery were used for patients with multiple brain metastases, those with a single brain lesiondemonstrated a survival advantage, but those with 2-3 lesions did not as demonstrated in a singlerandomized trial (RTOG 95-08).[2] However, SRS can readily treat multiple lesions, and in somereports, even 10 or more lesions were routinely treated[37, 31]; the addition of SRS to WBRThas been shown to improve local control in randomized trials, even in the setting of multiple brainmetastases.[22] An added potential benefit of SRS is the ability to repeat the procedure for additionallesions that may develop subsequently and thereby potentially avoid WBRT and its attendanttoxicities, primarily delayed cognitive decline. Several retrospective studies were undertaken toexplore the role of adjuvant WBRT after SRS (or upfront), suggesting an increase in tumor controlat the SRS sites and a prevention of new brain metastases(Table 2). This observation was confirmedfrom a phase III trial from Japan.[33] In this prospective randomized multicenter phase III studyof patients with 1-4 brain metastases, SRS alone was compared with SRS and WBRT with theprimary endpoint of an expected di↵erence in survival of 30% (70% vs. 59% at 1 year). Mediansurvival was 7.5 months after SRS with WBRT and 8 months after SRS alone. A non-significantdi↵erence of 36% (P>0.05) in one-year survival between the two arms was noted. At 2 years,adjuvant WBRT resulted in an increased control rate at the SRS sites of 80%, versus 50% for SRSalone (local tumor progression was defined as a radiographic increase of 25% in the bidirectionalproduct of a metastatic lesion; no consistent attempt was made to distinguish radionecrosis fromtumor recurrence which is potentially problematic given the higher expected rates of radionecrosisin the SRS group a priori), and a decreased risk for new brain metastases of 50%, versus 75% forradiosurgery alone (only initial SRS treatment was allowed; repeat SRS for new brain metastaseswas not allowed). No significant reduction in neurologic deaths was observed. Overall survival (8months) was not prolonged and the proportion of patients with KPS �70 at 12 months was alsonot significantly increased by WBRT added to SRS (27% for SRS alone vs. 34% for WBRT+SRS).Similar results were found in a three-armed phase III trial and in a small trial of the Trans-TasmanRadiation Oncology Group that closed early.[38, 39] It is important to note that these studiesonly permitted the use of WBRT as salvage treatment; salvage SRS, even to sites of new brainmetastases, was not permitted. It is, therefore, not surprising that rates of new brain metastaseswere decreased (but not eliminated) with WBRT which presumably controls subclinical disease anddelays radiographic and/or clinical detection of “new” brain metastases on serial follow-up.

Similarly, in a recent study by Kocher et al.[36], the risk of intracranial relapse was significantlyreduced by WBRT compared to SRS alone, but neither survival time nor the time period withfunctional independence was increased. In a retrospective review, Sneed et al.[40] demonstratedthat brain control allowing for primary salvage therapy is equivalent for initial treatment with SRSalone compared to SRS+upfront WBRT. The benefits of WBRT in patients with a limited numberof brain metastases (1-3) seem marginal. The EORTC study by Kocher et al. was criticized forthe use of World Health Organization performance scale (WHO PS) as a measure of functionalindependence. WHO PS is a rudimentary measure that is susceptible to significant bias and inter-as well as intra-observer variability, especially in the context of a non-blinded trial design. Therelative weakness of WHO PS as a useful endpoint for the e↵ect of any of the intracranial therapies

15


used in the EORTC trial is underscored by the observation that, in a multivariate analysis, the onlyfactors with significant impact on survival with WHO PS <2 were the initial WHO PS (0 vs. 2,P=0.04) and the presence of macroscopic tumor outside the brain (present vs. absent, P<0.001)WBRT was not statistically significantly superior, and if no treatment has a correlation with thatendpoint, it would logically be di�cult to observe a survival benefit from WBRT (P=0.53). Thisargues in favor of inclusion of more specific tools that take into account brain-specific symptoms,QoL outcomes, and measures of cognitition.

Three factors probably explain the lack of e�cacy of WBRT on both functionally independentand overall survival. First, the performance status (KPS or other) is subject to some interpretivevariability, which makes it a soft endpoint in many trials. Second, if follow-up imaging is regularlyperformed, brain recurrences are often detected by MRI before becoming symptomatic. Only 25%to 40% of patients without initial WBRT will receive salvage WBRT at recurrence. Salvage ra-diosurgery can be used for patients with limited number of recurrent metastases independently ofinitial treatment, hopefully avoiding irreversible neurologic deterioration. The majority of publishedrandomized phase III trials that compare initial WBRT with SRS (or WBRT+SRS to SRS alone)do not specify the salvage therapy even in the setting of limited “new” brain metastases. It is ourpractice at UCSF to use SRS for salvage treatment of a limited number of brain metastases irrespec-tive of initial therapy (WBRT or SRS). Third, patients with brain metastases have a high risk ofsystemic progression requiring treatments that cause deterioration of functional status independentof the type of initial treatment of brain disease. The situation looks di↵erent in trials that studiedthe role of surgery or radiosurgery added to WBRT[2, 41, 27], where functional independence[2],survival in subgroups[2], and overall survival were increased by the addition of aggressive local ther-apy (either surgery or SRS) to WBRT in subsets of patients.[41, 27] In most studies, acute toxicityis more frequent in the WBRT arm, but the long-term e↵ects of WBRT are of greater concernbecause it has been shown that WBRT may significantly impair learning and memory functions inlonger-term survivors.[32] Most trials, with the exception of a study by Chang et al.[32], either donot use neurocognitive endpoints or only use MMSE to screen for gross cognitive dysfunction.

3.4 Neurocognitive Outcomes

There is a well-documented association between disease progression in the brain and decrease inQoL as well as in multiple cognitive domains.[42, 43] Unfortunately, most published clinical trialsused MMSE as an NCF outcome measure[24, 33, 34], or did not include NCF as an endpoint atall (Table 2). Several of these trials reported that few patients developed cognitive decline afterWBRT treatment, many patients with abnormal pretreatment scores improved over time, and mostpatients remained stable. Unfortunately, MMSE is unable to make these types of determinations.The MMSE is a screen for dementia, and it is true that there is a little chance of incorrectly diag-nosing cognitive impairment when a person performs in the markedly abnormal range. However, aperformance in the supposedly normal range (score �27 of 30 possible points) does not mean thatthe individual is free of significant cognitive problems, nor does stability of the MMSE score overtime mean that the person has not experienced significant changes, either for better or worse.[12]Moreover, the sensitivity of the MMSE in a brain tumor population is very poor. Meyers et al.[44]administered the MMSE in conjunction with a comprehensive neuropsychological evaluation of 67brain tumor patients to assess the diagnostic accuracy of the MMSE using each patient’s perfor-mance on the comprehensive evaluation to determine whether they were impaired (e.g. performanceon 2 or more tests at the 7th percentile or below). They found that 52 patients were classified asimpaired on the basis of the neuropsychological battery, whereas only 26 of dose 52 patients wereconsidered abnormal on the basis of the MMSE (25th percentile or below; 27/30 points). This

16


yields an unacceptably poor sensitivity of only 0.50 (95% CI, 0.36 to 0.64).[44]Formal, objective, and standardized neurocognitive testing is a sensitive measure of brain func-

tion. Furthermore, it has been demonstrated that the combination of clinical prognostic variablesand brain function assessments seems to predict survival better than the prognostic variables alonein primary brain tumor patients[45], and in patients with leptomeningeal or parenchymal brainmetastases.[43, 46] A screening tool such as the MMSE has not been demonstrated to predict sur-vival in cancer populations. The MMSE also does not measure cognitive functions that are likely tobe a↵ected by radiation therapy. It contains items that briefly assess aphasia, apraxia, orientation,and attention. However, cognitive functions a↵ected by radiation are related to frontal-subcorticalwhite matter dysfunction and include impairments of learning and memory, processing speed, ex-ecutive function, and fine motor control.[47, 48] These impairments cannot be detected by MMSE.

In aggregate, there has been ample demonstration that brief neurocognitive test batteries arefeasible and well tolerated by patients in large clinical trials, and that they yield important andunique information regarding treatment e↵ects.[12] There has been some reluctance to use moresensitive cognitive test batteries because of concerns about increased cost. However, the ability todetect meaningful cognitive deterioration and improvement in clinical trials, to ultimately assist inmedical decision making and to inform accurately on post-treatment e↵ects, is essential. The useof a screening tool that lacks adequate sensitivity and may provide misleading information is notcost-e↵ective or helpful.

The only study to date that utilized comprehensive neurocognitive testing was that by Changet al.[32] In this study, 58 patients were stratified by RPA class (class 1 vs. 2), number of brainmetastases (1-2 vs 3), and radioresistant histology (melanoma or renal cell carcinoma vs other), andrandomized in a 1:1 fashion between SRS+WBRT (group 1) and SRS alone (group 2). Patientsin group 1 received upfront SRS followed by WBRT to 30 Gy (12 fractions, 2.5 Gy per day) thatwas completed within 3 weeks of randomization. Formal neurocognitive testing and quality of life(QoL) instruments were administered at baseline (pre-treatment) and at each follow-up visit (1, 2,4, 6, 9, 12, 15, and 18 months following completion of the last radiation treatment). The batteryof neurocognitive tests included HVLT-R (total recall, delayed recall, and delayed recognition),Wechsler Adult Intelligence Scale - III (WAIS-III) digit span and digit symbol, Trail Making Testparts A and B, Multilingual Aphasia Examination Controlled Oral Word Association (COWA), andLafayette Grooved Pegboard. The trial was stopped prematurely after recruitment of 58 patientsbased on the early stopping rules because it was determined that patients treated with SRS+WBRTwere at a greater risk of a significant decline in learning and memory function by 4 months, as shownby HVLT-R, compared with the group that received SRS alone. The study was highly criticizedfor basing its conclusions on neurocognitive outcomes at an early timepoint (4 months) when it hasbeen suggested by prior longitudinal studies in long-term survivors of WBRT that an early declinein cognitive performance occurs at about the 2-4 month point, but subsequently rebounds.[23]Other criticisms of the study include a significant imbalance between the study groups, with thecombined group (SRS+WBRT) having a worse prognosis at the outset. The combined therapygroup included patients with a greater volume of disease whereas the SRS alone group containedexcess of women, single metastasis, RPA class I patients, and an absence of patients with lung andabdominal metastases. Though the patients were well matched in terms of number of lesions, thedisproportionately higher volume of disease in the combined therapy group biases the neurocognitivefunction performance in favor of the SRS alone group – the baseline neurocognitive function ishighly correlated with volume of lesions, but not with number of metastases.[42] Furthermore, thestudy by Chang et al.[32], though randomized, was likely not powered to detect meaningful outcomedi↵erences between the two treated groups given the small numbers of evaluated patients consequentto the early stopping of the trial due to an observed early timepoint di↵erence.

17


3.5 Summary

There is strong evidence from randomized phase III studies that upfront SRS is not associated witha survival detriment compared to WBRT (the standard-of-care treatment) in patients with multiplebrain metastases although WBRT does reduce the risk of intracranial disease progression.[33, 36,38, 39, 32, 31] This lack of survival di↵erence is likely due to multiple factors, including the use ofe↵ective salvage therapy for intracranial disease and the strong survival dependence on the extentand control of extra-cranial disease. It has also been well documented that WBRT results in delayedNCF decline which is believed to be progressive with adverse impact on the QoL.[32] While NCFendpoints have often been dismissed or underreported in patients with brain metastases, they aregaining increasing importance as the number of long-term survivors with metastatic disease increasesdue to improved systemic therapies (up to 30% of patients are alive at 1 year). Additionally,the number of patients with successfully treated brain metastases is growing; it is this patientpopulation that is particularly susceptible to adverse NCF e↵ects of various therapies. In turn, thistranslates to increased economic costs to society from patients requiring continuous care and beingunable to work. Most studies, with the exception of one by Chang et al.[32], relied on MMSE tomeasure NCF after treatment. One of the most commonly cited concerns about inclusion of morecomprehensive cognitive test batteries in clinical trials is their cost. In this study, we propose to useonline testing (oNCF). The oNCF is designed to e↵ectively measure the cognitive domains mosta↵ected by radiation therapy (RT) (and likely by other cytotoxic therapies) such as impairments oflearning and memory, processing speed, executive function, and fine motor control. We will directlycompare the neurocognitive outcomes of patients treated with upfront SRS and WBRT and considerthe impact on functional outcomes of any additional salvage therapy for metastatic brain disease.The aim is to determine the overall impact of two main radiation treatment modalities for multiplebrain metastases on neurocognitive and QoL outcomes and to compare the relative economic costsof these two approaches during the follow-up period.

4 Participant Selection

4.1 Conditions for Patient Eligibility

Note: Exceptions to the eligibility criteria are not permitted.

• Pathologically (histologically or cytologically) proven diagnosis of a non-hematopoietic malig-nancy other than small cell lung cancer and germ cell malignancy within 5 years of registra-tion. If the original histologic proof of malignancy is greater than 5 years, then pathologicalconfirmation is required (e.g. from extra- or intra-cranial disease).

• Patients with �5 measurable brain metastases on a diagnostic-quality contrast-enhanced MRIobtained within 30 days prior to registration.

• Patients with 10 cc largest tumor volume, and 15 cc total tumor volume.

• History/physical examination within 30 days prior to registration.

• If an open biopsy is performed, the patient must be at least one week post biopsy. Thisrequirement does not apply to patients who undergo stereotactic biopsies.

• Age �18 years.

• Karnofsky performance status �70 (RTOG RPA Class I & II).

18


• Minimum pre-treatment oNCF score �70.

• Patients must provide study-specific informed consent prior to study entry.

• Women of child-bearing age must have a negative, quantitative serum pregnancy test 14days prior to study entry, or have a documented reason why such a test is not necessary (e.g.history of tubal ligation).

• Patients must be able to speak and read English fluently (required for the use of online NCFtesting).

• Patients must demonstrate basic computer literacy skills, defined as at least one-hour perweek spent using a computer, and have access to an internet terminal (required for the use ofonline NCF testing).

4.2 Conditions for Patient Ineligibility

• Clinical (e.g. multiple new cranial nerve deficits in the absence of obvious radiographic diseaseto explain symptoms) or radiographic evidence of leptomeningeal disease.

• Patients with measurable brain metastasis(es) resulting from small cell lung cancer and/orgerm cell malignancy

• No documentation of prior cytotoxic or other therapy for malignancy if such therapy waspreviously received. Note: This does not apply to patients with synchronous metastases atinitial diagnosis.

• Contraindication to MR imaging, such as implanted metal devices or foreign bodies, severeclaustrophobia, or contraindications to contrast agent administration.

• Estimated glomerular filtration rate (eGFR) <60 within 6 weeks prior to registration.

• Prior radiation therapy to the brain.

• Severe, active co-morbidity, defined as follows:

– Unstable angina, and/or congestive heart failure requiring hospitalization within the last6 months.

– Transmural myocardial infarction within the last 6 months.

– Acute bacterial or fungal infection requiring intravenous antibiotics at the time of regis-tration.

– Hepatic insu�ciency resulting in clinical jaundice and/or coagulation defects.

– Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiringhospitalization, or precluding study therapy at the time of registration.

– Uncontrolled, clinically significant cardiac arrhythmias.

– Radiologic or clinical evidence of hydrocephalus, or history of previously treated hydro-cephalus.

• Women of childbearing potential and male participants who are sexually active and not will-ing/able to use medically acceptable forms of contraception; this exclusion is necessary becausethe radiation treatment involved in this study is potentially teratogenic.

19


4.3 Pre-Treatment Evaluations

Note: This section lists baseline evaluations needed before the initiation of protocol treatment thatdo not a↵ect eligibility.

4.3.1 Required Evaluations

• Patients that meet the eligibility criteria for the study must be reviewed and discussed at amulti-disciplinary tumor conference.

• Each patient must undergo a formal Radiation Oncology consultation and have a documentedcomprehensive medical history and physical examination; all neurologic deficits should bedocumented and graded whenever possible. Prior therapeutic history for the primary cancershould be carefully documented with times, dates, doses, and duration of therapy, if available.

• The following patient and caregiver assessments must be administered within 14 days priorto treatment (see Section 20.4 for details):

– The patient will complete EORTC Quality of Life Questionnaire - Core 30 (QOL-30),Brain Cancer Module - 20 (BCM20), and EuroQol Group Questionnaire - 5D (EQ-5D)QoL measurements.

– The patient will complete self-reported measures of depression (BDI-II), anxiety (BAI),qualify of life (FACT-Br), cognition (FACT-COG), and fatigue (Fatigue Severity Scale).

– The caregiver assessment will include measures of frontal symptoms (FrSBE), neuropsy-chiatric symptoms (NPI), functional abilities (Functional Activities Questionnaire), andcognition (E-cog).

• Two short oNCF assessments (Lumosity’s Brain Power Test) must be completed within 14days prior to radiosurgery. The two oNCF sessions must be performed at least 7 days apartto control for practice e↵ects and to establish a robust baseline performance.

• Each enrolled patient is required to undergo pre-treatment diagnostic MR imaging that will in-clude the standard high-resolution anatomic MR sequences (e.g. T1- and T2-weighted images,FLAIR).

4.3.2 Recommended Evaluations

• Re-staging to confirm the extent of systemic disease evaluated clinically, radiographically,and/or serologically, as appropriate for the underlying malignancy.

• Re-staging is considered current if completed within 30 days prior to treatment and if therewas no change in therapy since the last re-staging.

5 Recruitment Plan

• All 120 patients with documented brain metastases will be recruited by the North AmericanGamma Knife Consortium (NAGKC) member institutions (see Appendix F). All NAGKCmember institutions have extensive experience with the use of GK, and their respective prac-tices include a large number of patients with brain metastases. Brain metastases are theprimary indication for GK treatment in majority of these institutions. On an annual basis, itis expected that approximately 60 patients will be enrolled on this trial within the consortium.

20


• The anticipated accrual rate is 5 patients per month, with the anticipated total recruitmentperiod of 24 months.

• All patients considered for the study will be presented at the corresponding institutional multi-disciplinary radiosurgery tumor board to ensure appropriateness and safety of the treatmentwithin the context of this protocol.

6 Registration

6.1 Online Registration

Patients can be registered only after eligibility criteria are met. Each research coordinator (or othersta↵/investigator involved with the study) at a participating institution will be assigned a usernameand password to access the secure, encrypted study-specific database at the coordinating center.To get a username and password:

• The research coordinator (or other requesting sta↵) must have completed Human SubjectsTraining (or equivalent) and been issued a certificate of completion.

• A representative from the institution (or requesting sta↵) must complete the Password Au-thorization Form that can be requested from the coordinating center or the study PrincipalInvestigator (PI) (see Section 22.2.1).

A NAGKC institution can register a patient by logging onto the study-specific website (http://www.baranilab.com, going to “Database Login” and selecting the link for “New Patient Regis-tration.” The system will trigger a verification algorithm that ensures that all regulatory require-ments (IRB approval, Human Subjects Training, etc.) have been met by the institution. A seriesof registration screens will guide the user through the registration process and will ensure that theeligibility checklist, the study-specific consent form, etc. have been completed.

Once the system has verified that the patient is eligible and that the institution has met regulatoryrequirements, the system will assign a patient-specific case number. The system will then proceedto a screen that confirms that the patient has been successfully registered and enrolled in the study.At this time, the system will also randomly assign the patient to a treatment group (upfront SRS orWBRT). From this screen, a patient registration card can be printed for inclusion in the patient’smedical record. Furthermore, an email confirmation will be sent to the registering institution con-taining the same information.

If the patient is ineligible or the institution has not met regulatory requirements, the system switchesto a screen that includes a brief explanation for the failure to register the patient. This screen canbe printed and email generated at the user’s request.

Institutions can contact the study PI or the research coordinator (see Section 22.2.1) at the mainstudy coordinating center.

7 Stereotactic Radiosurgery

Note: Gamma knife Perfexion is the only acceptable radiosurgical device for treatment of multiplebrain metastases in this study[49]. All subsequent radiosurgical details are specific to the Gammaknife radiosurgery.

21

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7.1 It is possible at the time of radiosurgery that one of the following scenariosoccurs:

• The largest identified metastasis exceeds the 10 cc volume limit. Any such lesion should notbe treated with radiosurgery. Management of such lesions is at the discretion of the treatingphysician. If WBRT is a component of the treatment, guidelines in Section 8 must be followedand these patients will continue their follow-up per protocol guidelines.

• If additional lesions are identified on the radiosurgery planning MRI scan (compared to thediagnostic/screening MRI scan), radiosurgery should be delivered to these additional lesionsprovided that volume criteria are met (the total volume 15 cc and the largest lesion 10 cc)and the treating physician deems this case safe and appropriate for radiosurgical treatment.Any cases where the total lesion volume exceed 15 cc must be discussed with the study PI anda written rationale for doing so needs to be provided within 48 hours of treatment. Otherwise,the patient will simply be followed closely o↵-study.

7.2 Timing

SRS must be delivered within 21 days of registration, and after discussion at a multi-disciplinaryradiosurgery tumor board/conference.

7.3 Localization and immobilization

• Frame-based immobilization is required for this study. Patients will be required to undergoplacement of a stereotactic head frame by an experienced neurosurgeon. This frame is attachedto the skull using four pins that pierce anesthetized skin at four predetermined points.

• All patients will undergo a GK planning MR scan with the head frame in place, and appro-priately attached localizer fiducial box. MR images will be reviewed by the treating physicianbefore the patient is removed from the scanner to ensure that all fiducial marks are appropri-ately visualized and that the scan quality is acceptable for SRS treatment planning.

• The head frame will be removed at the end of therapy by a qualified radiation oncologistand/or neurosurgeon.

7.4 Target volume determination

• Every target lesion must be delineated on GammaPlan software.

• Three-dimensional spoiled gradient (3D-SPGR) multi-plane MRI scan (or similar MR se-quences as judged to be appropriate by the consulting radiologist) will be required to allowaccurate contouring of both the target and critical normal structures.

• Target volume determination will be based on a double-dose gadolinium MRI planning scan.In patients in whom double-dose contrast is contraindicated, conventional dose gadolinium-enhanced MRI may be used. The use of CT for target determination is not allowed on thisstudy.

• The target volume will include the enhancing portion of the metastatic lesion. Surroundingareas of edema will not be considered part of the target volume.

22


7.5 Critical structures

The optic nerves, chiasm, brainstem, and other eloquent parts of the brain deemed at risk fromtreatment injury will be contoured by the treating radiation oncologist. Care should be taken tominimize the dose to these structures. The recommended single-fraction limit to the anterior opticstructures is 8 Gy max dose, 12-15 Gy max dose to the brainstem (15 Gy only if the target lesionlies within the brainstem; maximum target volume 1 cm3), and 18 Gy max dose to the motor orsensory cortex for lesions that involve these structures. For critical normal structures not explicitlymentioned herein and of concern to the treating physician, the QUANTEC single-fraction criteriashould be followed[50].

7.6 Dose & prescription

• The dose will be prescribed to the isodose surface, which encompasses the margin of the metas-tasis (50-90% [maximum=100%]), as defined by target delineation on the imaging studies.

• The prescribed dose is dependent on the prescription isodose volume (IDV) as shown inAppendix E. The prescription IDV is defined as the volume (cm3) that is encompassed by theprescription isodose line (IDL).

7.7 Radiosurgical (SRS) technique

Patients may only be treated with an FDA-approved stereotactic localization and treatment pro-cedures/devices. For the purposes of this study, only the Gamma Knife Perfexion radiosurgicalsystem is allowed given its superior normal brain tissue dosimetry compared to other SRS treat-ment modalities in the setting of multiple brain metastases[49].

7.8 Radiosurgery (SRS) treatment planning data

• GammaPlan version 9.x (or higher) must be use used for planning.

• Isodose distributions must be calculated, and the prescription isodose line clearly designatedfor each target lesion.

• The treatment planning data must be exported in DICOM-RT format if GammaPlan 10.x isused or in LGP file format for GammaPlan 9.x and uploaded into a study-specific database.Note: Only GammaPlan 10.x has the ability to calculate high-resolution (1mm3 dosegrid)for the whole brain); older GammaPlan versions 9.x cannot produce such high resolutioncalculations for the whole brain, requiring the use of LGP file format for later recalculationof the whole-brain dose.

• The SRS treatment parameters worksheet must be completed; the worksheet will minimallycontain the following dosimetric parameters:

– Target number. In cases of new lesions treated at subsequent SRS sessions, the numberingwill resume from the last numbered lesion in the previous session (e.g., if lesions #1-4were treated at the first session and 2 new lesions are treated at a second SRS session,the new lesions will be numbered as #5 and #6. If a target lesion #2 is re-treated, itwill be called #2 again at the subsequent session.).

– Lesion location; descriptive location is adequate (if MNI coordinates are available, theseshould be recorded)

23


– Lesion previously treated with Gamma knife (yes/no)

– Prescribed dose (Gy)

– Max dose (Gy)

– Prescription IDL (%)

– Prescription IDV (cm3)

– 12-Gy IDV (cm3)

– 8-Gy IDV (cm3)

– Target volume (cm3)

– Target volume within prescription IDV (cm3)

– Percent target coverage (%)

– Target dimensions (cm): L/R, A/P, Sup./Inf.

– Total treatment time

8 Whole-brain Radiation Therapy

8.0.1 Timing

WBRT must start within 21 days of registration, and after discussion at a multi-disciplinary radio-surgery tumor board/conference.

8.0.2 Localization, simulation, immobilization, and target volume

• Patients will be immobilized in the supine position using an immobilization device such as anAquaplast mask over the head. Patients will be treated in the immobilization device.

• A non-contrast treatment-planning CT scan must be acquired with the patient in the sameposition and immobilization device as for treatment. Note: CT simulation scan and CT-basedplanning is required for this study.

• The Clinical Target Volume (CTV) is defined as the whole brain parenchyma to C1 (if noposterior fossa metastasis) or C2 (if MRI evidence of posterior fossa metastasis).

• The Planning Target Volume (PTV) is defined as the CTV plus a 3-5 mm geometric margin(institution-dependent).

8.0.3 Critical Structures

The lenses, globes, optic nerves, and optic chiasm will be contoured as per the clinical experience ofthe treating physician. Care should be taken to minimize the dose to the lens and globes. Dose toany point within the anterior optic structures cannot exceed 35 Gy. For critical normal structuresnot explicitly mentioned herein, the QUANTEC dose-volume criteria should be followed[50].

24


8.0.4 Dose & prescription

The following prescription guidelines must be followed and any deviations >10% must be reportedto the PI.

• The whole-brain PTV will receive 30 Gy in 10 fractions. Treatment will be delivered oncedaily, 5 fractions per week, over 2 to 2.5 weeks. Breaks in treatment should be minimized.

• The dose will be prescribed either to mid-plane or such that 95% of the whole brain PTV iscovered by the prescription dose.

• Dose inhomogeneity must not exceed 15% relative to the prescription dose.

8.0.5 WBRT technique

Megavoltage equipment capable of delivering either 4MV or 6MV static photon beams with multi-leaf collimator (MLC) leaf width no greater than 1cm (ideally, no greater than 5 mm), or the useof custom-made blocks, is required. The use of photon energies higher than 6 MV is discouraged,and “scalp-sparing” or other non-traditional WBRT techniques are not permitted.

8.0.6 Documentation requirements

• Weekly verification orthogonal films or weekly cone-beam CT (CBCT) are required.

• The dates of therapy must also be recorded.

• The treating physician must complete at least two on-treatment evaluations (at least 5 daysapart) during the course of WBRT.

8.0.7 Radiation therapy interruptions

• Radiotherapy will be continued without interruption if at all possible.

• If the sum total of radiotherapy interruptions exceeds 3 normally scheduled treatment days,the treatment will be considered an unacceptable deviation from the protocol. This shouldbe reported to the coordinating center (see Section 22.2.1) and the institutional PI and thepatient will be considered inevaluable on final data analysis.

9 Salvage Therapy for Progression within the Brain

The choice of salvage therapy for brain progression is at the discretion of the treating team. Thechoice and details of salvage therapy must be recorded. The most common salvage therapy optionsare listed below.

9.1 Salvage Stereotactic Radiosurgery

If there are new brain metastases on the follow-up MRI, salvage (repeat) SRS treatment may beconsidered for the new lesions per SRS guidelines (Section 7). The patient may receive multipleSRS treatments provided that such repeat treatments are deemed to be safe and appropriate by thetreating physician, and only if there is concurrence of multi-disciplinary Radiosurgery Tumor Board,or a similar team (such concurrence must be documented in the clinical record independently of thetreatment protocol).

25


9.2 Salvage Whole-brain Radiation Therapy

Patients who are not eligible for salvage radiosurgery because SRS criteria are not met or themulti-disciplinary radiosurgery tumor board (or the treating physician) deems SRS to be unsafe orinappropriate, salvage WBRT may be administered per WBRT guidelines (see Section 8).

9.3 Other Salvage Therapies

Other salvage therapy is at the discretion of the treating physician, and should be performed onlyafter concurrence of a multi-disciplinary Radiosurgery Tumor Board, or a similar team. Such concur-rence must be documented in the clinical record independently of the treatment protocol. Patientswho undergo “non-RT” salvage therapies will be considered non-analyzable (major protocol vio-lation) for the purposes of this study. The patients will still continue to be followed per protocolguidelines but will not be included in the primary analysis.

The dates and type of all salvage therapy must be reported to the study PI within one week of suchtherapy, and the form of salvage treatment recorded in the study-specific database.

If the patient undergoes salvage craniotomy, MRI with perfusion and/or 11C-methionine (11C-met)PET are highly recommended pre-operatively. Reports of pathology from any salvage craniotomyand the above scan results should be recorded and archived in the study-specific database.

10 Central Dosimetry Review

A review of the SRS and WBRT plans will be performed centrally by the study PI at the coordi-nating center after all treatment plans have been centrally collected in the appropriate electronicformat. The SRS plans from Gamma Plan 9.x that were submitted in LGP file format will be im-ported into Gamma Plan 10.x for high-resolution calculation at the whole brain level and convertedinto a corresponding DICOM-RT format for review and processing.

The central review will be conducted by the study physicist and a radiation oncologist at the coor-dinating center and compliance with dosimetric parameters verified. Any treatment deviations willbe recorded and reported to the treating institution.

The central dosimetry review will take place every 3 months.

11 Criteria for Response Assessment

Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters onday-of-GK or WBRT and follow-up contrast-enhanced, T1-weighted MRI (diagnostic quality), andthe product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alter-natively, direct volumetric measurements via threshold-based contouring can be used to calculatethe lesion volume directly. If direct volumetric measurements are done, all subsequent measure-ments must be performed using the same method and the same software package. The method oflesion volume calculation must be specified on the response assessment forms and recorded in thestudy-specific database.

26


11.1 Response Definitions

• Complete Response (CR): Complete disappearance of contrast enhancement.

• Partial Response (PR): A decrease in volume of �50% compared with the lesion volumeon the day of SRS.

• Progressive Disease (PD): To assess PD, the lesion diameter must be at least 5 mm andthe lesion in question cannot be later interpreted as radiation necrosis (see Section 12). Lesionmeasurements under 5 mm are deemed unreliable for assessing PD. Note: Di↵erent PD criteriaapply to small lesions (1 cm) in order to minimize the relative errors in measurement of smalltargets near the spatial resolution limits of diagnostic MRI.

– For lesions 1 cm in axial diameter at the time of SRS, PD is defined as an increasein volume �50% compared with the smallest prior lesion measurements.

– For lesions >1 cm in axial diameter at the time of SRS, PD is defined as an increasein volume �25% compared with the smallest prior lesion measurements.

– After salvage WBRT, any “new” lesions are considered progressive disease (even ifpreviously identified lesions have demonstrated some treatment response).

• No Response (NR): Lesions not fitting CR, PR, PD, or necrosis criteria are scored as “NoResponse.”

A lesion may be scored at both necrosis and progressive disease (see Section 12).

11.1.1 “New” Lesions

The Response Assessment definitions (Section 11.1) do not apply to “new,” or previously untreated,brain metastases. If “new” lesions are identified on follow-up MR imaging, the response should bescored as Untreated Disease (UD). Note: The label UD does not apply to patients who havecompleted WBRT; these patients should be scored as PD.

12 Radiation Necrosis

12.0.2 Background

The central nervous system (CNS) is exposed to ionizing radiation in a number of clinical situa-tions, predominantly those involving cancer treatment. Although any type of normal tissue damageis undesirable, the CNS injury that can occur after radiotherapy is associated with a high rate ofmorbidity and is especially devastating. Radiation-induced CNS injury has been well described interms of histological and functional criteria as well as radiobiologic parameters, though the under-lying cellular and biochemical processes remain poorly defined.

Classically, radiation-induced CNS injury has been divided into three categories based on time of ex-pression: acute, early-delayed, and late-delayed. Acute radiation encephalopathy is expressed daysto weeks after irradiation and is uncommon under current radiotherapy protocols. Early-delayedinjury occurs from 1 to 6 months after radiotherapy and can involve transient demyelination withsomnolence after brain irradiation or Lhermittes syndrome after spinal irradiation. Acute andearly-delayed injuries are normally reversible and resolve spontaneously. In contrast, late-delayede↵ects, which occur more than 6 months after irradiation, are not completely reversible and may

27


be progressive, causing the majority of the morbidity and mortality of radiation-induced CNS in-jury. Late-delayed injury is characterized by demyelination, vascular abnormalities, and ultimatelynecrosis that is generally restricted to the white matter.

Radiation necrosis should be in the di↵erential diagnosis for any patient with progressive neurologicalsymptoms or enlarging enhancing brain lesion with a history of intracranial radiation therapy orSRS several months or more previously to the equivalent of at least 12 Gy in a single dose. A majordilemma in the diagnosis of radiation necrosis is di↵erentiating it from recurrent or persistent tumor.Metastatic tumor recurrence and radiation necrosis often have a similar appearance on conventionalcontrast-enhanced MRI[51, 52]. Because of this, it is often di�cult to distinguish which entity isresponsible for the appearance of an enlarging lesion. Traditionally, a patients clinical course, biopsyor resection, and serial imaging of the lesion of interest for several months have been used to tryto distinguish between tumor recurrence and radionecrosis[51, 53, 52]. Any investigation short ofextensive tissue examination lacks diagnostic sensitivity and specificity. Anatomic and physiologicMRI, and positron emission tomography (PET) imaging have all been used in an attempt to definethe best non-invasive method to diagnose radiation necrosis[54, 55, 56], though there is no evidenceto date that any of these investigations is clearly superior to the other modalities. The estimatedrate of radiation necrosis is 15-20% (estimate based on anecdotal experience).

12.0.3 Definition

In cases of suspected, symptomatic radiation necrosis, the case management should be discussed ata multi-disciplinary Radiosurgery Tumor Board. It is recommended that patients with suspectedradiation necrosis on follow-up MR imaging should undergo MR perfusion or 11C-methionine PETimaging if available at the treating institution to help distinguish necrotic lesions from recurrenttumor as the management of these is di↵erent. For the purposes of this study, radiation necrosisshould be considered in cases where:

• A previously treated lesion in question meets the criteria for PD on a scan that is at least 3months from the completion of SRS (to the lesion in question) or salvage WBRT.

• The perfusion MR and/or 11C-methionine PET (if such imaging is available at the treating in-stitution) characteristics are suggestive of necrosis (not tumor vascularity and/or metabolism).

12.0.4 Recommended Radiation Necrosis Management

All cases of suspected radiation necrosis should be discussed at a multi-disciplinary RadiosurgeryConference. The following procedures are recommended for the management of suspected radiationnecrosis:

• If asymptomatic, continued serial imaging per protocol schedule is recommended (diagnosticMRI every 3 months; Section 20.2); perfusion MR and/or 11C-methionine PET imaging is atthe discretion of the treating physician and may depend on the availability of such imaging atthe treating institution. Note: More frequent imaging is at the discretion of the treating physi-cian but 3-month interval scans must still be obtained. The Study Manager (Section 22.2.1)will be notified that the patient is being observed for suspected radiation necrosis.

• If symptomatic:

– The patient should have directed perfusion MR and 11C-methionine PET imaging (ifavailable at the treating institution).

28


– Unless contraindicated, the administration of glucocorticoid (e.g. dexamethasone) alongwith a GI prophylaxis (e.g. proton pump inhibitor, H2-receptor antagonist, or similar)is recommended, and is at the discretion of the treating physician. If glucocorticoidsare administered, the dose, duration, and course of therapy will be recorded. Patientsshould resume normal follow-up schedule if tolerating therapy. It is permissible to obtainmore frequent scans at the discretion of the treating physician but 3-month intervalscans must still be obtained. Note: If other therapy is administered, the type, dose,duration, and course must be reported to the Study Manager at the coordinating center(Section 22.2.1).

– If the focus (or foci) of suspected radiation necrosis is located in non-eloquent brain(or surgery is otherwise advisable/possible), craniotomy for surgical excision is recom-mended. A decision to proceed with craniotomy will be based upon the discussion andrecommendations of a multi-disciplinary Radiosurgery Tumor Board. Such discussionsmust be documented in the clinical and research record. The pathology results fromsuch a procedure must be recorded and reported to the study coordinating center (Sec-tion 22.2.1).

– Other treatments, including hyperbaric oxygen therapy, are at the discretion of the treat-ing physician. Any treatments for suspected and/or documented radiation necrosis mustbe reported.

13 Comprehensive Quality Assurance Review

The quality assurance review will occur every 3 months and will include the following components:

• Verification of the Dosimetry Compliance Criteria record (see Section 10)

• Verification of completeness of clinical documentation and its entry in the secure researchdatabase

• Review of the oNCF completion rates

• Review of the anatomic MR imaging, including quality assessment, treatment response as-sessment, problems, and completion rates

• Review of the adverse events (Section 15), including workup, documentation, and managementof radiation necrosis

• Review of protocol logistics and any patient complaints

14 Radiation Adverse Events

14.1 Acute, 90 days from treatment start

Possible adverse events include hair loss, erythema of the scalp, headache, pin site tenderness,nausea and vomiting, lethargy, and transient worsening of neurologic deficits. Reaction in the earcanals and on the ear should be observed and treated symptomatically (particularly in patients whoundergo WBRT). See Table 3 for reporting guidelines.

29


14.2 Late, >90 days from treatment start

Possible adverse events include radiation necrosis, cognitive dysfunction, visual di�culties, dimin-ished hearing, focal neurologic deficits, seizure, accelerated atherosclerosis, and radiation-inducedneoplasms. See Table 4 for reporting guidelines.

14.3 Other

If significant increase in reaction of the normal tissue occurs, the event should be reported on theappropriate case report form (CRF), and the study PI notified in writing.

15 Radiation Adverse Event Reporting

15.1 Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Re-quirements

Adverse Events (AEs) as defined in the tables below and all Serious Adverse Events (SAEs) will bereported to the PI at the study coordinating center and the Institutional Review Board (IRB) or acorresponding committee that oversees human subjects research.

Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratoryfinding), symptom, or disease temporally associated with the use of a medical treatment or pro-cedure regardless of whether it is considered related to the medical treatment or procedure (at-tribution of unrelated, unlikely, possible, probably, or definite). [Cancer Therapy Evaluation Pro-gram (CTEP), NCI Guidelines: Expedited Adverse Event Reporting Requirements. January 2005;http://ctep.cancer.gov/reporting/adeers.html]

Definition of an SAE: Any adverse experience occurring during any part of protocol treatmentand 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 disabillity/incapacity

• A congenital anomaly/birth defect

Important medical events that do not result in death, are not life-threatening, or do not requirehospitalization may be considered an SAEs, when, based upon medical judgment, they may jeop-ardize the patient and may require medical or surgical intervention to prevent one of the outcomeslisted in the definition. Any pregnancy occurring on the study must be reported as a medicallysignificant event.

SAEs attributed to the protocol therapy (possible, probable, or definite) should also be reported(Table 4).

Note: All deaths on study require both routine and expedited reporting regardlessof causality to the protocol PI; reporting to the IRB is governed by the reporting

30

http://ctep.cancer.gov/reporting/adeers.html


guidelines outlined in Tables 3 and 4. Attribution to treatment or other cause mustbe provided. “On study” is defined as during the protocol period.

15.2 NCI Common Terminology Criteria for Adverse Events (CTCAE)

This study will utilize the descriptions and grading scales found in the CTEP Active Versionof the NCI Common Terminology Criteria for Adverse Events (CTCAE) for grading all adverseevents. The CTEP Active Verstion of the CTCAE is identified and located on the CTEP websiteat: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Allmembers of the clinical care team should have access to a copy of the CTEP Active Version ofCTCAE.

AEs and SAEs that meet the criteria (defined above) experienced by patients accrued to this protocolmust be reported to the protocol PI and the treating institution’s IRB according to the reportingguidelines outlined in Tables 3 and 4.

16 Criteria for Removal from Study

Patients may be removed from the study at the discretion of the treating physician for unacceptabletoxicity – reasons for removal must be clearly documented on the appropriate case report form, andthe study PI must be notified.

The patient may withdraw from the study at any time for any reason. The treating physician mustnotify the study PI about this in writing.

17 Surgery

Not applicable to this study, except as specified in Sections 9 and 12.0.4 on salvage therapy andradiation necrosis management, respectively.

18 Drug Therapy

Not applicable to this study.

19 Other Therapy

• SRS: There are no restrictions on the administration of chemotherapy or targeted therapiesduring SRS. If the systemic agents are known radiation-sensitizers, the prescription dose canbe lowered at the discretion of the treating physician. It is strongly recommended (but notrequired) that prescription SRS guidelines are followed as closely as possible (Section 7 andFigure E).

• WBRT: Chemotherapy or targeted therapies during WBRT or over subsequent 7 days arediscouraged, but can be administered at the discretion of the treating team. Any systemictherapy given during the course of WBRT must be carefully documented.

31

http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


Tab

le3:

Criteriaforreportingrequ

irem

ents

forad

verseevents

(AEs)

andseriou

sad

verseevents

(SAEs)

that

occurwithin

30

day

sof

thedateof

thelast

protocoltreatm

ent.

Grade

33

4&

54&

5

Unexpected

Expected

Unexpected

Expected

withHospitalization

w/o

Hospitalization

withHospitalization

w/o

Hospitalization

--

Unrelated

Unlikely

10calendar

day

sNot

required

10calendar

day

sNot

required

10calendar

day

s10

calendar

day

s

Possible

Probable

Definite

10calendar

day

s10

calendar

day

s10

calendar

day

sNot

required

24hou

rs;5calen-

dar

day

s10

calendar

day

s

32


Tab

le4:

Criteriaforreportingrequ

irem

ents

forad

verseevents

(AEs)

andseriou

sad

verseevents

(SAEs)

that

occur>30day

sof

thedateof

thelast

protocoltreatm

ent.

Grade

33

4&

54&

5

Unexpected

Expected

Unexpected

Expected

withHospitalization

w/o

Hospitalization

withHospitalization

w/o

Hospitalization

--

Unrelated

Unlikely

Not

required

Not

required

Not

required

Not

required

Not

required

Not

required

Possible

Probable

Definite

10calendar

day

sNot

required

Not

required

Not

required

24hou

rs;5calen-

dar

day

s10

calendar

day

s

33


• Any systemic agents (chemotherapy or targeted therapies) used during the course of thestudy, including follow-up period, must be carefully documented in the study-specific database,including dose, route, schedule, dose reductions, toxicity etc.

20 Patient Assessments

20.1 Study Schema

See study schema in Section 1.

20.2 Assessments Schedule

The assessment/procedure schedule is illustrated in Table 5. All patients will be required to completeoNCF testing every 10-12 weeks in the o�ce/clinic setting. It is encouraged, but not mandated,that patients attempt to complete oNCF assessments outside of the o�ce/clinic setting at intervalsnot more frequent than every two weeks.

The oNCF assessment must be performed every 10-12 weeks in the clinic/o�ce set-ting under direct supervision of the on-site study coordinator. It is encouraged thatpatients complete oNCF assessments outside of the o�ce/clinic setting (e.g. home) amore frequent intervals that 10-12 weeks but not more frequent than every 2 weeks. Itis recommended that patients are reminded to complete oNCF testing at least monthlyby a telephone call from an on-site study coordinator.

Patient “self-reported” questionnaires as well as caregiver assessments can be accessed online andgiven to patients every 10-12 weeks in the o�ce/clinic setting under direct supervision of the on-sitestudy coordinator.

20.3 Clinical Evaluations

Complete and symptom-directed physical examination will be performed by a licensed physician orphysician’s assistant or nurse practitioner or nurse. It is expected that vital signs (blood pressure,respiratory rate, pulse rate, and temperature) will be obtained in the sitting position. Patientsshould be sitting for 3-5 minutes prior to obtaining vital signs. Laboratory studies are not required,except for pregnancy test and eGFR as specified above.

20.4 Neurocognitive Evaluations

20.4.1 Online Neurocognitive Function (oNCF) Assessments

The Brain Power TestTM (BPT) [Lumos Labs, Inc., San Francisco, CA] is an online battery ofneurocognitive assessments based on versions of six common tasks from the domains of neuropsy-chology and cognitive psychology. The assessments include versions of the Trail Making Test (partsA and B), a Choice Reaction Time Test, a Reverse Visual Memory Test, a Speeded ArithmeticTest, and a Grammatical Reasoning Test. Assessments assess performance across the domains ofvisual attention, cognitive flexibility, speed of processing, working memory, problem solving, andreasoning, respectively. These six assessments are scored individually and also aggregated into anoverall performance index. Norms are based on results from a broad, population-wide sample, ages13-80. The battery is short, taking approximately 20 minutes to complete, and is intended for

34


Tab

le5:

Studyassessment/procedure

schedule.

Event

-6wksto-1d

-30d

to-1d

-14d

to-1d

0d

q12-16days

(every

2wks)

q10-12wks

(every

3mo)

Diagn

osis

Mag

netic

Reson

ance

(MR)

X

StagingStudies(option

al)

X

Inform

edCon

sent

X

Med

ical

History

XX

PhysicalExam

XX

Heigh

tX

Weigh

tX

Vital

Signs

XX

X

eGFR

XX

Pregn

ancy

Test

X

KPS

XX

XX

Patient“self-reported”Assessm

ents

XX

Caregiver

Assessm

ents

XX

Qualityof

Life(Q

oL)Assessm

ents

XX

oNCF

Xscreenin

gX

Xa

Xb

Anatom

icMR

XX

StudyTreatment(SRSor

WBRT)

X

Respon

seAssessm

ent

X

CostDataCollection(U

B-04)

X

aOption

al:Patients

canchoose,

butdonot

haveto,complete

theseassessments

outsideof

theo�

ce/clinic

setting.

bMan

datory:oNCF

must

becompletedin

theo�

ce/clinic

settingunder

supervisionof

theon

-sitestudycoordinator.

35


repeated measurements across time, as each task has randomized elements of stimulus presentation.In the Trail Making Test Part A, participants click on circles with numbers in them in ascendingnumerical order. Part B requires participants to switch between letters and numbers in ascendingalphabetical and numerical order. In each case, scores are based on the time to accurately completea set of stimuli. In the Choice Reaction Time Test, participants indicate with a button click whenthey see a target stimulus (a particular type of fruit) and withhold responding when non-targets(di↵erent kinds of fruit) are displayed. Reaction times are measured and errors counted. The Re-verse Visual Memory Test requires participants to remember the order in which a series of blockswere highlighted and respond by clicking on the blocks in the reverse order. After each correct trial,an additional block is added to the span, and testing progresses until two errors in a row are madeat a given level. The score is equal to the last successfully completed level. The Speeded ArithmeticTest has participants indicate which side of an inequality is greater, or whether the two sides areequal. The score equals the total number of problems solved in 90 seconds. The GrammaticalReasoning Test requires participants to indicate whether statements are correct based on presentedstimuli. The stimuli are squares and triangles arranged side-by-side. Statements are of the form,The square/triangle is/is not to the right/left of the triangle/square. Participants indicate whethereach statement is true or false. The score is equal to the total number of correct responses minusthe number of errors for the 90 second trial period.

The oNCF assessment must be performed every 10-12 weeks in the clinic/o�ce setting under directsupervision of the on-site study coordinator. It is encouraged that patients complete oNCF assess-ments outside of the o�ce/clinic setting (e.g. home) a more frequent intervals that 10-12 weeks butnot more frequent than every 2 weeks. It is recommended that patients are reminded to completeoNCF testing at least monthly by a telephone call from an on-site study coordinator.

Tests that comprise the oNCF assessment battery are z-normalized at individual and aggregate lev-els; the normalized scores have a mean of 100 points and standard deviation (SD) of 15 points. Thetest-retest reliability of the oNCF battery is shown in Figure 2. These preliminary data are basedon measured outcomes of normal subjects/volunteers who have used oNCF assessment battery viaLumosity.com website [data courtesy of Lumosity, Inc., San Francisco].

Note: The oNCF test battery has not been validated or compared against standard neuropsychologist-driven assessments. This validation is subject of a parallel companion clinical trial (UCSF trial12105).

20.4.2 Quality of Life (QoL) Evaluation

Completion of the QoL measurements [QOL-30, BCM20, and EQ-5D] is mandatory for this protocol.Institutions must administer the baseline and follow-up assessments for the QOL-30, the BCM20,and the EQ-5D.

• QOL-30 and BCM20. The QOL-30 and BCM20 were developed and validated for use in braintumor patient population. The QOL-30 is a 30-item self-report questionnaire that asks thepatients to rate items on a 4-point scale, with 1 “not at all” to 4 “very much.” The instru-ment measures several domains, including physical functioning, role functioning, emotionalfunctioning, cognitive functioning, social functioning, fatigue, pain, nausea and vomiting, sev-eral single items (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial impact).The BCM20 consists of 4 scales comprised of multiple items (future uncertainty, visual dis-order, motor dysfunction, and communication deficit) and 7 single items (headache, seizures,

36


y"="0.9328x"+"10.743"r"="0.9079"R²"="0.8243"

0"

20"

40"

60"

80"

100"

120"

140"

160"

0" 20" 40" 60" 80" 100" 120" 140" 160"

Score&on

&test&2&

Score&on&test&1&

Test-Retest&Reliability&for&oNCF&Ba9ery&

Figure 2: Test-retest reliability data for oNCF test battery. These preliminary data are based on measuredoutcomes of normal subjects/volunteers who have used oNCF assessment battery via Lumosity.com websitewith an interval of at least 2 weeks between test 1 and test 2 [data courtesy of Lumosity, Inc., San Francisco].

drowsiness, hairloss, itching, di�culty with bladder control, and weakness of both legs). Thecombined instrument takes an average of 8 minutes to complete by patients with primarybrain tumors[57].

• EQ-5D. The EQ-5D is a 2-part, patient self-administered questionnaire that takes approxi-mately 5 minutes to complete[58]. The first part consists of 5 items covering 5 dimensionsincluding: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Eachdimension can be graded on 3 levels including: 1 “no problems”, 2 “moderate problems”,3 “extreme problems.” Health states are defined by a combination of the leveled responsesto the 5 dimensions, generating 243 health states to which “unconsciousness” and “death”are added[59]. The second part is a Visual Analog Scale (VAS) evaluating current state ofhealth, measured on a 10-point interval scale. Worst imaginable health state is scored as“100” at the top. Both the 5-item index score and the VAS score are transformed into autility score between 0 “worst health state” and 1 ”best health state.” The index score ofthe VAS score can be used in the quality-adjusted survival analysis depending on the healthstate(s) of interest[60].

37


20.4.3 Patient “Self-Reported” Measures

The patient will complete self-reported measures after completing the above (QoL questionnaires,Section 20.4.2) of depression (Beck Depression Inventory, BDI-II)[61], anxiety (Beck Anxiety Inven-tory, BAI)[62], quality of life (FACT-Br) [http://www.facit.org/FACITOrg/], cognition (FACT-Cog) [http://www.facit.org/FACITOrg/], and fatigue (Fatigue Severity Scale)[63].

20.4.4 Caregiver Assessments

The caregiver assessment will include measures of frontal symptoms, Frontal Systems Behavior Scale(FrSBE), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)) [http://npitest.net/],functional abilities (Functional Activities Questionnaire)[64], and cognition (Everyday Cognition(E-Cog))[65].

20.5 Cost Data

The Billing Department will provide the study coordinator with a paper copy of the UB-04 billingform for all enrolled patients at the study site hospital (or healthcare facility) during the previousquarter in a timely fashion (e.g. within 2 weeks of request). The UB-04 data will be requested forall medical care provided to the study subject (not just study-related treatments/interventions).The UB-04 is a one-page, universal billing form that is used to report uniform data on charges,diagnoses and procedures to Medicare on all hospital inpatient, outpatient, and emergency servicesand is familiar to all hospital billing departments.

20.6 Anatomic Magnetic Resonance Imaging

Established institutional MR imaging protocols for brain metastases will be used for diagnosticpurposes, including patient follow-up. It is recommended that axial MRI slice thickness is 3 mm(1.5 mm ideal). Some inter-institutional variability is expected and will be tracked. Note: TheGK treatment planning scans are non-diagnostic (therapeutic) and specified in Section 7. Thediagnostic MR imaging should be completed on either 1.5 or 3.0 Tesla magnet (3.0T preferred). Forexample, a UCSF brain metastases MR imaging series include: three-plane localizer, axial di↵usion-weighted imaging, axial pre-contrast T1-weighted imaging, 3D-CUBE FLAIR (reformatted in axialand coronal plane), axial T1-weighted post-contrast imaging, and coronal 3D-SPGR post-contrastimaging. In cases of suspected radiation necrosis (or recurrent tumor), perfusion MRI sequencesare added (Section 12).

20.7 OPTIONAL: Perfusion MR Imaging (pMRI)

Perfusion MR imaging should be considered in cases of suspected radiation necrosis to help distin-guish radiation necrosis from recurrent tumor[54].

21 Biostatistics

21.1 Study Endpoints

21.1.1 Primary Endpoint

Neurocognitive function, 6-months post WBRT/SRS treatment as measured by the online neu-rocognitive function (oNCF) composite z-score.

38

http://www.facit.org/FACITOrg/

http://www.facit.org/FACITOrg/

http://npitest.net/


21.1.2 Secondary Endpoints

• Neurocognitive function, 12-months post WBRT/SRS treatment as measured by the onlineneurocognitive function (oNCF) composite z-score.

• Neurocognitive function at all time points as measured by the online neurocognitive function(oNCF) composite z-score.

• Quality of life (patient-reported measures) as measured by Beck Depression Inventory, BeckAnxiety Inventory, FACT-Br, FACT-Cog, Fatigue Severity Scale, EQ-5D, BCM-20, and QOL-30.

• Quality of life as measured by caregiver assessments including Frontal Systems BehaviorScale, Neuropsychiatric Inventory, Functional Activities Questionnaire, and Everyday Cog-nition Questionnaire.

• Salvage therapy.

• Time to death.

21.2 Exploratory Endpoint

• To determine what healthcare cost data can be collected in patients with metastatic diseasewithin a context of a multi-institutional clinical trial.

21.2.1 Sample Size

This study looks at the di↵erence from baseline to 6-months post-treatment in neurocognitivefunction between SRS and WBRT treatment. The primary endpoint will be neurocognitive functionas measured by the relative change in oNCF composite z-score from the start of treatment to 6months after the start of treatment. The sample size calculations address the primary hypothesisthat there will be smaller decline in neurocognitive function for SRS than WBRT. We do notexpect an improvement in neurocognitive function; at best, we anticipate no-change. The null andalternative hypotheses are:

H0 : 4 oNCFSRS = 4 oNCFWBRT vs. Ha : 4 oNCFSRS 4 oNCFWBRT

where 4 oNCF j denotes the mean change in neurocognitive function between baseline and 6-months post-treatment for treatment j in this patient population. For the jth treatment and an indi-vidual patient i, the relative change is calculated as: 4 oNCF j,i = (oNCF j,i,0�oNCF j,i,6)/ oNCF j,i,0,where oNCF j,i,0 and oNCF j,i,6 are the patient’s score at baseline and 6 months after treatment.With 39 patients per treatment arm (i.e. assuming only 65% of the patients are able to take the 6-month oNCF), we will have 90% power to detect an e↵ect size of 0.74 using a one-sided two-samplet-test and alpha = 0.025. Regardless of the actual treatment received and subsequent salvagetherapy, every e↵ort will be made to acquire the 6-month data on all patients that are randomized.

21.2.2 Interim Analysis

One interim analysis will be performed on the relative change in oNCF composite z-score from thestart of the treatment to 6 months after the start of the treatment after the first 60 patients have aminimum of 6 months of follow-up. This will occur approximately at 18 months from the beginning

39


of the study. The assumptions used in the sample size calculations will be evaluated at the interimanalysis. If it appears that the treatment e↵ect is smaller than expected, we may request samplesize increase to achieve the desired study power. Alternatively, the study will be stopped if theinterim analysis demonstrates a significant di↵erence between the two treatment groups.

21.2.3 Analysis Plan

Primary Objective: The primary study endpoint is neurocognitive function as measured byoNCF composite z-score. For analysis purposes, the composite z-score is calculated by averagingz-scores of all oNCF subtests.

The primary objective is to compare the relative change in neurocognitive outcome (i.e. thechange in the online neurocognitive function (oNCF z-score) between baseline and 6 months forsurviving patients in upfront WBRT vs. SRS treatment groups. It is anticipated that only 65% ofthe patients will be able to take the 6-month oNCF.

The change can be defined by the Reliable Change Index (RCI) as an increase/decrease of atleast 4.5 points from baseline resulting in three categories: deterioration, no change, or improved.The RCI is derived from the standard error of measurement (SEM) for the oNCF test calculatedas: SEM = SDx(1-r)0.5, where r is the test-retest reliability and SD is the standard deviation of thetest scores. The oNCF z-score is normed to have a mean of 100 with a standard deviation of 15 anda test-retest coe�cient of 0.91.Percentage of patients in each treatment arm who show meaningfullosses or gains in the oNCF z-score between baseline and 6-months will be provided by frequencytables.

The primary assessment will be based on the mean relative di↵erence from baseline to 6-monthsbetween the treatment arms. We hypothesize that the mean change in neurocognitive function willbe less for the SRS treated patients than those treated with WBRT. Descriptive statistics of theactual change scores will be provided along with the mean (median) change score and standarddeviations (quartiles). The di↵erence between treatments will be tested via a one-sided two-samplet-test with a significance level of 0.025. Analysis will be completed after all live patients reach a12-month time point.

Interim Analysis: To allow for two analyses, the alpha level at each time point will be calculatedusing the O’Brien and Fleming spending function (approximately 0.0038 at 18 months and 0.0238at the end of study.

Secondary Objectives: The purpose of the secondary objectives is to better understand changesin neurocognitive and QoL measures over time. As such, all analyses will be focused on describingany observed changes over time. Analysis will be completed after all live patients reach a 12-monthtime point. Following are the objectives and intended analyses:


This analysis will be identical to that described in the primary analysis.

• To estimate stability or change in z-scores for oNCF assessments over all study endpoints insurviving patients treated with upfront WBRT vs. SRS.

This assessment of change over time can be achieved by employing an analysis of covariance modelthat relates the continuous oNCF outcome to the classification factor (treatment group) and thecontinuous covariate, time of oNCF exam, as well as an interaction term.

40


• To compare the relative impact of initial therapy (upfront WBRT or SRS) on patients’ QoL(patient-reported measures) as measured by Beck Depression Inventory, Beck Anxiety Inven-tory, FACT-Br, FACT-Cog, Fatigue Severity Scale, EQ-5D, BCM-20, and QOL-30 over allstudy timepoints.

and. . .

• To compare the relative impact of initial therapy (upfront WBRT or SRS) on patients’ QoLas measured by caregiver assessments (Frontal Systems Behavior Scale, Neuropsychiatric In-ventory, Functional Activities Questionnaire, and Everyday Cognition Questionnaire) over allstudy timepoints.

For both objectives and similar to the primary analysis, when possible, an Reliable Change Index(RCI) for each test in the QoL battery will be calculated and the proportion of patients withsignificant change between baseline and each time point will be assessed and compared between thetwo treatment groups. To assess change over time, as above, a random-e↵ects analysis of covariancemodel will be employed. If an RCI is not available for a test, the assessment will be based on themean relative di↵erence between time points as in the primary analysis.

• To compare proportions of patients in the two treatment groups (upfront WBRT vs. SRS) thatrequire salvage therapy as a function of systemic disease control (controlled vs. uncontrolled).

For this secondary objective, a competing risks analysis will be employed. The analysis will in-clude two events: salvage therapy as the event of interest and death without salvage therapy as thecompeting risk. Time to event will be modeled with those patients alive without salvage therapycensored at the time of their last examination prior to the analysis. The model will include covari-ates for treatment group and systemic disease control as well as an interaction.

Note: We believe that expected changes in oNCF as detailed in the primary and secondary objec-tives are clinically meaningful. Our goal is to try to confirm this by tracking caregiver and patients’own perceptions of their QoL over time. Since caregiver data has not been previously collected inclinical trials of this type, we cannot comment on the expected concordance of caregiver perceptionsand the results gained from oNCF testing.

• To compare the overall survival between patients in upfront WBRT vs. SRS treatment groups.

Overall survival will be calculated from date of original diagnoses to death and also from the date ofstudy registration to death. The latter will be the secondary endpoint for assessment of benefit ofthese therapies. For patients who are still alive at the time of final analysis, overall survival will becensored at the last contact date. Survival time will be estimated using the Kaplan-Meier productlimit curve and the survival experiences of the two treatment groups compared via a log-rank test.

Exploratory Objective: Patients will be asked to provide informed consent to reflect the factthat researchers will be requesting billing information from the hospital and clinic at the studysite. The billing data will be obtained from radiation oncology, neurosurgery, and hospital billingdepartments during the trial period every quarter (Section 20.4.3). A ‘Medicare’ costing approachwill convert hospital charges to costs, using publicly available information from Medicare cost re-ports. Charges will not be reported publicly. Proprietary costs accounting information will notbe requested. The purpose of this data collection is to determine what data can be collected inpatients with metastatic disease within a context of a multi-institutional trial. Since this approach

41


has not previously been done in a context of a prospective, multi-institutional clinical trial in apatient population with metastatic disease, any post hoc analysis will be subject to the availabilityof the collected data but every attempt will be made to determine direct and indirect costs of thetwo study treatments. Data collection may be complicated by regional di↵erences in healthcarepatterns as well as tendency for patients to receive care in one or more healthcare systems.

21.2.4 Surviving Fraction Estimates

The Surviving Fraction (SF) estimates are based on a recently published article by Serizawa etal.[31] and are shown in a table below.

Months post SRS

0 1 2 3 4 5 6 7 8 9 10 11 12

SF 1.00 0.94 0.88 0.83 0.77 0.71 0.65 0.59 0.53 0.48 0.42 0.36 0.30

22 Data Safety Monitoring Plan

22.0.5 Interim Analysis to Monitor Study Progress

Interim reports will be prepared once each year until final analysis has been accepted for presen-tation or publication. In general, these reports will contain information about the accrual ratewith projected completion date for the accrual phase, exclusion rates and reasons, pre-treatmentcharacteristics of patients accrued, compliance rate of treatment delivered with respect to the pro-tocol prescription, and the frequency and severity of adverse events. The UCSF Data and SafetyMonitoring Committee (DSMC) will review the study once a year with respect to patient accrualand morbidity. The DSMC will also review the study on an “as needed” basis.

22.1 Data and Safety Monitoring Plan

The UCSF DSMC will be the monitoring entity for this study. The DSMC will audit study-relatedactivities approximately every year to determine whether the study has been conducted in accor-dance with the protocol, local operating procedures, FDA regulations, and Good Clinical Practice(GCP). In addition, DSMC will regularly review serious adverse events and protocol deviationsassociated with the research to ensure the protection of human subjects. Results of the DSMCaudit will be communicated to the IRB and the appropriate regulatory authorities at the time ofcontinuing review, or in an expedited fashion, as needed. Interim analysis will be performed asdescribed in Section 21.2.2.

22.2 Data Management Issues

All data should be submitted to the Study Manager (contact information in Section 22.2.1) forentry into an electronic database. UCSF will be the coordinating site for protocol-related datacollection, storage, and maintenance. Study-specific forms will be created and made available forstructured data entry; original documents will be scanned and stored in the database as PDF at-tachments. Data that is already electronic, e.g. imaging and RT planning datasets, will be stored inthe database electronically in a secured Radiation Therapy - Picture Archiving and Communication

42


System (RT-PACS) that will reside on the same database server. Note: The database server hascompleted the UCSF Information Technology risk assessment and is the only permissible locationfor study-specific patient data storage for this study.

Any problems with data management issues should be reported to the study PI (contact informationin Section 22.3) in writing as soon as they occur, preferably < 5 working days. The study PI andthe Study Manager are responsible for performing the Quality Assurance review as described inSection 13.

22.2.1 Study Manager Contact Information

Marilyn Robinson, CCRPDepartment of Radiation OncologyUniversity of California, San Francisco1600 Divisadero Street, Suite H-1031, Box 1708San Francisco, CA 94143-1708

Tel: 415-353-4294Fax: 415-353-9883Pgr: 415-443-6604Email: [email protected]

22.3 Study Principal Investigator Contact Information

Igor J. Barani, M.D.Department of Radiation OncologyUniversity of California, San Francisco505 Parnassus Avenue, Room L-08, Box 0226San Francisco, CA 94143-0026

Tel: 415-353-8950 (clinic)Tel: 415-353-1195 (academic)Fax: 415-680-2440Pgr: 415-443-3913Email: [email protected]

23 Protection of Human Subjects

All patients must provide written informed consent prior to registration and treatment. Onlythe treating physician (and/or qualified members of his/her research team) at each participatinginstitution are authorized to obtain informed consent. All members of the qualified research teammust have completed the appropriate human subjects research and privacy training required by theirhome institution and this documentation (e.g. certificate of completion) must be made availableupon request. The patient will sign three copies of the informed consent. One copy will become partof the patient’s medical record, one copy will be stored in the patient’s research file (and scannedinto the study database), and one copy will be given to the patient to keep.

43

mailto:[email protected]

mailto:[email protected]


23.0.1 Consent Procedures

Procedures for obtaining Research Informed Consent: Before any protocol-specific procedures arecarried out, investigators and/or designated sta↵ will fully explain the details of the protocol, studyprocedures, and the aspects of patient privacy concerning research-specific information. In additionto signing the treatment-specific Informed Consent, all patients must sign an IRB (or equivalentregulatory body) approved, study-specific Informed Consent. Both consent forms must be kept onfile and scanned electronically into the study-specific database. The original signed documents willbecome part of the patient’s medical record, and each patient will receive a copy of the signeddocuments.

24 References

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[2] DW Andrews, CB Scott, PW Sperduto, AE Flanders, LE Gaspar, MC Schell, M Werner-Wasik, W Demas, J Ryu, JP Bahary, L Souhami, M Rotman, MP Mehta, and WJ Jr Curran.Whole brain radiation therapy with or without stereotactic radiosurgery boost for patientswith one to three brain metastases: phase iii results of the rtog 9508 randomised trial. Lancet,363(9422):1665–1672, 2004.

[3] M. E. Linskey, D. W. Andrews, A. L. Asher, S. H. Burri, D. Kondziolka, P. D. Robinson, M. Am-mirati, C. S. Cobbs, L. E. Gaspar, J. S. Loe✏er, M. McDermott, M. P. Mehta, T. Mikkelsen,J. J. Olson, N. A. Paleologos, R. A. Patchell, T. C. Ryken, and S. N. Kalkanis. The role ofstereotactic radiosurgery in the management of patients with newly diagnosed brain metastases:a systematic review and evidence-based clinical practice guideline. J Neurooncol, 96(1):45–68,2010.

[4] A. D. Norden, P. Y. Wen, and S. Kesari. Brain metastases. Curr Opin Neurol, 18(6):654–661,2005.

[5] LJ Schouten, J Rutten, HA Huveneers, and A Twijnstra. Incidence of brain metastases in acohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer,94(10):2698–2705, 2002.

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[7] JD Johnson and B Young. Demographics of brain metastasis. Neurosurg Clin N Am, 7(3):337–344, 1996.

[8] JS Barnholtz-Sloan, AE Sloan, FG Davis, FD Vigneau, P Lai, and RE Sawaya. Incidenceproportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan detroitcancer surveillance system. J Clin Oncol, 22(14):2865–2872, 2004.

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[11] AB Lassman and LM DeAngelis. Brain metastases. Neurol Clin, 21(1):1–23, vii, 2003.

[12] CA Meyers and PD Brown. Role and relevance of neurocognitive assessment in clinical trialsof patients with cns tumors. J Clin Oncol, 24(8):1305–1309, 2006.

[13] B Borgelt, R Gelber, S Kramer, LW Brady, CH Chang, LW Davis, CA Perez, and FR Hendrick-son. The palliation of brain metastases: final results of the first two studies by the radiationtherapy oncology group. Int J Radiat Oncol Biol Phys, 6(1):1–9, 1980.

[14] B Borgelt, R Gelber, M Larson, F Hendrickson, T Gri�n, and R Roth. Ultra-rapid high doseirradiation schedules for the palliation of brain metastases: final results of the first two studiesby the radiation therapy oncology group. Int J Radiat Oncol Biol Phys, 7(12):1633–1638, 1981.

[15] Clinicaltrials.gov. Dexamethasone and supportive care with or without whole-brain radiationtherapy in treating patients with non-small cell lung cancer that has spread to the brain andcannot be removed by surgery.

[16] LR Coia. The role of radiation therapy in the treatment of brain metastases. Int J RadiatOncol Biol Phys, 23(1):229–238, 1992.

[17] AR Harwood andWJ Simson. Radiation therapy of cerebral metastases: a randomized prospec-tive clinical trial. Int J Radiat Oncol Biol Phys, 2(11-12):1091–1094, 1977.

[18] JM Kurtz, R Gelber, LW Brady, RJ Carella, and JS Cooper. The palliation of brain metastasesin a favorable patient population: a randomized clinical trial by the radiation therapy oncologygroup. Int J Radiat Oncol Biol Phys, 7(7):891–895, 1981.

[19] KJ Murray, C Scott, HM Greenberg, B Emami, M Seider, NL Vora, C Olson, A Whitton,B Movsas, and W Curran. A randomized phase iii study of accelerated hyperfractionationversus standard in patients with unresected brain metastases: a report of the radiation therapyoncology group (rtog) 9104. Int J Radiat Oncol Biol Phys, 39(3):571–574, 1997.

[20] D Antoniou, K Kyprianou, GP Stathopoulos, C Skarleas, G Kolitsi, M Veslemes, J Dimitroulis,P Giamboudakis, K Marosis, O Armenaki, C Papageorgiou, and C Katis. Response to radio-therapy in brain metastases and survival of patients with non-small cell lung cancer. OncolRep, 14(3):733–736, 2005.

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[64] RI Pfe↵er, TT Kurosaki, CH Jr Harrah, JM Chance, and S Filos. Measurement of functionalactivities in older adults in the community. J Gerontol, 37(3):323–329, 1982.

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A Patient Informed Consent Form

University of California, San Francisco

Consent to Participate in a Research Study


WHOLE-BRAIN RADIOTHERAPY (CC121010/NAGKC 12-01)

This is a clinical trial, a type of research study. Your study doctor, Igor J. Barani MD, or one ofhis associates, will explain the clinical trial to you. Clinical trials include only people who chooseto take part. Please take your time to make your decision about taking part. You may discuss yourdecision with your friends and family. You can also discuss it with your health care team. If youhave any questions, you can ask your study doctor for more explanation.

You are being asked to take part in this study because you have cancer that has spread to the brain.

Why is this research study being done?

The standard treatment for patients with five or more brain metastases is whole-brain radiationtherapy [WBRT] that treats all structures in the brain (cancer as well as normal brain tissue) andcan only be done once. Though whole brain radiation can destroy cancerous brain cells, it can alsodestroy healthy brain cells. The death of healthy brain cells can lead to cognitive function (learningand memory) problems in patients treated with this form of cancer therapy. In fact, approximately50 percent of patients who receive whole brain radiation experience impaired cognitive function.Some patients who receive this treatment may develop dementia over time.

Stereotactic radiosurgery (also known as gamma knife radiosurgery) is being used to treat metastaticbrain lesions at some institutions. The gamma knife really isn’t a knife at all. This procedure doesnot involve cutting. The head is placed in a frame, to prevent motion during the treatment. Beamsof gamma radiation are focused on the tumor(s). Where these beams intersect, cancerous cells aredestroyed. Gamma knife radiosurgery targets only the brain cancer; normal brain tissue is spared.

Whole brain radiation is known to carry a significant risk of cognitive decline in the long run. Somestudies and research have shown that the benefits of radiosurgery can be as e↵ective as whole brainradiation without as much cognitive decline.

The goal of this study is to show stereotactic (gamma knife) radiosurgery causes less cognitive de-cline. We will compare the e↵ects (good and bad) of the whole brain radiation therapy and gammaknife radiosurgery to find out how the tumor and/or treatment a↵ect your brain function over time.We will do this by performing a series of neurocognitive assessments, or tests of memory, reasoning,and higher brain function, before your radiation treatment and at regular intervals after treatment.

Once the gamma knife radiosurgery or whole-brain radiation treatment has been done, your tu-mor(s) will be checked periodically with MRI scans, but no further treatment will be given unlessyour tumor(s) grows again or new tumor(s) is identified and we have consulted with all of yourtreating physicians.

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How many people will take part in the research study?

About 120 people will take part in this study. Up to 20 people will take part at UCSF.

What will happen if I take part in this research study?

Before you begin the study. . .

You will need to have the following exams, tests or procedures to find out if you can be in the study.These exams, tests or procedures are part of regular cancer care and may be done even if you donot join the study. If you have had some of them recently, they may not need to be repeated. Thiswill be up to your study doctor.

• Physical exam and neurological exam: You will have a physical and neurological examination,similar to those done for your regular medical care. The exam will take about 1 hour.

• MRI scan of the brain (with and without contrast): These scans are part of standard braincancer care and will take about 1 hour.

• Pregnancy testing: If you are a female and are of childbearing potential, a blood test will bedone at the initial visit to make sure you are not pregnant. Women of childbearing potentialare defined as those who have not yet reached menopause and have not undergone tuballigation or hysterectomy. Patients who have reached menopause or are at least 50 years oldand have had no menses for at least 24 months and/or have had hysterectomy, will not needa pregnancy test.

During the main part of the study. . .

If the exams, tests and procedures show that you can be in the main part of the study, and you chooseto take part, then you will need the following tests and procedures. None of these tests will delayyour treatment. If it is determined by your healthcare team that these exams, tests or procedureswill delay your treatment, you will be o↵ered the Gamma knife or whole-brain radiation treatmentand will be asked not to participate in the study. Your participation or lack of participation in thisstudy will in no way a↵ect the quality or the type of treatment that you need.

• You will be given access codes for online (web-based) cognitive testing that you can do athome. Two of these online tests will need to be completed 7-days apart before your treatment.Each online assessment takes approximately 20 minutes to complete. You and your primarycaretaker will also be asked to complete a short-series of questionnaires about your quality oflife that will take about 20 additional minutes to complete.

• You will meet with the radiation specialist (oncologist) who will perform either Gamma Kniferadiosurgery or whole-brain treatment in the clinic in order to have a complete explanationof the details of the treatment. This will include a discussion of the benefits and risks of thetreatment (these are also described later in the document).

• You will be ”randomized” into one of the study groups described below. Randomizationmeans that you are put into a group by chance. A computer program will place you in oneof the study groups. Neither you nor your study doctor can choose the group you will be in.You will have an equal chance of being placed in either group.

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If you are assigned to Gamma Knife treatment, then the following will take place:

• On the day of your treatment you will be brought into the hospital, and taken to the treatmentarea used for Gamma knife preparation. An intravenous catheter will be placed in order togive you fluids and/or small doses of medications for sedation (relaxation) should you becomeparticularly anxious during the procedure, and to give you medications to stop a seizure ifyou should have one.

• A stereotaxic frame, which is a metal device used to help guide radiation, will be placed onyour head. At four places, the skin will be cleaned with antiseptic solution, local anestheticwill be injected into the skin, and four small pins will be placed into the skin in order to attachthe stereotaxic frame to your skull. If a non-invasive stereotaxic frame, a frame that does notrequire the use of pins to attach to your head, is available for your procedure, a bite block(mold of your teeth while you bite down) will be created and attached to the frame to keepyour head still and help guide the radiation treatment.

• You will be taken, with the frame still on your head, to the MRI area where an MRI will beperformed. In most cases, sedating medications such as Ativan will be administered throughthe intravenous catheter in order to provide sedation and to reduce the chance that you willhave a seizure during the MRI.

• After the MRI, you will rest while your treatment is planned on a computer and approvedby your neurosurgeon and radiation oncologist. This planning process may take a couple ofhours.

• You will then be taken to the Gamma knife treatment area where radiosurgical treatment willbe performed. This involves having your head attached by way of the stereotaxic frame to theGamma knife machine. A series of radiation doses will be administered. The entire treatmentwill last several hours, depending on the number, size, shape, and locations of the lesionsthat will be treated. During this time, you will be in the treatment room by yourself witha video camera and microphones monitoring you. Your blood pressure (using an automaticcu↵), oxygen saturation, and heart rate (using a finger clip) will be monitored throughoutthe procedure. You will be able to speak to your nurses and doctors using a microphone. Inmost cases, you may be given additional sedating (relaxing) medication to make it easier torest comfortably during the treatment and to reduce your chances of having a seizure duringtreatment. If you have a long treatment, you may be able to take a brief (several minute)treatment break before resuming treatment again. You should discuss this with your treatingphysician before initiating treatment. The stereotaxic frame will be removed from your headimmediately after treatment, and small bandages will be placed on your skin.

• You will remain in the hospital for a short period of observation (30 minutes to a few hours).It is very likely that you will be able to go home at the end of the day. Since this is anoutpatient procedure, most patients go home at the end of the day unless there is a medicalindication to keep them in the hospital longer.

You can find additional information about Gamma Knife radiosurgery at http://www.elekta.com/patient_international_gamma_knife_surgery.php.

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If you are assigned to whole-brain radiation treatment [WBRT], then the following willtake place:

• Your radiation doctor (oncologist) will schedule a special CT scan (CT simulation scan).This scan will be done in a simulated treatment position so that your treating team canappropriately design the whole-brain radiation treatment.

• During the simulation CT scan, you will lie on your back with head on a rigid headrest. Theradiation oncology treatment team will make a plastic mask for your head to keep it stillduring treatment. The mask is made by placing a plastic mesh set in a U-shaped frame intowarm water so that the plastic softens before it is stretched over your face. When the plasticcools, it hardens and creates a permanent impression of your face. The mask frame is thenattached to the table to ensure that your head remains still during the scan and later duringtreatment.

• CT scan images obtained in this treatment position are then sent to a radiation therapy-planning computer where your radiation doctor (oncologist) and his team design and calculatethe appropriate whole-brain radiation treatment. These calculations are double- checked andverified before treatment starts. This process may take several days to complete.

• On your first treatment day, you will be positioned by radiation therapists in exactly the sameposition as you were on the simulation CT scan. The mask will be used to hold your headstill as before. The therapists will then take an X-ray image of your head to make sure thatyou are appropriately positioned before they start treatment.

• The treatment machine will then rotate to either right or left side of your head before totreat with the first beam, and then will rotate to the opposite side to treat with the secondbeam. The total treatment time will be approximately 15-20 minutes, including positioningand position verification.

• When you are done with the treatment, the therapists will remove your mask and keep it inthe room for your next treatment. You will have a total of 10 such treatments given 5 days aweek, Monday through Friday, as an outpatient. You will be free to go home after each dailytreatment, and will not be treated on weekends.

You can find additional information about External Beam Radiation Therapy on the National Can-cer Institute website at http://www.cancer.gov/cancertopics/coping/radiation-therapy-and-you/page3.

When you are finished receiving radiation treatment. . .

You will need the following tests and procedures. They are part of regular cancer care.

• Physical exam and neurologic exam: You will have a physical and neurological examination,similar to those done for your regular medical care, every 10-12 weeks (2.5-3 months). Eachexam will take about 1 hour.

• MRI scan of the brain (with and without contrast): This anatomic scan is part of standardbrain tumor care and will take about 1 hour. It will be done each time you return for a regularphysical and neurologic exam.

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You will also need the following tests and procedures done that are either being tested in this studyor being done to see how the treatment is a↵ecting your body.

• Phone call to check symptoms: All patients who enroll on the study will receive a phone callwithin 30 days after undergoing Gamma knife or whole-brain treatment, to see if they arehaving any symptoms or complaints. Patients can opt to receive additional phone calls andreminders from the treating team.

• Online brain function testing: All patients who enroll on the study will be asked to complete ashort 20-minute online brain function (cognitive) assessment every 2 weeks (twice per month,at least 10-14 days apart).

• Quality of Life Questionnaire: You will be asked to complete a self-reported (if patient) andcaregiver quality of life questionnaires every 10-12 weeks (2.5-3 months). These questionnairestake approximately 15-20 minutes to complete and can be done online or at your physicianso�ce during your follow-up visits.

Cost Data: Because one aspect of the trial is to collect cost data to determine whether one typeof treatment costs significantly more than the other, you will be asked to give the Medical Centerpermission to release some of the information regarding cost of treatments to the investigators.Specifically, your treating medical center (or healthcare system) will provide the investigators withbilling information for any inpatient or outpatient care that you receive during the study, includingfollow-up period. The billing information will contain information on any diagnoses that you have,any procedures that are performed and the charges for the care that you receive at these placesduring the course of the trial. These data will be kept in the same way that other data will, andthe investigators will make every attempt to preserve the confidentiality of this information.

Where will this study take place?

All study procedures and tests will be done at participating North American Gamma Knife Con-sortium (NAGKC) institutions in the USA and Canada, accept for online cognitive testing whichwill be done on the online website of Lumosity.com.

At UCSF, all clinic visits, radiation treatment planning and radiation treatments will be performedat University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143.

How long will I be in the study?

After you are finished receiving Gamma knife radiosurgery or whole-brain radiation therapy, thestudy sta↵ will ask you to visit the o�ce for follow-up exams until there are indications (eitherthrough your symptoms and/or MRI scans) that the Gamma knife radiosurgery or whole-brain ra-diation is not controlling the brain metastases, or if additional brain metastases are found, or untila time when it is determined that di↵erent treatment for your tumor is needed. If you are eligibleto receive other treatment for your brain cancer, such surgery, chemotherapy, or other treatments,we would like you to continue to be closely monitored according to this protocol. We would liketo keep track of your medical condition for the rest of your life even if you choose to discontinuefollow-up online neurocognitive testing. We would like to do this by contacting you or your otherdoctors periodically to obtain information about the status of your health.

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Can I stop being in the study?

Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stoppingor decide to stop. He or she will tell you how to stop your participation safely.

It is important to tell the study doctor if you are thinking about stopping so you can discuss whatfollow-up care and testing could be most helpful to you. The study doctor may stop you from takingpart in this study at any time if he/she believes it is in your best interest, if you do not follow thestudy rules, or if the study is stopped.

What side e↵ects or risks can I expect from being in the study?

You may have side e↵ects while on the study. Everyone taking part in the study will be watchedcarefully for any side e↵ects. However, doctors dont know all the side e↵ects that may happen. Sidee↵ects may be mild or very serious. Your health care team may give you medicines to help lessenside e↵ects. In some cases, side e↵ects can be serious, long lasting, or may never go away. There isalso a risk of death.

In this study, your health care team will closely monitor you with frequent visits, neurocognitivetesting, and imaging designed to identify treatment- and/or cancer-related problems early. Oncesuch problems are identified, you will receive the appropriate feedback and suggestions on how youand your family can cope with them. If social services are identified that may be useful, your healthcare team will make every attempt to help arrange those. There are no e↵ective brain rehabilitationprograms for patients treated for brain cancer with radiation.

You should talk to your study doctor about any side e↵ects you experience while taking part in thestudy.

The risks and side e↵ects related to the Gamma Knife radiosurgery are:

Likely:

• Soreness at the sites where the pins are attached to your skull (this usually lasts for one ortwo days)

• Headache after the removal of the head frame (this usually resolves one day after treatment)

• Fatigue, sleepiness (temporary)

Less Likely:

• Brain swelling, which may cause existing or previous neurologic symptoms to get worse

• Mu✏ed hearing (temporary)

• Potential infection at the pin sites

• Small area of hair loss over the treated tumor(s) about 3 weeks after Gamma Knife (regrowthusually occurs about 3 months after the procedure)

Rare but Serious:

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• Seizures

• Severe headaches

• Paralysis

• Coma

• Radiation necrosis (formation of dead tissue), which can cause brain swelling months laterand require steroids (or other drugs) or surgery

• A second new cancer caused by radiation, in the brain or nearby organs

• Visual system injury with the possibility of permanent blindness

The risks and side e↵ects related to the whole-brain radiation therapy [WBRT] are:

Likely:

• Hair loss, which may be permanent

• Dry mouth

• Headaches

• Nausea and/or vomiting

• Scalp reddening or tanning and irritation (Your skin will be examined once a week duringradiation therapy)

• Memory loss, which can occur in the first few months after whole-brain radiotherapy and maybe permanent

Less Likely:

• Temporary worsening of tumor-like symptoms such as seizures or weakness (or other neurologicproblems)

• Drainage of clear fluid from the ears or plugging of the ears with decreased hearing

• Behavioral change and/or increased sleepiness (occurring four to ten weeks after radiotherapy,temporary)

• Cataracts and eye damage with the possibility of impaired vision

Rare but Serious:

• Radiation necrosis (formation of dead tissue), which can cause brain swelling months laterand require steroids (or other drugs) or surgery

• Hardening of the arteries in the brain, which may lead to strokes

• A second new cancer caused by radiation, in the brain or nearby organs

• Eye damage with the possibility of permanent blindness

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Online neurocognitive and quality of life questionnaires: You may find some of the ques-tions in the questionnaires to be frustrating or private. If any questions in the questionnaires makeyou feel uncomfortable, you may skip those questions and not give an answer.

Blood drawing (venipuncture) risks: Drawing blood may cause temporary discomfort fromthe needle stick, bruising, and infection.

MRI risks: Because the MRI machine acts like a large magnet, it could move iron-containingobjects in the MRI room during your examination, which in the process could possibly harm you.Precautions have been taken to prevent such an event from happening; loose metal objects, likepocketknives or key chains, are not allowed in the MRI room. If you have a piece of metal in yourbody, such as a fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or apacemaker, you will not be allowed into the MRI room and cannot have a MRI.

Having a MRI may mean some added discomfort for you. In particular, you may be bothered byfeelings of claustrophobia and by the loud banging noise during the study. Temporary hearing losshas been reported from this loud noise. This is why you will be asked to wear earplugs. At timesduring the test, you may be asked to not swallow for a while, which can be uncomfortable.

Contrast agent (gadolinium) risks: A few side e↵ects of gadolinium injection such as mildheadache, nausea, and local pain may occur. Rarely (less than 1% of the time) low blood pressureand lightheadedness occurs. This can be treated immediately with intravenous fluids. Very rarely(less than one in one thousand), patients are allergic to gadolinium. These e↵ects are most com-monly hives and itchy eyes, but more severe reactions have been seen which result in shortness ofbreath.

Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. Thecondition is called nephrogenic sclerosing fibrosis (NSF). It can cause skin to tighten or scar andcan damage internal organs. Sometimes it can be life threatening. There are no reports of NSFin patients with normal kidney function. Before you have a MRI scan requiring an injection ofgadolinium contrast, you will have a blood test to check the function of your kidneys. Based onyour medical history and the results of the test, a doctor will decide whether it is safe for you toundergo the MRI scans.

Reproductive risks: You should not be pregnant or father a baby while on this study becausethe treatment in this study can a↵ect an unborn baby. Women should not breastfeed a baby whileon this study. It is important to understand that you need to use birth control while on this study.Check with your doctor about what kind of birth control methods to use and how long to use them.Some methods might not be approved for use in this study.

Randomization risks: You will be assigned to a treatment program by chance, and the treatmentyou receive may prove to be less e↵ective or to have more side e↵ects than the other study treatmentor other available treatments.

Unknown risks: The experimental treatments (or more extensive follow-up) may have side e↵ectsthat no one knows about yet. The researchers will let you know if they learn anything that mightmake you change your mind about participating in the study.

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For more information about risks and side e↵ects, ask your study doctor.

Are there benefits to taking part in the study?

Taking part in this study may or may not make your health better. The purpose of this study is toidentify the type, severity, and time course of cognitive changes after radiation treatment for braincancer that may ultimately lead to improved treatments and post-treatment patient care.

We do know that the information from this study will help define the future treatment of brainmetastases.

What other choices do I have if I do not take part in this study?

Your other choices may include:

• Getting treatment or care of you cancer without being in a study.

• Taking part in another study, if available.

• Receiving Gamma knife radiosurgery o↵ study.

• Receiving whole-brain radiation therapy o↵ study.

• Getting no treatment.

• Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness,appetite problems, and other problems caused by cancer. It does not treat the cancer directly,but instead tries to improve how you feel. Comfort care tries to keep you as active andcomfortable as possible.

Please talk to your doctor about your choices before deciding if you will take part in this study.

Will my medical information be kept private?

We will do our best to make sure that the personal information in your medical record is keptprivate. However, we cannot guarantee total privacy. Your personal information may be given outif required by law. If information from this study is published or presented at scientific meetings,your name and other personal information will not be used.

Data on cost of treatment will also be collected and analyzed as part of this study. With yourpermission, we can collect this information through your treating institutions billing (or equivalent)o�ces. We will not share this information with anyone. Our research with this information mayhelp us better understand cost-e↵ectiveness of treatments. Any publications or presentations thatresult from this research will not identify you in any way.

Organizations that may look at and/or copy your medical records for research, quality assuranceand data analysis include:

• North American Gamma Knife Consortium (NAGKC) and the NAGKC coordinating site(University of California - San Francisco, UCSF)

58


• The National Cancer Institute (NCI) and other government agencies, e.g. the Food and DrugAdministration (FDA), involved in keeping research safe for people.

• The UCSF Helen Diller Family Comprehensive Cancer Center

• The Committee on Human Research, an institutional review board, a committee who is in-volved in keeping research safe at UCSF.

• The UCSF Principal Investigator, Igor Barani, MD, and his designees

A Data Monitoring Committee (DMC) will be regularly meeting to monitor safety and other datarelated to this study. The Committee members may receive confidential patient information, butthey will not receive your name or other information that would allow them to identify you by name.

Participation in research may involve a loss of privacy, but information about you will be handledas confidentially as possible. A medical record will be created because of your participation in thisstudy. Your consent form and some of your research test results will be included in this record.Therefore, your other doctors may become aware of your participation. Hospital regulations requirethat all health care providers treat information in medical records confidentially.

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required bylaw. This Web site will not include information that can identify you. At most, the Web site willinclude a summary of study results. You can search this Web site at any time.

What are the costs of taking part in this study?

You and your health plan/insurance company will need to pay for the costs of all visits, treatmentsand tests for treating your cancer in this study. Some health plans will not pay these costs for takingpart in studies. Check with your health plan/insurance company to find out what they will pay for.Taking part in this study may or may not cost you or your insurance company more than the costof getting regular cancer treatment. Radiosurgery is an accepted treatment for a metastatic braintumor as is whole-brain radiation therapy, and we expect that insurance companies will usually payfor it. Your doctors will ask the insurance company for treatment authorization ahead of time. Ifyour insurance company does not agree to pay for the radiosurgery (Gamma knife), your doctorswill tell you and you can talk about other treatment options. MRIs are a requirement of this studyand are required at baseline, for treatment planning, and follow-up. These MRIs are consideredstandard of care and will be billed to your insurance.

Neither you nor your insurance company will be billed for the neurocognitive testing procedures,as these are being done solely for the research study.

For more information on clinical trials and insurance coverage, you can visit the National Cancerinstitutes website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.

You can print a copy of the Clinical Trials and Insurance Coverage information from this website.

Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them tosend you a free copy.

59


Will I be paid for taking part in this study?

You will not be paid for taking part in this study.

What happens if I am injured because I took part in this study?

It is important that you tell your study doctor(s) and/or the UCSF principal investigator, IgorBarani, MD, if you feel that you have been injured because of taking part in this study. You cantell the study doctor in person or call him/her at 415-353-7175.

Treatment and Compensation for Injury: If you are injured as a result of participation in thisproject, treatment will be available. The costs of this treatment may be covered by the Universityof California, depending on a number of factors. The University does not normally provide anyother form of compensation for injury. For further information about this, you may call the o�ceof the Committee on Human Research at 415-476-1814.

What are my rights if I take part in this study?

Taking part in this study is your choice. You may choose either to take part or not to take part inthe study. If you decide to take part in this study, you may leave the study at any time. No matterwhat decision you make, there will be no penalty to you and you will not lose any of your regularbenefits. Leaving the study will not a↵ect your medical care. You can still get your medical carefrom your institution.

We will tell you about new information or changes in the study that may a↵ect your health or yourwillingness to continue in the study.

In the case of injury resulting from this study, you do not lose any of your legal rights to seekpayment by signing this form.

Who can answer my questions about the research study?

You can talk to your study doctor about any questions or concerns you have about this study.Contact the principal investigator, Igor Barani, MD, and/or your study doctor, at (415) 353-8900or (415) 353-7175.

For questions about your rights while taking part in this study, call the o�ce of The Committeeon Human Research (CHR), UCSFs Institutional Review Board (a group of people who review theresearch to protect your rights at 415-476-1814.

Where can I get more information?

You may call the National Cancer Institute’s Cancer Information Service at:1-800-4-CANCER (1-800-422-6237)

You may also visit the NCI Web site at http://cancer.gov/

• For NCIs clinical trials information, go to: http://cancer.gov/clinicaltrials/

60

http://cancer.gov/

http://cancer.gov/clinicaltrials/


• For NCIs general information about cancer, go to http://cancer.gov/cancerinfo/

You will get a copy of this form. If you want more information about this study, ask your studydoctor.

CONSENTYou have been given copies of this consent form and the Experimental Subjects Bill of Rights to keep.

You will be asked to sign a separate form authorizing access, use, creation, or disclosure of healthinformation about you.

PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participateor to withdraw at any point in this study without penalty or loss of benefits to which you areotherwise entitled.

If you wish to participate in this study, you should sign below.

Date Participant

Date Person Obtaining Consent

Date Printed Name of Person Obtaining Consent

Date Translator Signature (if applicable)

61

http://cancer.gov/cancerinfo/


B Caregiver Informed Consent Form

University of California, San Francisco

Consent to Participate in a Research Study


WHOLE-BRAIN RADIOTHERAPY (CC121010/NAGKC 12-01)

Medical research studies (clinical trial) include only people who choose to take part. Take your timeto make your decision about participating. You may discuss your decision with your family, friendsand with your health care team. If you have any questions, you can ask your study doctor.

You are being asked to take part in this study because you are the primary caregiver for someone whohas a cancer that has spread to the brain, and they will be receiving radiation therapy with eitherwhole brain radiation therapy or stereotactic radiosurgery (gamma knife) as part of their treatment.

Why is this study being done?

Radiation to the brain can lead to cognitive function (learning and memory) problems. We are try-ing to find out if Gamma Knife radiosurgery causes less cognitive decline than whole brain radiationin patients with 5 or more brain metastases. Whole-brain radiation therapy [WBRT] is consideredstandard-of-care treatment for these patients, but published literature demonstrates that patientstreated and re-treated (as needed) with radiosurgery experience the same overall survival as thosetreated with WBRT. Radiosurgery has the theoretical potential to reduce post-treatment cognitivedecline by focusing radiation on the “visible” brain lesions without treating the surrounding nor-mal brain tissue. Because of this and unlike WBRT, Gamma Knife radiosurgery does not treatmicroscopic, or “invisible,” disease in the brain and may therefore need to be repeated if new brainmetastases develop over time. WBRT can only be given once. Patients who develop new lesionsafter WBRT can generally still be treated with Gamma Knife radiosurgery provided that the diseaseburden does not make such treatments unsafe.

As part of the main study, we will ask the person you are caring for to complete quality of life(QoL) forms and neurocognitive testing to find out their own perceptions of their QoL and abilityto think, learn and remember over time.

In addition to the person you are caring for, we also want to know your perception of their quality oflife and how well they are able to think, learn, remember over time. This will be done to determinewhether measured changes in their (patients) cognitive function after treatment and over time areclinically significant and meaningful.

How many people will take part in the study?

The caregivers of about 120 people will take part in this study nationwide. Up to 20 caregivers willtake part at UCSF.

What will happen if I take part in this research study and how long will I be in thestudy?

62


If you agree to participate, you will be asked to complete four (4) questionnaires: Frontal SystemsBehavior Scale (FrSBE), Neuropsychiatric Symptoms Inventory (NPI), Functional Activities Ques-tionnaire, and Everyday Cognition (E-Cog) assessment before the person you are caring for beginsradiation treatment, then every 10-12 weeks (3 months). This will be done primarily in clinic, butmay also be done at home.

It will take about 30 minutes to fill out the questionnaires each time you are asked to complete them.

If you decide to take part in this Quality of Life study, the only thing you will be asked to do is fillout the questionnaires. You may change your mind about completing the questionnaires at any time.

What side e↵ects or risks can I expect from being in the study?

You may find some of the questions in the questionnaires to be embarrassing or private. If anyquestions in the questionnaires make you feel uncomfortable, you may skip those questions and notgive an answer.

Will my personal information be kept private?

Data are housed in a password-protected database. We will do our best to make sure that yourpersonal information will be kept private. However, we cannot guarantee total privacy. Your per-sonal information may be given out if required by law. If information from this study is publishedor presented at scientific meetings, your name and other personal information will not be used.

Organizations that may look at and/or copy your responses to the questionnaires for research,quality assurance, and data analysis include:

• North American Gamma Knife Consortium (NAGKC) and the NAGKC coordinating site(University of California - San Francisco, UCSF)

• The National Cancer Institute (NCI) and other government agencies, e.g. the Food and DrugAdministration (FDA), involved in keeping research safe for people.

• The UCSF Helen Diller Family Comprehensive Cancer Center and its designees including aData Monitoring Committee (DMC) that regularly meets to monitor safety and other studydata

• The Committee on Human Research, an institutional review board, a committee who is in-volved in keeping research safe at UCSF.

• The UCSF Principal Investigator, Igor Barani, MD, and his designees

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required bylaw. This Web site will not include information that can identify you. At most, the Web site willinclude a summary of study results. You can search this Web site at any time.

What are the costs of taking part in this study?

There will be no costs to you for participating in this study.

63


Will I be paid for taking part in this study?

You will not be paid for taking part in the study.

What are my rights if I take part in this study?

Taking part in this study is your choice. You may choose either to take part or not to take part inthe study. If you decide to take part in this study, you may leave the study at any time. No matterwhat decision you make, there will be no penalty to you nor will the person you are caring for loseany of their regular benefits. Leaving the study will not a↵ect the person you are caring for medicalcare. They can still get their medical care from our institution.

We will tell you about new information or changes in the study that may a↵ect your willingness tocontinue in the study.

In the case of injury resulting from this study, you do not lose any of your legal rights to seekpayment by signing this form.

Who can answer my questions about the study?

You can talk to your study doctor about any questions or concerns you have about this study. Youmay contact the study doctor, Igor J. Barani, MD, at the UCSF Department of Radiation Oncologyat either (415) 353-8900 or 415-353-7175.

If you wish to ask questions about the study or your rights as a research participant to someoneother than the researchers or if you wish to voice any problems or concerns you may have aboutthe study, please call the O�ce of the Committee on Human Research (CHR) UCSFs InstitutionalReview Board (a group of people who review the research to protect your rights) at 415-476-1814.

Where can I get more information?

You may call the National Cancer Institute’s Cancer Information Service: 1-800-4CANCER (1-800-422-6237)

You may also visit the NCI Web site at http://cancer.gov/

• For NCIs clinical trials information, go to: http://cancer.gov/clinicaltrials/

• For NCIs general information about cancer, go to http://cancer.gov/cancerinfo/

You will get a copy of this form. If you want more information about this study, you may ask thestudy doctor.

CONSENTYou have been given copies of this consent form and the Experimental Subjects Bill of Rights tokeep. You will be asked to sign a separate form authorizing access, use, creation, or disclosure ofhealth information about you.

64

http://cancer.gov/

http://cancer.gov/clinicaltrials/

http://cancer.gov/cancerinfo/


PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participateor to withdraw at any point in this study without penalty or loss of benefits to which you areotherwise entitled.

If you wish to participate in this study, you should sign below.

Date Participant

Date Person Obtaining Consent

Date Printed Name of Person Obtaining Consent

Date Translator Signature (if applicable)

65


C Experimental Subject’s Bill of Rights

The rights below are the rights of every person who is asked to be in a research study. As anexperimental subject, I have the following rights:

1. To be told what the study is trying to find out,

2. To be told what will happen to me and whether any of the procedures, drugs, or devices aredi↵erent from what would be used in standard practice,

3. To be told about the frequent and/or important risks, side e↵ects, or discomforts of the thingsthat will happen to me for research purposes,

4. To be told if I can expect any benefit from participating, and, if so, what the benefit mightbe,

5. To be told of the other choices I have and how they may be better or worse than being in thestudy,

6. To be allowed to ask any questions concerning the study both before agreeing to be involvedand during the course of the study,

7. To be told what sort of medical treatment is available if any complications arise,

8. To refuse to participate at all or to change my mind about participating after the study isstarted. This decision will not a↵ect my right to receive the care I would receive if I were notin the study,

9. To receive a copy of the signed and dated consent form,

10. To be free of pressure when considering whether I wish to agree to be in the study.

If have other questions, I should ask the researcher or the research assistant conducting the study.Every institution conducting human subjects research has a regulatory body, such as an InstitutionalReview Board (IRB) (or equivalent), that can provide additional information about your rights. Theresearcher and/or research assistant conducting this study can provide you with the appropriatecontact information.

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D Karnofsky Performance Status Scale

Score Description100 Normal, no complaints; no evidence of disease.90 Able to carry on normal activity; minor signs and symptoms of disease.80 Normal activity with e↵ort; some signs or symptoms of disease.70 Cares for self; unable to carry on normal activity or to do active work.60 Requires occasional assistance, but is able to care for most of his/her personal needs.50 Requires considerable assistance and frequent medical care.40 Disabled; requires special care and assistance.30 Severely disabled; hospital admission is indicated although death not imminent.20 Very sick; hospital admission necessary; active supportive treatment necessary.10 Moribund; fatal processes progressing rapidly.0 Dead.

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E Radiosurgery Single-Fraction Prescription Guidelines

400 3 6 9 12 15 18 21 24 27 30 33 36

20

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Prescription Isodose Volume (cc)

Do

se (G

y)

Radiosurgery Dose-Volume Relationship

Figure 3: Single-fraction radiosurgery dose-volume relationship and prescription guidelines for an individualtarget. For the purposes of this protocol, all patients should be dosed according to this relationship unlessproximity to critical normal structures or other reasons preclude application of the derived dose safely. Formultiple lesion targets in close proximity, the dose may lowered by 1-2 Gy (orange band) at the discretionof the treating physician. It is not recommended that dose be reduced in patients previously treated withWBRT, but this decision will be up to the treating physician. Any deviations from these prescriptionguidelines must be recorded and justified in writing. Note: It is not recommended that target lesionsbe treated with doses <15 Gy.

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F Target Volume Screening Diagram

0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.12.22.3 2.5 2.7 2.9 3.1 3.3 3.5 3.7 4 4.3 4.6 4.9 5.2 5.65.9 6.30.7

0.8

0.9

1

1.1

1.2

1.31.41.51.61.71.81.9

2.12.22.3

2.5

2.72.93.13.33.53.7

44.34.64.95.25.65.96.3

0.7

0.7

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Max. Superior−Inferior Dimension (cm)

Max

. Ant

erio

r−Po

ster

ior D

imen

sion

(cm

)

Max. Right−Left Dimension (cm)

Figure 4: This diagram permits rapid screening of the largest lesion volume (<10 cc) from linear measure-ments. A combination of maximum linear measurements in any two planes can be used to determine thelargest permissible linear dimension in the third plane that would result in an estimated volume of 10 cc.Note: The protocol eligibility limits the largest intracranial tumor volume to 10 cc.

69