lessons learned from radiation oncology clinical trials · rtog 9811 anal canal is ef ﬁ cacy of...

Review

Lessons Learned from Radiation Oncology Clinical Trials

Fei-Fei Liu1, for theworkshopparticipants, PaulOkunieff2, Eric J. Bernhard3, HelenB. Stone3, StephenYoo4, C.Norman Coleman3, Bhadrasain Vikram5, Martin Brown6, John Buatti7, and Chandan Guha8

AbstractA workshop entitled "Lessons Learned from Radiation Oncology Trials" was held on December 7–8,

2011, in Bethesda, MD, to present and discuss some of the recently conducted radiation oncology clinical

trials with a focus on those that failed to refute the null hypothesis. The objectives of this workshop were to

summarize and examine the questions that these trials provoked, to assess the quality and limitations of the

preclinical data that supported the hypotheses underlying these trials, and to consider possible solutions to

these challenges for the design of future clinical trials. Several themes emerged from the discussions: (i)

opportunities to learn from null-hypothesis trials through tissue and imaging studies; (ii) value of

preclinical data supporting the design of combinatorial therapies; (iii) significance of validated biomarkers;

(iv) necessity of quality assurance in radiotherapy delivery; (v) conduct of sufficiently powered studies to

address the central hypotheses; and (vi) importance of publishing results of the trials regardless of the

outcome. The fact that well-designed hypothesis-driven clinical trials produce null or negative results is

expected given the limitations of trial design and complexities of cancer biology. It is important to

understand the reasons underlying such null results, however, to effectively merge the technologic

innovations with the rapidly evolving biology for maximal patient benefit through the design of future

clinical trials. Clin Cancer Res; 19(22); 6089–100. �2013 AACR.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose.

Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the lessons learned from null or negative clinical

trials in radiation oncology and how to improve the design of radiation oncology clinical trials in the future.

Acknowledgment of Financial or Other SupportThis activity does not receive commercial support.

IntroductionClinical trials involving radiotherapy (RT) for cancer are

initiated to identify novel technologic and biologicapproaches that can improve local tumor control, dis-ease-free survival (DFS), and overall survival (OS); reduce

toxicity; and/or enhance quality of life. The design of thesetrials should be based on solid preclinical evidence support-ing such approaches; however, often, patients participatingin the experimental arm fare no better than control subjects(1). A similar trend is currently being reported for drug

Authors' Affiliations: 1Department of Radiation Oncology, Princess Mar-garet Cancer Center, Toronto, Ontario, Canada; 2Department of RadiationOncology, University of FloridaShandsCancerCenter,Gainesville, Florida;3Radiation Research Program, Division of Cancer Treatment and Diagno-sis, National Cancer Institute, Bethesda; 4Molecular Radiation Therapeu-tics Branch, Division of Cancer Treatment and Diagnosis, and 5ClinicalRadiation Oncology Branch, National Cancer Institute, Rockville, Mary-land; 6Department of Radiation Oncology, Stanford University, Palo Alto,California; 7Department of Radiation Oncology, University of Iowa Hospi-tals and Clinics, Iowa City, Iowa; and 8Department of Radiation Oncology,Albert Einstein College of Medicine andMontefioreMedical Center, Bronx,New York

This article is dedicated to the memory of Dr. Kian Ang, a leader inradiation oncology, who was continuously improving outcome for our

patients with cancer, through the methodical conduct of high-impactclinical trials.

Corresponding Authors: Fei-Fei Liu, Department of Radiation Oncol-ogy, Princess Margaret Cancer Center, 610 University Avenue, Tor-onto, ON M5G 2M9, Canada. Phone: 416-946-2123; Fax: 416-946-4586; E-mail: [email protected]; Bhadrasain Vikram, ClinicalRadiation Oncology Branch, National Cancer Institute, Rockville, MD20852. E-mail: [email protected]; and Chandan Guha, Departmentof Radiation Oncology, Albert Einstein College of Medicine and Mon-tefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-13-1116

�2013 American Association for Cancer Research.

ClinicalCancer

Research

www.aacrjournals.org 6089

on February 8, 2020. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst September 16, 2013; DOI: 10.1158/1078-0432.CCR-13-1116

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combination trials (2). To identify possible reasons forthese negative outcomes, and to propose pathways toincrease the likelihood of "success," a workshop entitled"Lessons Learned fromRadiationOncology Trials"washeldonDecember 7–8, 2011, inBethesda,MD, sponsoredby theRadiation Research Program of the National Cancer Insti-tute (NCI; Bethesda, MD). The objectives of the workshopwere to assess the quality, quantity, and limitations of thepreclinical data that supported the hypotheses underlying afew recently completed trials and to consider potentialimprovements inmethods generating these trials. Attendeesincluded radiation and medical oncology clinical trialists,radiation biologists, clinician-scientists, radiation physi-cists, statisticians, and representatives from the pharmaceu-tical industry. To provide common ground for dialogue,results from 10 recently completed clinical trials fromseveral different malignancies were discussed (Table 1),which included the spectrum of positive, negative, and nulloutcomes.

Summary of Clinical TrialsCentral nervous system tumors

Two studies focused on glioblastoma multiforme werepresented and discussed. The Radiotherapy and OncologyGroup (RTOG) 0525/EORTC 26052-22053 was an inter-national phase III randomized clinical trials (RCT) deter-mining whether dose-intensifying adjuvant temozolomidecould improve OS (3). The overall conclusion was "noevidence for improvement," although the prognostic valueof MGMT (O-6-methylguanine-DNA-methyltransferase)promoter methylation status was confirmed.

The second phase I/II RTOG 0211 trial examined theaddition of an EGF receptor (EGFR) tyrosine kinase inhib-itor (TKI; gefitinib) to radiotherapy for patients with glio-blastoma multiforme, which failed to show any OS benefitwith the combinatorial approach (4). In fact, tumors withelevated SRC or PTEN expression fared worse with the TKI,illustrating the complex signaling cascades underlyingmostglioblastoma multiforme.

Head and neck squamous cell carcinomaDespite the success of the landmark cetuximab plus radio-

therapy combination for patients with locally advancedsquamous cell carcinoma of the head and neck (LAHNSCC;refs. 5, 6), the results of more recent trials have been disap-pointing. The RTOG 0129 asked whether accelerated frac-tionated radiotherapy (AFX) plus cisplatin (CDDP) wouldimprove OS for patients with LA HNSCC (7); in fact, nodifference was observed between the standard versus AFXgroup, suggesting that CDDP likely offsets tumor cell repop-ulation during fractionated radiotherapy.

The TROG 02.02 trial examined the value of adding ahypoxic cytotoxic agent, tirapazamine, to CDDP-RT forpatients with LA HNSCC (8). Disappointingly, this studyalso showed no difference in outcome, but its results under-scored the importance of quality assurance in radiotherapydelivery (9), as well as raising questions about the clinicalimportance of tumor hypoxia (10). A third trial (RTOG

0522) asked whether the addition of cetuximab to CDDP-RT could improve progression-free survival (PFS; ref. 11);this study not only failed to show an advantage to the triplemodality but also observed greater acute toxicities. Further-more, cetuximab and CDDP seemed to have overlappingmechanisms of action; hence, using complementary tumor-icidal agents would likely be more effective.

Lung malignanciesThe four-arm RTOG 0617 trial compared OS differences

between high- versus standard-dose conformal radiothera-py with concurrent chemotherapy (carboplatin and pacli-taxel), with or without cetuximab for patients with stageIIIA/IIIB non–small cell lung carcinoma (NSCLC). Theresults showed no difference in OS between the high- (74Gy) versus standard-dose (60 Gy) patients (12), even sug-gesting an inferior survival with the high-dose arm, possiblyrelated to treatment-related deaths, which may underscorethe importance of quality assurance in radiotherapy plan-ning and delivery (13).

Gastrointestinal malignanciesThe RTOG 9811 phase III RCT addressed the efficacy of

substituting CDDP for mitomycin C (MMC), in the stan-dard 5-fluorouracil (5-FU)/MMC/RT regimen for anal canalcarcinoma. The results showed no difference in DFSbetween the two treatment arms, but the CDDP groupexperienced a significantly higher colostomy rate (14). Themajor design flaw related to two new hypotheses of drugand sequence, both being addressed simultaneously, withthe new drug being CDDP, delivered in an inductionmanner. Consequently, it remained unclear whether thenegative results were related to an ineffective drug, anineffective sequence, or both.

The RTOG 0020 phase II randomized trial of gemcita-bine/paclitaxel/RT, followed by a farnesyltransferase inhib-itor (FTI; R115777) for unresectable pancreatic cancer,showed that maintenance of FTI failed to improve clinicaloutcome and yet was associated with increased toxicities,highlighting the challenges to inhibiting K-ras, an estab-lished oncogenic target in this disease (15).

Genitourinary malignanciesThe RTOG 94-13 trial, a complex four-arm randomiza-

tion of whole pelvis versus prostate-only radiotherapy, withsecondary randomizationofneoadjuvant versus concurrenthormone scheduling (16, 17) reported no significant dif-ference in PFS for any group. This was an underpoweredfour-arm trial that failed to address the issues of field size ortiming of androgen suppression. There might also havebeen an unpredicted biologic interaction between concur-rent androgen suppression with radiotherapy, supportingan argument for the importanceof companion translationalstudies to acquire biologic insights.

The EuropeanOrganisation for Research and Treatment ofCancer (EORTC) 22961 trial showed that long-term andro-gen suppression (total of 3 years) was marginally superior toshort-term treatment (6 months) when patients were also

Liu et al.

Clin Cancer Res; 19(22) November 15, 2013 Clinical Cancer Research6090




Tab

le1.

Rad

iatio

non

cology

clinical

trials

once

ntraln

ervo

ussystem

,he

adan

dne

ck,lung

,gas

trointes

tinal,a

ndge

nitourinarymaligna

ncies

prese

nted

anddiscu

ssed

byworks

hoppartic

ipan

ts

Trial

Target

tumor

site

Primaryobjective(and

resu

lts)

Acc

rual

period

Patientsac

crue

d(completedor

rand

omized

)Notable

seco

ndaryfind

ings

Ref

RTO

G05

25EORTC

2605

2-22

053

Glio

blastom

amultiforme

Doe

sdo

se-inten

sifyingad

juva

nttemoz

olom

ideim

prove

OS?

(noev

iden

ceforim

prove

men

t)

Janu

ary20

06to

June

2008

1,17

3(833

)—MGMTwas

valid

ated

asaprog

nostic

marke

r.—New

prog

nostic

marke

rswerereve

aled

:IDH1,

G-C

IMP,m

RNAprofiles.

(3)

RTO

G02

11Glio

blastom

amultiforme

Istheco

mbinationof

EGFR

TKinhibition

(Ires

sa)w

ithRTsa

fean

deffica

ciou

s?(noOSbe

nefitforpatientstrea

ted

with

gefitin

ibþ

RTvs

.RTalon

e)

June

2003

toJa

nuary20

12Pha

seI:31

Pha

seII:

147

(119

)

—Correlativ

eim

mun

ohistoch

emical

analysis

oftis

sueforprogn

ostic

marke

rsof

survival

(src,IGF-IR,P

TEN,A

KT,

EGFR

,NF-kB

),an

dpredictiveva

lueof

thes

emarke

rsforge

fitin

ibresp

onse

—Som

emarke

rs(eleva

tedSrc

andPTE

N)

predictedforpo

orer

resp

onse

with

gefitin

ib.

(4)

RTO

G01

29HNSCC

Doe

sac

celeratedRTco

mbined

with

CDDPim

prove

survival

ofpatients

with

LAHNSCC?

(noev

iden

ceforim

prove

men

t)

July

2002

toMay

2005

743(721

)—CDDPoffset

tumor

clon

ogen

repop

ulation

duringtheco

urse

offrac

tiona

tedRT

(7)

TROG

02.02

HNSCC

Doe

sad

dingahy

pox

ictoxin

(tirapaz

amine)

toRT-CDDPregimen

improve

survival

forpatients

with

LAHNSCC?

(noev

iden

ceforim

prove

men

t)

Sep

tember

2002

toApril

2005

861(853

)—RTqua

lityas

suranc

eis

critica

l.—Nee

dfortumor

hypox

iastratifi

catio

n.(8)

RTO

G05

22HNSCC

Doe

sad

dingce

tuximab

tothe

RT-CDDPregimen

improve

PFS

forpatientswith

LAHNSCC?

(noev

iden

ceforim

prove

men

t)

Nov

ember

2005

toMarch

2009

940(895

)—Mec

hanism

ofce

tuximab

andCDDP.

Rad

iose

nsitiza

tionmay

overlap.

—Th

etripletregimen

was

asso

ciated

with

high

erratesof

muc

ositis-

and

cetuximab

-ind

uced

skin

reac

tions

.—Effec

tsof

HPVstatus

onresp

onse

tobe

inve

stigated

(11)

RTO

G06

17NSCLC

Doe

shigh

erRTdo

se(60vs

.74Gy

with

conformal

RT�

cetuximab

)con

fera

trea

tmen

tresp

onse

ben

efit?

(noev

iden

ceforim

prove

men

t)

Nov

ember

2007

toApril

2011

�500

(423

)—Fu

tility

analysis

resu

ltedin

clos

ureof

high

-dos

earms,

andthestan

darddos

eof

RTforstag

eIII

NSCLC

remains

at60

Gy;

surpris

ingly,

nosign

ifica

ntdifferen

cein

trea

tmen

t-relatedtoxicity

betw

een

high

-dos

evs

.stand

ardRTarms.

—RTO

Gha

sissu

edareque

stforpropos

alsto

cond

ucttran

slationa

lres

earchus

ing

materials

obtained

from

this

trial.

(12)

(Con

tinue

don

thefollo

wingpag

e)

Radiation Oncology Clinical Trials

www.aacrjournals.org Clin Cancer Res; 19(22) November 15, 2013 6091




Tab

le1.

Rad

iatio

non

cology

clinical

trials

once

ntraln

ervo

ussystem

,he

adan

dne

ck,lung

,ga

strointestinal,an

dge

nitourinarymaligna

ncies

prese

nted

anddiscu

ssed

byworks

hoppartic

ipan

ts(Con

t'd)

Trial

Target

tumor

site

Primaryobjective(and

resu

lts)

Acc

rual

period

Patientsac

crue

d(completedor

rand

omized

)Notable

seco

ndaryfind

ings

Ref

RTO

G98

11Ana

lcan

alIs

effica

cyof

CDDP-bas

ed(exp

erim

ental)therap

ybetter

than

mito

myc

in-bas

ed(stand

ard)

therap

yin

trea

tmen

tof

anal

cana

lca

rcinom

a?5-FU

/CDDPþ

RTvs

.5-FU/M

MC

þRT

Octob

er19

98to

June

2005

682(644

)—Nodifferen

cein

DFS

betwee

nthetw

oarms,

but

CDDP-bas

edtherap

yresu

lted

inasign

ifica

ntly

worse

colostom

yrate.

(14)

RTO

G00

20Pan

crea

ticca

ncer

Doe

sad

dition

ofmainten

ance

with

anFT

Iimprove

gemcitabine/pac

litax

elch

emo-RT?

Wee

klyge

mcitabine,

paclita

xel,an

dex

ternal

irrad

iatio

n(50.4Gy)

follo

wed

bytheFT

IR11

5777

;addition

ofFT

Ish

owed

noim

prove

men

tin

clinical

outcom

e,ye

twas

asso

ciated

with

increa

sedtoxicitie

s.

Nov

ember

2001

toSep

tember

2003

195(174

)—Mainten

ance

R11

5777

did

notincrea

sesu

rvival

andwas

asso

ciated

with

increa

sedtoxicitie

s.—Triald

idno

tad

dress

poten

tialfor

radiose

nsitiza

tionbyFT

I.—K-ras

was

know

nno

tto

beatarget

forFT

Iinh

ibition

.

(15)

RTO

G94

-13

High-ris

kprostate

canc

er

Doe

spe

lvic

RTim

prove

PFS

compared

with

prostate-on

lyRTam

ongpatients

with

ach

ance

oflymphno

de

invo

lvem

ent?

(noev

iden

ceforim

prove

men

t)

April

1995

toJu

ne19

991,32

3(1,292

)—Studyun

derpow

ered

forpairw

ise

comparison

s.—Lo

ng-term

follo

w-upresu

ltsrefuted

short-term

ben

efitrepo

rted

.—Sim

ilarEurop

eantrial,GETU

G-01,

show

edno

differen

cein

PFS

betwee

nthe

pelvisan

dprostate-on

lyarms.

(16)

EORTC

2296

1High-ris

kprostate

canc

er

Doe

slong

erdurationof

androg

ensu

ppress

ionim

prove

long

-term

outcom

e?(m

argina

limprov

emen

tin

long

-term

outcom

e)

April

1997

toNov

ember

2001

1,11

3(970

)—Lo

ng-term

was

margina

llysu

periorto

short-term

androge

nsu

ppress

ion.

(18)

Abbreviations

:HPV,h

uman

pap

illom

aviru

s;IDH,iso

citratede

hydroge

nase

1;IGF-IR,ins

ulin-likegrow

thfactor-Irece

ptor.

Liu et al.





treated with radiotherapy (18). The effect size was small; 5-year cumulative prostate-specific mortality differed by only2.5%, and the majority of patients had low Gleason scores.Hence,whether long-termandrogen ablation is beneficial formost patients or not remained unclear.

Emerging ThemesTable 2 summarizes the emerging themes and recom-

mendations from the workshop.

Preclinical studiesMany reasons could account for the success of the cetux-

imab-plus-radiotherapy RCT for HNSCC (5, 6), including(i) the universally reported prognostic value for EGFR over-expression (19–21); (ii) the role of EGFR in mediatingradiation resistance (22–24); (iii) the demonstration ofefficacy of EGFR inhibitors in several different preclinicalcancermodels (25–27); (iv) awell-designeddrug(28),whichwas highly efficacious and well-tolerated (29); and (v) awell-constructed and efficiently executed clinical trial (5).On the basis of the above success, and corroborating the

framework for preclinical studies as outlined byHarringtonand colleagues in the UK (30), it is recommended thatbefore any combinatorial treatments are considered withradiotherapy, one must start with an in vitro clonogenicassay of the novel drug of interest plus radiotherapy in

relevant preclinical cancer models. The MTT and apoptoticassays are simple but are poor substitutes for the morequantitative clonogenic survival assays, which until other-wise shown, will remain the gold standard for the evalua-tion of any radiation sensitizer,DNA repairmodification, orcombinations of radiotherapy with drug.

The Molecular Radiation Therapeutics Branch within theRadiation Research Program of the NCI (rrp.cancer.gov/aboutRRP/mrtb.htm) has already generated data for mul-tiple targeted agents combined with radiotherapy in panelsof human cancer cell lines; therefore, this resource shouldbe the first point of contact before embarking on anycombinatorial therapies. Next is the generation of in vivodata using different human cancer xenograft models, whichhave their limitations by only partially reflecting humantumor heterogeneity; furthermore, the tumor microenvi-ronment (e.g., hypoxia), stromal factors, or the humanmetastatic patterns are not completely recapitulated. Someorthotopic models might address such limitations (31, 32),as well as early-passaged human tumor xenografts. Analternative is the use of genetically engineered mouse mod-els (GEMM) of human cancers (33), which could be usefulfor lung cancer (34, 35) and soft tissue sarcomas (36).Recently, Guerin and colleagues at the SunnybrookResearch Institute (Toronto, ON, Canada) developed aclinically relevant murine model of postsurgical advanced

Table 2. Summary of recommendations from the workshop

Emerging themes

Preclinical studies

* Must conduct at least in vitro clonogenic assay* Contact theRadiationResearchProgramatNCI,which is coordinating thepreclinical and clinical studies formultiple targetedagentscombined with RT in panels of human cancer cells before embarking on combinatorial therapies

* Generate in vivo data using different human cancer xenograft models

Biomarkers

* Develop and validate tumor microenvironment predictive biomarkers* Develop and validate predictive biomarkers of sensitivity to molecular-targeted therapies* Use "clinical-ready" pharmacodynamic read-outs* Need for robust imaging methods for tumor identification, segmentation, and characterization across institutions

Clinical trial design

* Simple* Ensure study statistically powered (i.e., sufficient sample size)* Consider use of adaptive trial design

Quality assurance

* Conduct expeditious real-time quality assurance of RT plans

Publication bias

* Publish results of trials regardless of the outcome* Public sharing of raw data

International consortium

* Establish a consortium for the evaluation of radiation modifiers to expedite the discovery and translation of effective agents that willenhance the curative outcomes of RT for patients with cancer






metastatic breast cancer, which could be an improvedmodel on evaluating efficacy of antiangiogenic agents(37). This effort and other similar work highlight the needto focus on developing and using better preclinical models,which in turn might lead to higher success rates in clinicaltrials.

Many of these xenograft models are readily availablewithin the radiation oncology community, including thecentral nervous system(38), lung (39, 40), breast (41), headand neck (42), pancreas (32, 43), and cervix (31). Fundingfor these studies remains challenging, although some phar-maceutical companies could be interested as such data willinform the design of early-phase clinical trials. Finally,another potential solution could be the use of a panel ofmolecularly annotated first-generation xenografts harbor-ing high and low levels of the putative target (44); this couldguide clinically realistic radiotherapy and drug doses forsubsequent clinical trials.

Microenvironment as a targetOver 60 years of research on hypoxia and radiotherapy,

tumor response can be summarized in the followingmanner: (i) rodent and human tumors contain hypoxiccells; (ii) rodent tumors are more hypoxic than humantumors and thus will model only the most hypoxic ofhuman tumors; (iii) hypoxic human tumors are radiother-apy resistant; (iv) methods to overcome hypoxia in humantumors are less than perfect but are beneficial (45); and (v)the ideal methods to identify or treat hypoxic tumors donot yet exist.

Three limitations of the TROG 02.02 trial (8) relate toadministration of tirapazamine, quality assurance of radio-therapy plans, and human papillomavirus (HPV) status.The tirapazamine dose was sufficiently high to potentiateCDDP; however, it was administered with only nine of 35fractions, which could have compromised the anticipatedbenefit. Tumors were not selected for hypoxia, and 12% ofthese patients had noncompliant radiotherapy plans thatadversely affected tumor control (9), and these patientswere disproportionally distributed to the tirapazamine arm.Finally, TROG 02.02 was designed before the full apprecia-tion of HPV-associated oropharyngeal cancer, which seemsnot to benefit from hypoxic modifications (46), therebydiluting the potential benefit of tirapazamine.

Other tumor microenvironment properties, such asextracellular pH, angiogenesis, and interstitial fluid pres-sure, might also influence tumor response to radiotherapy,as well as targeting stromal cells, cytokines, and oxidativestress. To date, however, other than hypoxia, no phaseIII RCTs have evaluated such strategies with radiotherapyoutcome.

In summary, hypoxia is a negative predictor in sometumors treated with radiotherapy. Despite clear benefits inmultiple trials of hypoxia modifiers with radiotherapy, theresults have not been sufficiently dramatic to change clinicalpractice (47). Improved agents are being developed (48)and will be evaluated with hypoxia imaging conducted atcritically important times (49), which will help to improve

selection of appropriate patients for such therapeutic strat-egies and hopefully improve the likelihood of positiveclinical trials.

Biomarker studiesBiomarkers are germane to categorizing patients into

distinct risk groups for prognostic or predictive value,enriching cohorts for clinical trials, and tracking longitudi-nal response to therapies. With the emergence of dataderived from the International Cancer Genome Consor-tium (ICGC; www.icgc.org/) and The Cancer Genome Atlas(TCGA; cancergenome.nih.gov) deep-sequencing projects,this is anopportunemoment to capitalize on such resourcesto triage patients into genetically or proteomically definedgroups and to identify novel targets and actionable muta-tions for radiotherapy-combinatorial trials, although tumorheterogeneity will remain challenging (50). Many of theICGC/TCGA clinical data are not yet sufficiently mature toidentify robust prognostic markers; the role of radiotherapymight also be difficult to discern if such treatment detailsare lacking. Consequently, the value of well-annotatedbiospecimens linked to radiotherapy RCTs cannot beoverstated.

The landmark observation of the benefit of temozolo-mide to radiotherapy for glioblastoma multiforme (51)changed practice and led to the evaluation of temozolo-mide dose intensification (RTOG 0525), corroborating theprognostic value of MGMT methylation status. A transla-tional study evaluating primary glioblastoma multiformetissues from participants in multiple clinical trials showeda potential two-gene signature (DNF-kBIA plus MGMTmethylation), as well as suggesting a biologic explanationfor the lack of efficacy of erlotinib (52), as NF-kBIAdeletion and EGFR amplification emerged to be mutuallyexclusive aberrations in glioblastoma multiforme. Similarimportant insights have been derived from RCT tissuestudies for HNSCC, not only corroborating the superioroutcome for HPV-associated HNSCC (7), but also theirlimited benefit by hypoxic modifiers (46), which might inpart account for the negative TROG 02.02 trial (8, 10).These data clearly illustrate the value of correlative tissuestudies in providing biologic insights, and informing thedesign of future trials.

Another approach is the use of an adaptive trial design(53); in these trials, data gathered during trial progressionare used to change an aspect of the trial midway. In theBiomarkers-Integrated Approaches of Targeted Therapy forLung Cancer Elimination (BATTLE) trial, 40% of thepatients were randomly assigned to receive one of fourtreatments during the first phase of the trial (54). In thesecond adaptive phase, treatments were based on the resultsof previous biomarker testing during the first phase. Thistrial highlighted the potential advantage of an adaptivedesign, especially during complex trials that assess multipledrugs and biomarkers, and require tissue collection andbiomarker analysis (53). This is a very promising area ofinvestigation that should influence the design of futureradiotherapy–drug trials for lung cancer, which requires

Liu et al.





the analysis of multiple known mutations such as KRAS,EGFR, and EML4-ALK.Yet another critically important consideration is the use

of "clinical-ready" pharmacodynamic read-outs. Pharma-codynamic assays ofDNAdamage such as g-H2AX in tumortissues (55) or quantifying poly-ADP-ribose (PAR) levels inperipheral blood mononuclear cells (PBMC; ref. 56) mightbe highly applicable for radiotherapy clinical studies, asopposed to phosphorylated Akt (P-Akt), which is notori-ously unstable. This is an area of active investigation by theFrederick National Laboratory for Cancer Research, animportant resource for the radiation oncology researchcommunity.

Imaging biomarker studiesTumor response assessment in clinical trials has typically

been derived from longitudinal assessments of anatomi-cally based diagnostic images [computed tomography(CT) and MRI], using Response Evaluation Criteria inSolid Tumors (RECIST), which could be subject to observ-er bias, differences in scanning techniques, or lack ofquantitative rigor (57). In an effort to address these short-comings the NCI established the Quantitative ImagingNetwork (QIN) as a means to develop robust automatedand semiautomatic methods for tumor identification,segmentation, and characterization. Each institution inthis network has engaged teams of clinicians and research-ers to develop enhanced quality assurance methods forimage acquisition and data analysis and to improve inter-institutional reproducibility.The ability to quantify ametabolic tumor volumeonPET/

CT scans across institutions will be critical to providebiologic information and achieve an added level of consis-tency. These changes would also expand the use of molec-ular imaging with an array of novel positron emissiontomography (PET) tracers, as well as application ofadvanced MRI methods including spectroscopy, dynamiccontrast enhanced, and diffusion-weighted imaging. Thesynergy between the QIN and cooperative groups will becrucial for the future of radiotherapy research.

Design of clinical trialsIn designing complex clinical trials, there needs to be a

deep appreciation of the characteristics of the targetedpopulation and competing risks. For example, if theproportion of patients in a hypothetical "hypoxic cyto-toxic" trial is only 15%, depending on the anticipatedbenefit of the intervention, up to 1,000 patients might berequired to show a difference in outcome (as hypothe-sized by Dr. Quynh-Thu Le, Stanford University, Stan-ford, CA). Similarly, if the targeted population has com-peting risks (e.g., patients with lung cancer or HNSCC);the sample size needs to be increased significantly if OS isthe primary endpoint.Alternatively, if the design of clinical trials is complex

(e.g., RTOG 94-13 had a complex 2�2 design), and if theinteraction between the modalities is not fully appreciated,then this could lead to a potentially underpowered study. In

the RTOG 94-13 trial, at the time of its design, the interac-tion of hormonal therapy with radiotherapy for prostatecancer was not yet fully elucidated (58), underscoring theimportance of preclinical evaluations to better understandsuch potentially complex biology.

Importance of radiotherapy quality assuranceThe critical importance of quality assurance in radiother-

apy was succinctly illustrated in the aforementioned tira-pazamine trial, wherein deficient radiotherapy plans wereassociated with a 20% reduction in OS (9) that far out-weighed any potential benefits from biologically targetedagents. The fundamental principle is that if the tumor is notirradiated, it will not be controlled. Many internationalefforts have been undertaken to conduct prereviews ofintensity-modulated radiotherapy plans (59, 60) and qua-lity assurance programs for image-guided radiotherapyprotocols (61, 62). These are critically important endeavorsto ensure patient safety, treatment fidelity, and quality ofradiotherapy.

The recently completed RTOG 0617 trial for NSCLC wasa null trial, failing to show a benefit for the higher-doseradiotherapy arm. Multiple reasons might explain thisobservation, but there was a higher incidence of treat-ment-related deaths in the latter arm (discussed duringthe workshop), posing dosimetric considerations as onepossible explanation. Similarly, a review of RTOG gastro-intestinal trials uncovered a significant minority of unac-ceptable radiotherapy plans (discussed by Dr. Chris Will-ett, Duke University Medical Center, Durham, NC), whichmight also in part, account for their null results (63).Importantly, in trials in which unacceptable radiotherapyplans were corrected, positive results were then observed(63). By harnessing the capabilities of digital technology,pretreatment reviews of radiotherapy plans could beundertaken in an expeditious and resource-efficient man-ner. Several reports have highlighted that radiotherapyquality assurance is a critically important step in theclinical trial process that should result in improved clinicaloutcomes (64–66).

Data sharing and publication biasA current challenge in our biomedical research com-

munity is a tendency toward publication bias of positiveresults, documented decades ago wherein meta-analysesof published data would have overestimated the treat-ment benefit versus results from registered clinical trials(67). This tendency continues today, wherein more than20% of phase III clinical trial abstracts presented at theannual meeting of the America Society of Clinical Onco-logy (ASCO) remain unpublished after 6.5 years, or tooklonger than 5 years to be published (68).

The requirement to reproduce published data is afundamental tenet to achieve true medical advances. Thelack of data reproducibility is a major problem for drugdevelopment, wherein two thirds of these studies havesignificant inconsistencies (69, 70). One example relatesto motexafin gadolinium, which proceeded to phase III






testing (71) despite laboratory evidence documenting itslack of radiosensitization (72). The lack of reproducibilityhas costs to patients, for participating in treatments thatare unlikely to be beneficial, and to society. Pharmaceu-tical companies lose time and money on pursuing aca-demic discoveries that remain difficult to reproduce (73,74), which can be further compounded by off-targeteffects with siRNAs (75, 76).

In the current era of genomic medicine, this situationbecomes evenmore challenging (77); data fromonly two of18 microarray publications in Nature Genetics could bereplicated. The major problem is inaccessibility to theoriginal raw data files (78), with potentially dire conse-quences for patients (77). Science devoted its entire Decem-ber 2, 2011, issue to this very topic (79) and recommendedsix steps: (i) analytic validity (different platforms); (ii)repeatability (different scientists); (iii) replication (meta-analyses of different datasets); (iv) external validation (con-sistent large-scale datasets); (v) clinical validity (can predictclinical outcome); and (vi) clinical use (actually improvesclinical outcome) before any -omic data be used in clinicalmedicine. Similar guidelines have been suggested for pre-dictive or prognostic biomarkers based on five levels ofevidence, ranging from underpowered observationalreports to prospectively designed clinical trials examininga specific biomarker (80).

These recommendations have been developed to tem-per human nature, which prefers celebratory versus sober-ing news, the competition in science and academia, andthe explosive quadrupling growth in the number ofscientific journals from 1970 to 2011. e-Journals suchas BMC Research Notes encourage the publication of

negative data and replication of previously reportedresults. Recognizing the academic and societal value ofwell-conducted but null or negative publications wouldenhance the likelihood of such studies becoming publiclyavailable.

Consideration of an international consortiumThe clinical development of radiation modifiers is fre-

quently a secondary path, spin-off, or occasional after-thought to drug development by industry, academia, orgovernment (Fig. 1). Basic discovery defines a tumormolec-ular target, and if the developer considers this to be poten-tially useful in combination with radiotherapy, it will beincluded in the developmental plans (Fig. 1). In this con-text, the formation of an international consortium for theevaluation of radiation modifiers could be as a means topool resources developed in a collaborative manner toexpedite the discovery and translation of effective agents,which will enhance the curative outcomes of radiotherapyfor patients with cancer.

As shown in Fig. 1, there could be a stepwise progressionof examining molecular targets combined with radiother-apy, prioritized through a steering committee, with assign-ment of specific assays to different groups with such exper-tise. This will result in a pipeline of potential therapeuticcandidates advancing through in vitro, in vivo, pharmaco-kinetics/pharmacodynamic, and phase 0/I to II, and evenRCTs, if such targets fulfill the predefined criteria for pro-gression. Furthermore, the prompt publication of null,negative, or positive results can be of great benefit inavoiding patient toxicity as well as the needless expense indeveloping a less-than-adequate drug.

CCR Reviews

© 2013 American Association for Cancer Research

Development and assessment of radiation modifiers — An international consortium

In vivoIn vitroLab Clinic

HTP clonogenic

assays

(multi-log)

Newer HTP

assays (possibly

larger range)

Simple HTP

assays

(generally 1 log)

Basic science

discoveryPhase 0–I

Postmarket

—+

Phase III

Phase II

PK and PD

Patient-derived

xenografts

Mechanism of action during development and “bedside to bench”

PublishPublish

Tumor

xenografts

GEMMs–tumor,

normal tissues

Tumor

control

Standard

models Figure 1. Pathway of in vitro toin vivo to phase I/II/III clinical trials.Proposed model and activities ofan international consortiumthrough which potential drugs canbe provided from academia,industry, and government, andprioritized for evaluation througha steering committee. HTP,high throughput; PD,pharmacodynamic; PK,pharmacokinetics.

Liu et al.





ConclusionsSeveral recently conducted radiation oncology clinical

trials were presented and discussed at an NCI-US–spon-sored workshop. By nature, clinical trials, which areresource-intensive, can often lead to null observations;hence, it behooves us to capitalize upon each opportunityto maximize the derived information. To that end, impor-tant themes emerged from this workshop, including (i)deriving robust preclinical data; (ii) conducting companiontranslational studies; (iii) designing appropriately poweredclinical trials; and (iv) conducting expeditious real-timequality assurance of radiotherapy plans.The resources available through the NCI-US Molecular

Radiation Therapeutics Branch, the QIN, and the FrederickNational Laboratory for Cancer Research should be har-nessed by the radiation oncology biomedical research com-munity before embarking on the design of future radio-therapy clinical trials, particularly when combined withnovel targeted agents. The possibility of an internationalconsortium for the evaluationof radiationmodifiers shouldbe explored as a means to pool resources in this importantpursuit. Finally, we must remember that the focus of ourresearch efforts is the patient; our obligations are first andforemost, to them.

Workshop Participants

* Abrams, Jeffrey—NIH, Bethesda, MD* Ang, Kian—MD Anderson Cancer Center, Houston, TX* Ataman, Ozlem—AstraZeneca Corporation, Manchester,United Kingdom

* Bailey, Paul—Pfizer Corporation, New York, NY* Ben-Josef, Edgar—University of Pennsylvania,Philadelphia, PA

* Bentzen, Soren—University of Wisconsin, Madison, WI* Bradley, Jeffrey—Washington University, St. Louis,MO

* Bristow, Robert—Princess Margaret Cancer Centre,Toronto, ON, Canada

* Brown, J. Martin—Stanford University, Stanford, CA* Buatti, John—University of Iowa, Iowa City, IA* Camphausen, Kevin—NIH, Bethesda, MD* Chakravarti, Arnab—Ohio State University-James CancerHospital, Columbus, OH

* Choyke, Peter—NIH, Bethesda, MD* Chung, Christine—Johns Hopkins Medical Institute,Baltimore, MD

* Curran, Walter—Emory University, Atlanta, GA* DeWeese, Theodore—Johns Hopkins Medical Institute,Baltimore, MD

* Dewhirst, Mark—Duke University Medical Center,Durham, NC

* Dicker, Adam—Thomas Jefferson University Hospitals,Philadelphia, PA

* Doroshow, James—NIH, Bethesda, MD* Efstathiou, Jason—Massachusetts General Hospital,Boston, MA

* Galvin, James—Thomas Jefferson University Hospitals,Philadelphia, PA

* Garcia-Vargas, Jose—Bayer HealthCare, USA* Guha, Udayan—NIH, Bethesda, MD* Ha, Chul—University of Texas Health Science Center atSan Antonio, San Antonio, TX

* Hahn, Steve—University of Pennsylvania, Philadelphia,PA

* Hill, Richard—PrincessMargaret Cancer Centre, Toronto,ON, Canada

* Kirsch, David—Duke University Medical Center,Durham, NC

* Krishnan, Sunil—MDAndersonCancer Center, Houston,TX

* Le, Quynh-Thu—Stanford University, Stanford, CA* Langer, Corey—University of Pennsylvania,Philadelphia, PA

* Liao, Zhongxiang—MD Anderson Cancer Center,Houston, TX

* Mendonca, Marc—Indiana University, Indianapolis, IN* Machtay, Mitchell—University Hospitals Case MedicalCenter, Cleveland, OH

* Mehta, Minesh—Northwestern University, Chicago, IL* Miskel, Robin—Sanofi-Aventis Corporation, Boston, MA* Mitchell, James—NIH, Bethesda, MD* Pollack, Alan—University of Miami, Miami, FL* Prasanna, Pataje—NIH, Bethesda, MD* Teicher, Beverly—NIH, Bethesda, MD* vander Kogel, Albert—University ofWisconsin,Madison,WI

* Wang, Dian—Medical College of Wisconsin, Milwaukee,WI

* White, Julia—Medical College of Wisconsin, Milwaukee,WI

* Willett, Christopher—Duke University Medical Center,Durham, NC

* Williams, Jackie—Rochester Medical Center, Rochester,NY

* Winter, Kathryn—American College of Radiology,Reston, VA

* Zwiebel, James—NIH, Bethesda, MD

Authors' ContributionsConception and design: F.-F. Liu, P. Okunieff, C.N. Coleman, B. Vikram,J. Buatti, C. GuhaDevelopment of methodology: F.-F. Liu, P. Okunieff, B. Vikram, J. Buatti,C. GuhaAnalysis and interpretation of data (e.g., statistical analysis, biosta-tistics, computational analysis): C.N. Coleman, C. GuhaWriting, review, and/or revisionof themanuscript: F.-F. Liu, P.Okunieff,E.J. Bernhard, H.B. Stone, S. Yoo, C.N. Coleman, B. Vikram, M. Brown,J. Buatti, C. GuhaAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): B. Vikram

Grant SupportThis work has been supported by funds from the NCI.

Received April 23, 2013; revised August 6, 2013; accepted August 10, 2013;published online November 15, 2013.






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Liu et al.




2013;19:6089-6100. Published OnlineFirst September 16, 2013.Clin Cancer Res Fei-Fei Liu, for the workshop participants, Paul Okunieff, et al. Lessons Learned from Radiation Oncology Clinical Trials

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