for patients with HPV16-positive OPC is currently intensive and re-sults in substantial morbidity, albeit with a high survival rate, ongoingtrials are evaluating radiation deintensification among patients withHPV-positive OPC. Thus, there may be less intensive treatment op-tions in the future, especially for HPV-driven cancers diagnosed at anearlier stage.

On the basis of available data, we estimate that, in regions like theUnited States where rates of HPV-driven OPC are rare but increasing,the number of individuals in the population needed to be screened todetect one case of OPC is approximately 5,000 (assuming 70% oftumors are HPV16 positive and 90% assay sensitivity), and the num-ber of individuals who screened positive that would yield one case isapproximately 50 (assuming 99.0% specificity); this value decreases toapproximately 11 if specificity increases to 99.8% (Table 1). To put thisinto context, in comparison with cervical cancer screening,7,8 thenumber of individuals needed to screen to detect one cancer would behigher for OPC because of differences in incidence, whereas the num-ber of individuals who screen positive needed to detect one case wouldbe lower for OPC because of the high specificity of the HPV16 E6assay, especially if test characteristics can be further improved.

It is too early to judge the suitability of HPV16 E6 antibody as ascreening tool for OPC, and we will continue to evaluate this poten-tially important cancer prevention opportunity. However, becauseOPC is only a subset of head and neck cancers, even if this marker isproven successful as a screening test, efforts to evaluate markers fornon-HPV–related head and neck cancer are also important if we are tohave a global and meaningful impact.

Aimee R. KreimerNational Cancer Institute, National Institutes of Health, Bethesda, MD

Mattias JohanssonInternational Agency for Research on Cancer, Lyon, France

Allan HildesheimNational Cancer Institute, National Institutes of Health, Bethesda, MD

Michael PawlitaGerman Cancer Research Center, Heidelberg, Germany

Paul BrennanInternational Agency for Research on Cancer, Lyon, France

ACKNOWLEDGMENTWe thank Dr Anna Coghill for her input in the calculations related toHPV16 E6 positivity as a screening tool for oropharyngeal cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe authors indicated no potential conflicts of interest.

REFERENCES1. Castle PE: Teaching moment: Why promising biomarkers do not always

translate into clinically useful tests. J Clin Oncol 32:359-360, 20142. Kreimer AR, Johansson M, Waterboer T, et al: Evaluation of human

papillomavirus antibodies and risk of subsequent head and neck cancer. J ClinOncol 31:2708-2715, 2013

3. McShane LM, Altman DG, Sauerbrei W: Identification of clinically usefulcancer prognostic factors: What are we missing? J Natl Cancer Inst 97:1023-1025, 2005

4. de Martel C, Ferlay J, Franceschi S, et al: Global burden of cancersattributable to infections in 2008: A review and synthetic analysis. Lancet Oncol13:607-615, 2012

5. Anantharaman D, Gheit T, Waterboer T, et al: Human papillomavirusinfections and upper aero-digestive tract cancers: The ARCAGE study. J NatlCancer Inst 105:536-545, 2013

6. Ribeiro KB, Levi JE, Pawlita M, et al: Low human papillomavirus prevalencein head and neck cancer: Results from two large case-control studies inhigh-incidence regions. Int J Epidemiol 40:489-502, 2011

7. Nanda K, McCrory DC, Myers ER, et al: Accuracy of the Papanicolaou testin screening for and follow-up of cervical cytologic abnormalities: A systematicreview. Ann Intern Med 132:810-819, 2000

8. Meijer CJ Berkhof J, Castle PE, et al: Guidelines for human papillomavirusDNA test requirements for primary cervical cancer screening in women 30 yearsand older. Int J Cancer 124:516-520, 2009

DOI: 10.1200/JCO.2013.53.2697; published online ahead of print atwww.jco.org on December 23, 2013

■ ■ ■

US Food and Drug AdministrationApproval of Drugs for the Treatmentof Prostate Cancer: A New EraHas Begun

TO THE EDITOR: Before 2002, only three drugs were approved bythe US Food and Drug Administration (FDA) for the treatment ofprostate cancer (PC),1-3 as shown in Table 1, and only one of theseapprovals3 was based on a prolongation of survival from a randomizedclinical trial (RCT). Since then, that number has risen to 12,4 withnearly all new drug approvals (NDAs) a result of a survival benefit thatwas documented in an RCT. What changed?

In 1993, under the umbrella of the newly formed organizationcalled the Prostate Cancer Foundation (PCF),5 formerly the Associa-tion for the Cure of Cancer of the Prostate (CaP CURE), leadingscientific and clinical experts in the treatment of PC were assembledon a board whose mission was to use the resources of PCF to find a wayto expedite new treatments and improve outcomes for men facing a

diagnosis of advanced PC. Significant resources were initially pro-vided by the founder and chairman of this group, Michael Milken,who had been diagnosed with PC in 1993. This was followed by a largefundraising effort by PCF to perpetuate the revenue stream that wasneeded to support ongoing research initiatives. To date, $510 millionhave been raised for PC research, making this organization the largestprivate sponsor of PC research in the world, funding more than 1,600proposals at nearly 200 research centers in 16 countries.

The NDA for zoledronic acid4 was issued by the FDA in 2002.This was the first agent shown to decrease skeletal-related events (eg,compression fractures) in an RCT of men with PC whose primary siteof metastasis is the skeleton. The impetus for this RCT was a PCF-funded survivorship study that elucidated the relationship betweendeclining bone mineral density and hormonal therapy use in PC.Next, work by clinical leaders in the PCF Clinical Consortium contrib-uted to our understanding that PC was sensitive to taxane-basedchemotherapy regimens (ie, docetaxel; sanofi-aventis, Bridgewater,NJ)4; docetaxel was FDA approved in 2004 after the publication of twoRCTs, one of which was led by a PCF clinical investigator and showedan improvement in survival in men with castration-resistant andmetastatic PC. Moving forward, during this new era of NDAs for PC,

Correspondence

362 © 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

Tabl

e1.

Chr

onol

ogic

alS

umm

ary

ofN

ewD

rug

App

rova

lsG

rant

edby

the

FDA

for

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tmen

tof

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stat

eC

ance

r,In

clud

ing

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trib

utio

nby

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FTh

atLe

dto

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rova

l

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gY

ear

ofFD

AA

ppro

val

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ease

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teE

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oint

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ing

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val

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FC

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ibut

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ram

ustin

e19

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etas

tatic

PC

Clin

ical

resp

onse

rate

Pre

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FM

itoxa

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niso

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etas

tatic

PC

Qua

lity

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RH

agon

ist

1998

Loca

llyad

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edP

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urvi

val

Pre

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ledr

onic

acid

2002

Met

asta

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tal-r

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ase

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rw

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prov

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2004

CR

MP

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val

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ase

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vest

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ter

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2008

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2010

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ter

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pros

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sum

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ithbo

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and

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pert

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that

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rate

den

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for

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phas

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clin

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oval

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amid

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chle

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cept

orov

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sion

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esC

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adin

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fund

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vest

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ors

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eren

zalu

tam

ide.

The

land

mar

kR

CT

was

led

bya

PC

Fin

vest

igat

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adiu

m-2

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PC

afte

rdo

ceta

xel

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viva

lN

one

Abb

revi

atio

ns:

CR

MP

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ratio

n-re

sist

ant

met

asta

ticpr

osta

teca

ncer

;FD

A,

US

Food

and

Dru

gA

dmin

istr

atio

n;LH

RH

,lu

tein

izin

gho

rmon

e–re

leas

ing

horm

one;

PC

,pr

osta

teca

ncer

;P

CF,

Pro

stat

eC

ance

rFo

unda

tion;

RC

T,ra

ndom

ized

cont

rolle

dtr

ial.

Correspondence

www.jco.org © 2013 by American Society of Clinical Oncology 363Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18

Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

avoiding a testosterone flare became possible with a single agent in2008 with the approval of degarelix,4 a pure luteinizing hormone–releasing hormone antagonist. Then, in 2010 and 2011, three newagents were approved by the FDA for patients with PC: sipuleucel-T(Provenge; Dendreon, Seattle, WA),4 the first immunotherapy tostimulate the body’s immune system and prolong survival, remark-ably, in the absence of a prostate-specific antigen response; Jevtana(cabazitaxel; sanofi-aventis),4 another taxane-based chemotherapythat prolonged survival after disease progression during treatmentwith docetaxel; and finally, on September 16, 2011, the FDA grantedapproval for Xgeva (denosumab; Amgen, Thousand Oaks, CA)4 as atreatment to increase bone mass in patients who are at high risk offracture from receiving androgen deprivation therapy for nonmeta-static PC. PCF’s sentinel contributions leading to FDA approval fortwo of these three agents are described in Table 1. During the last 2years, abiraterone acetate4 and enzalutamide,4 two novel forms ofhormonal therapy that have been shown in the context of multi-institutional RCTs to prolong survival and improve patient-reportedhealth-related quality of life for men with castration-resistant andmetastatic PC, have been approved by the FDA and are now beingtested in earlier stages of the disease by cooperative groups around theworld. The expectation is that these agents will increase the probabilityof cure for men with newly diagnosed high-risk and nonmetastaticPC. PCF played the major role in defining the mechanism of actionof these drugs, and in one case, supported the research that led tothe discovery of the drug. In both cases, PCF clinical investigatorsled the RCTs that resulted in FDA approval, as detailed in Table 1.Finally, on May 15, 2013, the first radiopharmaceutical, radium-223,4 was found to prolong survival in men with PC and bonemetastasis refractory to conventional hormonal therapy.3 By selec-

tive uptake in bone and the short distance (� 1 mm) over whichthe charged particle (ie, alpha particle) acts, damage to surround-ing hematopoietic tissues was minimal.

Therefore, of the nine NDAs that occurred after 2002, six weredriven by research and collaborations that existed because of PCF, asshown in Table 1. Today, with federal funding initiatives for cancerresearch continuing to decline, the need for novel approaches, such asthat used by PCF to fund the research that lead to NDAs, are neededacross all cancers.

Anthony V. D’AmicoBrigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

REFERENCES1. Perry CM, McTavish D: Estramustine phosphate sodium: A review of its

pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy inprostate cancer. Drugs Aging 7:49-74, 1995

2. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or withoutmitoxantrone in men with hormone-refractory prostate cancer: Results of thecancer and leukemia group B 9182 study. J Clin Oncol 17:2506-2513, 1999

3. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients withlocally advanced prostate cancer treated with radiotherapy and goserelin. N EnglJ Med 337:295-300, 1997

4. Leibowitz-Amit R, Joshua AM: The changing landscape in metastaticcastration-resistant prostate cancer. Curr Opin Support Palliat Care [epub aheadof print on June 28, 2013]

5. Prostate Cancer Foundation. http://www.pcf.org/site/c.leJRIROrEpH/b.5699537/k.BEF4/Home.htm

DOI: 10.1200/JCO.2013.53.9528; published online ahead of print atwww.jco.org on December 16, 2013

■ ■ ■

Correspondence

364 © 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18Copyright © 2014 American Society of Clinical Oncology. All rights reserved.