DTIC ADA423256: Development of Internet-Accessible Prediction Models for Prostate Cancer Diagnosis, Treatment, and Follow-Up

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by  Defense Technical Information Center

REPORT DOCUMENTATION PAGE ‘laa no ort ose

4 RSET USE On ORT BATE “EREPORT T¥PE AND DATES COVERED
ita ie! Sanuary 2004 Annual {14 Dao 02-13 Dea a2)
Developnent of Internet -Accessibla Prediction wodele ‘ANDLT-92-1-0066

for Prostate

oar Diaguoaia, Treatment, end Follow-Up

Beer crag? sak Ot ete 20060602 033

‘Of ksiitary Medicine
Rockville, Marylané 26952-1428

Mal: Leungeuae.org

‘ROENCY HANIES) AND ADDRESSES) ‘ROBICY REPORT HUMBER
U.6. sxny Kedical Recearch and Materiel Cemand
Nort beteick, Maryland 21702-5012

original contains colar platea: A11 BITC reproductions will be in black sad white.

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Approved for Public Releste; Distribution Untimited

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ERT TER EMER OF PAGE
prostate canoer, prediction model, Taserne:, dakanare ase
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Award Number: DANDL7-02-/-066

TITLR: Developme:t of Internst-Accessible Fredictien Nedela
fox Prostate Cancer Diagnosis, Treatment, end Fellow-Up

PRINCTPAT. INVESTIGATOR: Leon L. sun, M.D., Ph.D.
Judd. Noul
Hongya Wu
Fatiha Bengouda,
Hongyan Wu
Mohammed Berrada

CONTRACTING ORGANIZATZO

Henry M. Jacksen Foundation for the
Advancement of Militazy Medicine
Rockville, Maryland 20682-1428

REPORT DATE; January 2004

PREPARED FOR: U.S, Army Medical Research and Materiel Command
Port Detrick, Maryland 21702-5012

DISTRIBULION STATENENT: Approved for Zublic Release;
Distribstien Unlimited

‘The views, opinions and/or findines consained in thie report are
those of the author(s) and phould nor be conetruad aa an official
Department of the army position, policy or decision uniess ac
designated by ccher decumentasion.
Table of Contents

Cover.

SF 298,

Table of Contents.

Inveduction..

Body.

Key Research Accomplishments.

Reportatte Outcomes.

Conclusions.

References.

Appendices.
INTRODUCTION

‘The “prostate specific antigen (PSA) era” (1988 lo preseat) has dramatically altesed the
epidemiology of prentale canoer [1-2 cosulting in CaP diugaosis and teatment at younger ag>
and eatlier stage with » longer pust-ieatenent life span, [3], With appresisey 221.000 cases of
proslate cancer diagnosed each yeur in the 1S, t0-th.2ds of which arc tresied hy surgery or
rllstion therapy, and wih as maany 38 40% of patients eventually relapsing, up 80,000 ren
per year may develop a biachensicel, or PSA-only, [ailure [4-8]. Up co 8% of diagnosed men will
die dus to atostote cence, the second leading cacsc of doufh for men in the United States, The
task of advising patients rewinding prostate cancoe (CaP) trealmont uptians remains extremely
chatlenging because of the great complesity ofthe interactions among many prognitic factors
affecting the clinical cancsc of th: diseuve [9-12]. This study socks to ameliorate tix problem by
veloping soltware to examine 4 comprhensive retrospective database of prostats euncer
patients andl ubjets of prostate cancer sorering m cinder to geteate statiseal outeoene
likelihoods fordezent combinations of progncslc und diagnostic facts aad treatanent options
‘The produets from this study are simee to improve early and accurate diagnosis and propor
teatient of CaP, emhy' lnwering healthcars costs and raiking surcival

Forte above pomposes, we proposed to: (1) Anafyze the dala by integrating the ews
powerful pmngaostic variables in three regression models: logistic egresy'07, Cx propprtianal
regression, and artificial nencat networks; (2) Buifd clinical medets predicting probability of
prostate cancer in die diagnosis phase, optimal primary trechnenL in the testment phase, and
optimal recurence ueatraeat aad autconic inthe follow-up phase; (7) Post these models 35
software on the Interne, sceeasible hy patients and playsicians as toc for public education
patient sel-text, and physician's desiicm auppont reference.

Clinical niadel devlopmicct inctades five phases: (L) Deta preparation: Clinicel data witl
fe rohiewed from the CPDR National Databuss, sorted, standardized, and mapped ita categories
of diagnos, reatnect, follow-up; (2) Dara warehcnning: The data will be stored into x dita
swurthouse; (2) Dats avalysis: Trattione!slaistical methods and/or other uow mathemiticul end
‘ompulutional cols such as dceaswn ines system and artical neural netwerks witl he used to
anvlyce the eflect of each pararater und the interactions ofthe factors on the Ce clinical
Procens; (4) Data modeling: Lhe probability and confidecce range for CaP catly detsticm,
‘optimal primagy teeatrent, uostment of ecunsence, and treatment of Late: stage see wil he
cealelated for each ofthe combinatiens uf the input vacables to establish predicrian meses (5)
‘Web application development: The develeyed nidels 9 be programmed sid posed on the
CPDR webpage.

nopy

‘The development schedule and progress al this praject are based on the Stateunent of
‘Work of the research proposst
Th the second year of the grunt proposed we have focused on dita analysis, creation af
predicarion mode's for paticnts before and alter treatment, aud srcation of predhction mextels far
palients hefore and afte: PSA rceorrence. Alsa, the implementation of the comograms, equations
and calealators to CPDR web site accessible tacsugh the Tneret is onguing as proposed.

1. Comnuation of daily data collection,

Avof the end of November 2003, the DoD-CPDR Nutionat Database contains 433,083
rocids an 19,56 men (Table 1), At is one ofthe larges! und ment comprehcnsive longitudinal
prostate-cancer dltulases inthe nation and world, The data frum crmsented patients was daily
coliected by woll-rained CPDR alalf with cho standardized database implemented in nine
military hospitals across the cxntry and one civilian hospital. Virgniy Mos Medical Center
{VMMC). that joined CPDR Natal Database in July 2003 (Luble 2, Jn uddition, che
retrospective data from the Wright-Patterson Medical Center deta 13 also entered inl the
database (Vable 2),

“The matti-center data provides a aqha feundalicn forthe project due to the eg
‘quanlites, varieties of clinical settings, and high unalylical assessment power, The results ane

proxiuels derived from this database have every likelihyod nt being reliable, representative,
practical, and bonofivi!
“Table 1. Records stonel in tre CPDR National Database (as of the cud vf November 2003)
ie BANC EANC MANC HGNC NCP MCSD NNMC VAC WHNG WPAFE WANG] Toto
Gonsont Tor 70S a8 GHOST tsetse.” at
Bio 207 913 2eNe tel 1708 oar Bes Hara tam aa) saa
Brachytheraay Fn ee ZT)
Cratherayy wos ee eee ee ot wg
Folow Upt 10800 ZOR 12947 ea 7G 25847 BE02B 12 ted — 267 ze] 141176
Follow Up? 710) 1918 gee0 Bend tagag DASEO GSU? «127608357 Dost] roUNO
‘General Info 200s 7s? Tese 15281289 aaD1za24 SRC6tS 179181] 19008
Hormone. Therapy | 1221 1209 Ste fou Gait 2498 D573 Sars 75 zata| aes
ab Results 8 sre resai| Tie
ed History too 7o7 16ar TEI 12M3 | 2a09 eae gee] 79 d2a7|_ 16005,
Neorpy 1 0 49210285 GD Tose] Stes
Panaloy S40 201 gas a2 42888651 BAS teal Ban
Phone Adoress | vee 708 174 1421 1271 2300 227) «98178 Sal 1aTDT
Prgatsiectomy Bal 2433674872] DGS BBG wy Tra] BIS
Radaton Dose | 252 203 48310837342 SB Dew tan| Aa
Radiaton Thoragy| 260 225515218508 eB gm 287 7 t87| BO
Roisin apo 737 1906 18/8 1900 2901 2419 -3BeIs Try sta7]| tase
staging tora 701 ait “ou 11221798 1700 «4 tod 7 ana7| 14800,
Suey a i 31g os zs gS 103g] Se
TRUS 27a S17 22691770 «1789 gOge 2B AE aTe 108 7aB) Bata
Tumor_siee aii 22 ss 8 ag tga sat
Bun Bisa _ WH _Soved tesa Gaia Faaor_s7319 Bd er01 Pood Te0ed) F563
“Table 2. Hospitals and thei=focationy wth wm active CPDR usaalose

Aabreyiaten Full Name: oy Sule
BAMC Brook Armny Medical Center Fi Sam Houston ‘Toxis

EAMG Eissohiower Army Medical Ceoier PL. Goreon Georgia

MAMC Madigan Army Medical Couter “Tacoma ‘Woshington
MGMC Malcolm Grow edieal Center Andrews AFR Maryland

NMce Naval Medical Center Forsmouth Virginia

NCSD ‘aval Medical Genter ‘San Diego Calfornia

NMC [National Navel Medical Center Bethesda Maykind

VMMC Virginia Mason Medics Center Seattle ‘Washington
WIMC Wilford Holl Medicul Center Lackland AFB, Texas

WNC WrightPatcrson Medica! Center Wright-Patterson AFB Ohio

WRAMC Wolter Reed Mavical Center Washington Distist of Columbia

2, Changing face of prostate cancer since the start of the PSA era (submitted t0.J Urol,
accepted as poster presentatina in AUAGS, soo Appendix 1).

PSA screening, cxpecially the mandatory screening for active duty milfery healthcare
system eneCicinvies, sreatlyimpuetsthe epicdemialepy p: prostate cancer in detection, diagaoss
trealment, recurrences and quality of life [19-17]. To build models fr preletian ashe
probabilities of rik ol prostate cancer, and autcoxne, thorough understanding af the ch ges al
prastare-cemevr clinical eaume de tn PSA soceening is cutie).

An chis stady, wo used 10,681 patients Utagnosed with prostate cancer betvoon 1990 and
‘2002 that weze registered in xe DoD-CPDR natienal database. Staristical analyses were
yerfarmed identilying significant trends in patients, thoie choices a treatment, and their

free cvivubtiy

As the PSA era progrested, patients became younger (<0), hid lower diuganstic PSA,
and wero more ikely to he Hingnowed with ctinical Tle disease. The number of diagnostic opsy
‘ores increased with the porestiige af wanes containing cancer decreasing over tims, Biopsics
‘with a diagnostic Glossor sum of 7 huve irumeased. Patients were almost twice as likely to
randefgo stipery Vs, extol beam ridiation by the later time of observation, The PSA.
recurtence-fiee and clinical mctastsis-froc survival a 1,5, an 10 years for radical
prosluteclamy patients were £8.0 vs, 99.4, 640 vs, 96.5, und 38.3 vs. 90.25%, respectively. The
clinicid motnsiann-free survival at 1,5, ad 10 years in extemal beara ntiationtheespy ss 99.3,
91,4, and 79.29% respectively. Disease-specitic mortality has cantinuct! to dreline aver the past
peelo-yeurs

We concluded that provlnv cancer‘ imcreasingRy diagnosed in younger men with,
clinically Tocalized discase allowing more patents to seek potentially curative treatment
‘Tum Warden has decreased over the past vclve years, The use cif serum PSA 28 a
scceening tool combined with TRUS biupsies lo diagnose prostate cancer appears to have
rudaned disease-specific mortality eee Appeatis |)

3. Raclal difference in locatinn, mumiher aud volume of prostate cancers based on 3
imenstonal reconstructed prostate quecirurns (iuhenitted (oJ Urol 2004, accepted as
poster presentation ba AUAOS; see Appendix 2)

“This sty nme ta identify whether there cxists any racial difference hesween Caucasian
(CM) and African American (AA) patients in suenber, location and volume of prose vuncer.
“The role c'age and pathotogical stiges cn the lurmor characteratics was elaitied

[A tort of 176 (135 €M and41 AA) cadiea! prostatoctomy specimens hal sere obtained
betsiogn 1993 acd 2000, and 2-imentional (3D) reconsteucted were nsod in thie study. Fash 3D
seconstructed specimen wes par.tioned into 24 slots anc! a cempichenerwe-combmaliom of these
24 stots ins considared, which resulted in 38 represcutativ> zones inctoding peripheral ane,
‘wansitin zone and eentral zone. Invesigstion into potenrial racial di erence in number, locsuion
and volume of canoer wax performed, We found that uo significant overal| difference sax found
jn tumor nombor between the CM and AA patients regardless of their ages. When sicified by
pathological stages, however, AA patients (stage T2) were found to have significamfly mare
tumors than, CM patients (P = 0.012). With or without stratificstion by puthological T sages,
there was no significant diferencia Tncatian between the fvo raoo groups. Inthe age
group oF 60 and 65, AA pationts were found lp have: more turers al une Teft mecial anterior
prostate: (p= 0.047). Furthe:, CM patients 65 or older wese found to have signilicanlly more
tumors 8 posterior hase (p = 0.035). Overalt, no significant diffezence was found in (ola tumor
volun, index tomar vahime, an inmar valamte at eack of the 2 zones between CM and AA
palients, When straificd by age, however, we ubserved an interesting trenck among patients
younger chan 60, AA pationts had consiscenlly larger tumor volumes at most of the 38 zones
{igure 1), Amoag prtvats between 60 und 65, there was ne appacent racial difference in tenor
‘islumyes. For patients older than 65, bowever, CM patienia had consistently larger nor
‘isluayes at mast ofthe 3% zonce (Figure 2). Fanhermume, CM patients 60 of oder were found to
hove significantly larger tuner volume a # number af ames han their AA counterpart.

‘We comcluded chat distribution of prostate cancer van by uccurataly evaluated using a 3D
reconstmetion approach. Overs], no significant ditfercnce was found in number, lozation oe
volume of tumors hetween Chand AA patients, Howewce, young Alricam American patents had
corsistetly lager tumoms compared to Fong Cauoastan min, while this rao vars rewsrsct by
ethnicity in oldex pation,
Figure, Racial onmaparisons af mesn tumor volumes st iadivieual zanes in men < 60 years old.

os

Mean tumor volumes

Indlidusl zones

Gipson]

TE eiigaiens a AA pales

‘AR pari,
A. Pre-and post-operative prognostic factors predicting PSA recurrence in Intermediate
risk prostate cancer patients (Submitted 20 # Urol 2004, Accepted is pwster presenta
in AUAGA, soe Appendix 3)

rodieting PSA recusnence inpatients with inteymestinte-ink Hiseave (preueatnent PSA 10-
2nghn, biopsy Gleasem usm 7 on elinieal stage 26) uated with radical prosintactcny fs an
imporsant clinical issuc. This sly was designed to identify the association of pre- und post-
suutgery prognostic factors prvicting Picclerical currence. A total of 864 patients whe had
intermeidnesisk disease aad reccived radical prastalectorny fn 1989 to 2KI2 wore reticved
from: Ih Tho CPDR Tri-Service Multi-comter Database, Putients with nec-adjuvant seatment,
post-surgery fallens-up time <6 months or withous biopsy core infrmation wane excluded, The
‘Kaplan-Moier methual was used to estimate the probability of PSA recurence (PSA > 0.2 mg/l)
Univaviat and miltivaiale Cox proporiona’ hazard analyses woro usea fo ove" ual the relate
isk of pre-and post-surgery factors for PSA recurrence

‘The reults showed chat ehe mechan follow-up for the 864 palients was 4.4 years. Among
‘hem, 282 (32.6%) develaped PSA recurronce. The 3-year and 3-year PS.A-tree recuctence 1ates
swore 0.39 and 72.08, cespectively, Seventy-four (8.4%) pales daveloped distant metastasis,
sm univoriute nnd mulvatiate analyses on pre surgery Factors: ace, percentage of pasiive biopsy
cores, and PSA were significant faciors for predicting PSA rsev-rence (p <0.08). When hou pre-
and post-murgory factors were pooled together for malivarite analysis, race peecentogs of
positive biapsy coves. pathologie Tleatoa sum, oad margin tatus were associated with the PSA
recurrence (p< 0.65),

‘We concluded that this study provided two sets of prognostic factor ees fr petal clinical
decision making presses in putienis wilh jutermediste-risk disoase (Lablo 3), Prior to suEEry,
ace, diagnostic PSA lovel and percenlaye al cancer positive biopsy cores wetc independent
predictors for PSA recurrence. Afterrdical proslaleclomy, cave, percentage of positive biopsy
‘he, pathologic Gleason sma and margin stalus could hs used as prognostic factors.

ourtonee Hise time

‘Table 3. Cox sogrossion rowuls of pretventmect taetors for P

Fastos, __.., Wazand eatin (5% C
Rave

AA v6, white & cher 178219752910)
Thingnstic PSA (agznl} 19126

4 lOve s4 1.66% (1.138 - 2429)

PAN 2084 174401197 - 2.541)
Peccentage of positive binpay cores p00?

> 30-50% vs, 230% (0.897 {0.638 - 1.259)

> 50% 95, NM 1,506 41.154 — 1.945)
“Table 4. Mativariate Cos regression vesulas of al pre- and post opentive factor fox PSA

recustence-fiee tne in che irggrmodiale-rivk patienls

Feors 7 ‘Agusted hayant ano OCD Pp

Prowoneaicnt factors

Race .0002
AAG. white & other 4.669 (1.275 -2.169)

Diagnostic PSA (agi) 0.0830
4-14 1.406 (0.988 - 2.062)
10 2.24 1.591 (0980 2.581)

Percentage of positive hnopay cores bons
30-50% vs. 30% 0936 (0.4649 - 1.291)
> 50% vs. £308 1.44 (1.081 - 1885

Postoperative factors

Pathologie tage oer
‘PTH vs, PTZ

Paholagie Gleason sum 0041
T8,2-6 (1.103 - 1.90)
310 ¥3.2-6 1.882 (1.242 -2.854)

Capsule 03607
Positive vs. nogative 1.098 (0.991.509)

Margins funaas
Positive va. ngutive 1.388 (1024 - 1.881)

Senainal vesicle ase
Positive vs, nogative 1.140 0.806._1.612)

5. How long should rvilieal prostatectomy he safely delayed (Submitted to J Urul 2004,
Accepted as podium presentation, sec Appendix 4).

‘This sty was gimed we evsluate the association of delayed radical prostszetiay wit PSA.
ectrence and to identify the prognostic Factors aad optimal obscrvaticn koterval im different risk
groupe of prostate cancer. We uted 3324 men retrieved from the CPD National Datwbast his
teceived defimtive surgival therapy inthe period 1988-2002. The study excluded patients whet
experienced teatment failure (postiperalive PSA never reached nadir or PSA recurrence
‘occusted within 6 months posl-operalvely), whe rece!ved adjuvant therapy, of whose follow-up
tiene was Tess chan G months. ‘he cohrrt wos then i vided ina 3 groups based oa the detay (25,
25-75 ant > 75 percentiles), Coivariate and multivariate Cox regression models were used to
cvalutate the efftd wf delay nn PSA recurtonce (PSA > 0.2 ngiial and prognostic variables. Then
the patients were: regrouped inte "low", “intermediate” and “high” risk groups. The “low” ric
cup included those with Gleason seare-< 7 and PSA <4 ngfinl white the “high” nsk group
Consisted of individuals with Gleason score >7 of PSA > 20 ngfes. The remamter of hs coboxt