C

Sbltccdesncft

C2

Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 1, pp. 48–55, 2006Copyright © 2006 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/06/$–see front matter

doi:10.1016/j.ijrobp.2006.03.029

LINICAL INVESTIGATION Prostate

TEMPORAL RELATIONSHIP BETWEEN PROSTATE BRACHYTHERAPYAND THE DIAGNOSIS OF COLORECTAL CANCER

SARAH A. GUTMAN, B.S.,* GREGORY S. MERRICK, M.D.,* WAYNE M. BUTLER, PH.D.,*KENT E. WALLNER, M.D.,† ZACHARIAH A. ALLEN, M.S.,* ROBERT W. GALBREATH, PH.D.,*‡

AND EDWARD ADAMOVICH, M.D.§

*Schiffler Cancer Center and Wheeling Jesuit University, Wheeling, WV; †Puget Sound Healthcare Corporation, Group HealthCooperative, University of Washington, Seattle, WA; ‡Ohio University Eastern, St. Clairsville, OH; §Wheeling Hospital,

Department of Pathology, Wheeling, WV

Purpose: To identify the location of pretreatment and posttreatment colorectal malignancies and posttreatmentcolorectal polyps in patients with clinically localized prostate cancer managed with brachytherapy.Methods and Materials: From April 1995 through July 2004, 1,351 consecutive patients underwent brachyther-apy for clinical stage T1b–T3a (American Joint Committee on Cancer, 2002) prostate cancer. Supplementalexternal beam radiotherapy (XRT) was administered to 699 patients. The median follow-up was 4.6 years.Operative and pathology reports were reviewed for all patients with pretreatment and posttreatment colorectalcancer and posttreatment colorectal polyps. Multiple parameters were evaluated for the development ofcolorectal cancer or colorectal polyps.Results: Colorectal cancer was diagnosed in 23 and 25 patients before and after prostate brachytherapy,respectively. No differences were identified in the distribution of colorectal cancers either before or aftertreatment (3 and 4 rectal cancers in the pre- and postbrachytherapy cohorts). Thirty-five of the 48 colorectalcancers (73%) were diagnosed within 5 years of brachytherapy with a peak incidence 1 year afterbrachytherapy. One hundred ninety-two colorectal polyps were diagnosed after brachytherapy, 160 (83%)occurred within 4 years of brachytherapy, and only 27 (14%) were located in the rectum. In multivariateCox regression analysis, prostate D90 (minimum percentage of the dose covering 90% of the target volume)predicted for posttreatment colorectal cancer. Rectal polyps were most closely related to patient age andpercent positive biopsies, whereas sigmoid/colon polyps were best predicted by patient age, planning volume,and supplemental XRT.Conclusions: Colorectal cancer was diagnosed with equal frequency before and after brachytherapy withcomparable geographic distributions. In addition, the vast majority of postbrachytherapy colorectal polyps werelocated beyond the confines of the rectum. © 2006 Elsevier Inc.

Prostate cancer, Brachytherapy, Rectal cancer, Pd-103, I-125.

cmmypiamAmf

h

g

INTRODUCTION

ince the late 1980s, permanent prostate brachytherapy haseen increasingly used as a curative treatment for clinicallyocalized prostate cancer with long-term biochemical con-rol, cause-specific survival, overall survival, and morbidityomparing favorably with competing modalities (1–4). Be-ause of the high probability of long-term survival afterefinitive treatment for early-stage prostate cancer, the lateffects of therapeutic intervention have been increasinglycrutinized. In particular, although radiation-induced malig-ancies are an infrequent sequelae of therapeutic radiation,onflicting results have accumulated regarding the potentialor pelvic external beam radiotherapy (XRT) to inducereatment-related rectal cancers (5–11).

Reprint requests to: Gregory S. Merrick, M.D., Schiffler Cancerenter, Wheeling Hospital, 1 Medical Park. Wheeling, WV

6003-6300. Tel: (304) 243-3490; Fax: (304) 243-5047; E-mail: A

48

Clarification of an association between XRT and rectalancer has been clouded by a relationship between the twoalignancies, possibly related to shared genetic or environ-ental factors (12, 13). Ozden and colleagues reported a 10-

ear cumulative incidence of prostate cancer of 10.7% inatients with a prior history of colorectal cancer, but only 3.8%n patients without colorectal cancer (12). Conversely, Mydlond Gerstein reported that 44% of patients with second primaryalignancies after prostate cancer had colorectal cancer (14).concordance exists between environmental factors known toodulate the risks of colorectal and prostate cancers (i.e., high

at, low calcium diet, and increased body mass index) (12, 15).Radiation-induced solid malignancies are widely believed to

ave a latency period of 5 to 15 years (16–18). Recently, a

merrick@urologicresearchinstitute.orgReceived Feb 8, 2006, and in revised form March 23, 2006.

ccepted for publication March 23, 2006.

loXutrsrSotpaiiMin

rirtcicc

uTct(sCpA(ptpr

iatboppwpust

do

waTvw(mitSTtfIcTgis

FngfH1Ldmt1tv

iifcssapct

tetuvicvi(S

49Brachytherapy and colorectal cancer ● S. A. GUTMAN et al.

arge retrospective cohort study using Surveillance, Epidemi-logy and End Results (SEER) registry data concluded thatRT increased the rate of rectal cancer compared with patientsndergoing radical prostatectomy (RP) (7). Ten years afterreatment, 1.0% vs. 0.5% of patients undergoing XRT and RPespectively developed rectal cancer (p � 0.0016) with notatistically significant difference in the incidence ofectosigmoid or colon cancers. A major shortcoming of theEER data are that irradiated patients were substantiallylder than RP patients and that the absolute relative risk forhe development of rectal cancer was most closely related toatient age than any other variable including treatmentpproach (7). Consistent with these findings, previous stud-es have documented that the incidence of colorectal cancerncreases with age (19). In contrast to the SEER study,

ovsas and colleagues reported that prostatic XRT did notncrease the risk of developing a second primary malig-ancy including rectal cancer (9).

Because of a known relationship between prostate andectal malignancies and multiple conflicting reports regard-ng the impact of therapeutic radiation on the incidence ofectal cancer, we evaluated the temporal relationship be-ween the diagnosis of colorectal cancer and clinically lo-alized prostate cancer in patients managed with permanentnterstitial brachytherapy. Specifically, we identified the lo-ation of pre- and postbrachytherapy colorectal malignan-ies and postbrachytherapy colorectal polyps.

METHODS AND MATERIALS

Between April 1995 and July 2004, 1351 consecutive patientsnderwent permanent interstitial brachytherapy for clinical stage1b–T3a (American Joint Committee on Cancer, 2002) prostate can-er by a single brachytherapist (G.S.M.). Before the formulation of areatment plan, all biopsy slides were reviewed by one pathologistE.A.). Our preplanning technique, intraoperative approach, and do-imetric evaluation have been described in great detail (20–23).alculation algorithms and seed parameters used in preplanning andostoperative dosimetry were those recommended by the Americanssociation of Physicists in Medicine (AAPM) Task Group No. 43

TG-43) (24). Patients were clinically staged by medical history,hysical examination, and serum prostate-specific antigen (PSA) de-erminations. Bone scans, computed tomography of the pelvis, androstatic acid phosphatase were obtained at the discretion of theeferring physician or the brachytherapist.

In our program, all patients with postbrachytherapy rectal bleed-ng undergo colonoscopy. Additionally, since 2001 all brachyther-py patients undergo colonoscopy within 18 months of implanta-ion if colonoscopy has not been performed within 4 years ofrachytherapy. At the time of initial prostate cancer consultation,perative and pathology reports were obtained and reviewed for allatients with a prior diagnosis of colorectal cancer. In addition, allostbrachytherapy colonoscopy operative and pathology reportsere obtained and reviewed for colorectal cancer and colorectalolyps. Based on the endoscopic, operative, and pathologic eval-ation, cancers or polyps were assigned to either the rectum,igmoid colon, or colon. Before the diagnosis of prostate cancer,

he incidence and location of colorectal polyps were not carefully t

ocumented and as such were not included in this analysis becausef concerns regarding completeness.The brachytherapy target volume consisted of the prostate gland

ith a periprostatic margin with a resultant planning volumepproximately 1.75 times the ultrasound-determined volume (20).he minimum peripheral dose (mPD) was prescribed to the targetolume with margin. The planned and executed treatment marginsere approximately 6 mm in all dimensions except posteriorly

approximately 3–4 mm) and at the bladder neck (small negativeargin) (20, 21, 23). Of the 1,351 patients, 1076 (79.5%) were

mplanted with Pd-103 and 275 (20.5%) with I-125. For mono-herapeutic approaches, the mPD was 125 Gy (National Institute oftandards and Technologies [NIST-99] for Pd-103 and 145 GyG-43 for I-125). The brachytherapy boost doses ranged from 90

o 115 Gy (mPD NIST-99) for Pd-103 and 110 Gy (mPD TG-43)or I-125. For Pd-103 cases implanted before March 2000 and for-125 implanted before September 1997, the dosimetry was recal-ulated to correspond with current dosimetric standards (25, 26).he brachytherapy procedure was performed with preloaded 18-auge needles using transverse and sagittal ultrasonography. Atmplantation, the prostate gland, periprostatic region, and base ofeminal vesicles were implanted (22, 23).

Of the 1,351 patients, 699 (51.7%) received supplemental XRT.or patients with less than a 10–15% incidence of pelvic lymphode involvement, the XRT target volume consisted of the prostateland/seminal vesicles (with 2-cm margins in all directions exceptor a 1.0-cm posterior margin) and first echelon lymph nodes.owever, for patients with a lymph node risk greater than 10–5%, the pelvic lymph nodes (superior border at approximately the5/S1 interface) were included in the target volume. XRT waselivered via a four-field conformal technique with custom treat-ent devices. Supplemental XRT was delivered before brachy-

herapy. Most patients received 45 Gy or its equivalent, whereas62 patients received 20 Gy as part of a prospective randomizedrial. In addition, 531 patients (39.3%) received androgen depri-ation therapy (median duration, 4 months; range, 3–36 months).Patients were monitored by physical examination including dig-

tal rectal examination and PSA determinations at 3–6-monthntervals. Clinical, treatment, and dosimetric parameters evaluatedor the development of colorectal cancer or postbrachytherapyolorectal polyps included patient age; clinical T-stage; Gleasoncore; pretreatment PSA; percentage of biopsies positive; isotope;upplemental XRT; prostate volume; perineural invasion; percent-ge of the target volume receiving 100%, 150%, and 200% of therescribed dose (V100/150/200); minimum percentage of the doseovering 90% of the target volume (D90); tobacco status; hyper-ension; and diabetes.

One-way analysis of variance and two-sided Pearson chi-squareest were applied to the clinical, treatment, and dosimetric param-ters of the three patient cohorts to determine the significance ofhe differences. Predictors for cancer and polyps were chosensing a univariate Cox regression analysis. Variables with a uni-ariate significance of p � 0.10 were then included in a multivar-ate forward conditional Cox regression. When several highlyorrelated variables met this criterion, only the most significantariable was included with the exception of dosimetric parameters,n which case D90 was chosen because of its dosimetric relevance27). All data were analyzed using Statistical Package for Socialciences, version 14.0 software (SPSS, Inc., Chicago, IL). Statis-

ical significance was set at p � 0.05 for all analyses.

rrttnti0tw

tcpcrcar

bi

AFPG%UPP

M

S

X

I

A

PT

HD

pr

50 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 1, 2006

RESULTS

Table 1 summarizes the clinical, treatment, and dosimet-ic parameters for the study population stratified by colo-ectal cancer status. The mean and median follow-up forhe entire cohort was 4.8 � 2.5 years and 4.6 years, respec-ively. Of the 1,351 patients, colorectal cancer was diag-osed in 23 and 25 patients before and after prostate brachy-herapy, respectively. No statistically significant differencesn any of the parameters except for clinical stage (p �.001) were discerned between the three cohorts. Althoughhe absolute number of colorectal cancers is small, patients

Table 1. Clinical, treatment, and dos

Continuous variables

No colorectal cancer(n � 1303)

Pretreatmeca

(n �

Mean � SD Median Mean � S

ge at implant (years) 66.0 � 7.4 66.7 67.7 � 7.ollow-up (years) 4.8 � 2.5 4.6 4.0 � 1.retreatment PSA (ng/mL) 8.2 � 5.9 6.7 9.6 � 7.leason score 6.7 � 0.9 7.0 7.0 � 0.positive biopsies 38.5 � 25.3 33.3 42.6 � 25

ltrasound volume (cm3) 34.5 � 9.4 34.2 31.5 � 8.lanning volume (cm3) 64.7 � 12.9 65.3 61.0 � 12rostateV100 (% volume) 95.9 � 5.4 97.7 96.4 � 3.V150 (% volume) 66.3 � 14.8 69.7 68.9 � 14V200 (% volume) 37.2 � 12.8 38.3 40.1 � 12D90 (% volume) 113.1 � 26.9 117.5 119.9 � 14ost recent PSA (ng/mL)for disease-free patients 0.05 � 0.12 �0.04 0.02 � 0.

Categorical variables Count (%) Count (%

tageT1b–T2b 1220 (93.6) 20 (87.0)�T2c 83 (6.4) 3 (13.0)

RTYes 669 (51.3) 13 (56.5)No 634 (48.7) 10 (43.5)

sotopePd-103 1036 (79.5) 21 (91.3)1–125 267 (20.5) 2 (8.7)

DT duration0 months 795 (61.0) 9 (39.1)�6 months 348 (26.7) 7 (30.4)�6 months 160 (12.3) 7 (30.4)

erineural invasion 380 (29.2) 11 (47.8)obaccoNever 495 (38.0) 5 (21.7)Former 605 (46.4) 14 (60.9)Current 203 (15.6) 4 (17.4)

ypertension 625 (48.0) 13 (56.5)iabetes 152 (11.7) 4 (17.4)

Abbreviations: ADT � androgen deprivation therapy; D90 � minrostate-specific antigen; V100 � percentage of the target voluadiotherapy.

* p values calculated by one-way analysis of variance.† p values determined by 2-sided Pearson chi-squared.

ith either prebrachytherapy or postbrachytherapy colorec- b

al cancer presented with a more advanced prostate cancerlinical stage (p � 0.001). Of the 23 patients who developedrebrachytherapy colorectal cancer, 13 subsequently re-eived supplemental XRT as part of their brachytherapyegimen and 17 of the 25 patients with postbrachytherapyolorectal cancer received supplemental XRT. To date, 2nd 5 of the patients with pre- and postbrachytherapy colo-ectal cancer, respectively, have died of colorectal cancer.

Table 2 summarizes the distribution of pre- and post-rachytherapy colorectal malignancies. No differences weredentified in the distribution of colorectal cancers either

parameters of the study population

rectal Posttreatmentcolorectal cancer

(n � 25)

p*

All patients(n � 1351)

edian Mean � SD Median Mean � SD Median

67.7 67.7 � 6.4 68.8 0.315 66.1 � 7.4 66.85.0 5.3 � 2.6 5.0 0.186 4.8 � 2.5 4.66.6 9.2 � 3.9 7.5 0.389 8.3 � 5.9 6.77.0 6.6 � 1.0 7.0 0.143 6.7 � 0.9 7.0

37.5 42.5 � 27.0 37.5 0.549 38.7 � 25.3 33.332.9 34.3 � 9.4 33.4 0.316 34.4 � 9.4 34.265.3 66.4 � 14.2 65.0 0.378 64.6 � 13.0 65.3

97.4 96.2 � 3.8 96.5 0.889 95.9 � 5.3 97.771.8 66.3 � 14.5 68.5 0.719 66.4 � 14.7 69.639.8 36.5 � 13.6 36.7 0.520 37.2 � 12.8 38.319.6 117.7 � 15.6 113.6 0.338 113.3 � 26.6 117.5

0.04 0.08 � 0.26 �0.04 0.291 0.05 � 0.13 �0.04

Count (%) p† Count (%)

19 (76.0) 0.001 1259 (93.2)6 (24.0) 92 (6.8)

17 (68.0) 0.230 699 (51.7)8 (32.0) 652 (48.3)

19 (76.0) 0.342 1076 (79.5)6 (24.0) 275 (20.5)

16 (64.0) 820 (60.7)7 (28.0) 0.080 362 (26.8)2 (8.0) 169 (12.5)6 (24.0) 0.126 397 (29.4)

6 (24.0) 506 (37.5)14 (56.0) 0.327 633 (46.9)

5 (20.0) 212 (15.7)12 (48.0) 0.718 650 (48.1)2 (8.0) 0.590 158 (11.7)

percentage of the dose covering 90% of the target volume; PSA �ceiving 100% of the prescribed dose; XRT � external beam

imetric

nt coloncer

23)

D M

6909.9

8.7

3.5.0.9 1

05 �

)

imumme re

efore or after treatment (3 and 4 rectal cancers in the pre-

alcdifcpc

btpobcOTScptc

cD

(mawgaptpVpmppfmptr

l

RSC

F

51Brachytherapy and colorectal cancer ● S. A. GUTMAN et al.

nd postbrachytherapy cohorts, respectively). Figure 1 il-ustrates the number of patients developing colorectal can-er over time. Of the 48 colorectal cancers, 35 (73%) wereiagnosed within 5 years of brachytherapy with a peakncidence 1 year after brachytherapy. With a maximumollow-up of 10.8 years, no patient has developed colorectalancer beyond year 8. None of the 48 colorectal canceratients were diagnosed with multiple colorectal malignan-ies.

One hundred forty-six patients developed 192 post-rachytherapy colorectal polyps, with 27 (14%) located inhe rectum (Table 3). The diagnosis of colorectal polypseaked 1 year after brachytherapy and steadily decreasedver time, with no patient diagnosed with rectal polypseyond year 6 (Fig. 2). One hundred sixty (83%) of theolorectal polyps occurred within 4 years of brachytherapy.f the 27 rectal polyps, only 5 were limited to the rectum.he other 22 were associated with sigmoid or colon polyps.even of the 23 patients with prebrachytherapy colorectalancer were diagnosed with postbrachytherapy colorectalolyps. Four of the 7 patients developed colorectal polyps inhe same colonic location as their pretreatment colorectalancer.

In univariate Cox regression analysis, postbrachytherapyolorectal cancer was most closely associated with V100,

90, and a more advanced prostate cancer clinical stage

Table 2. Distribution of colorectal cancer

Location

Pretreatmentcolorectal cancer

(n � 23)

Posttreatmentcolorectal cancer

(n � 25)

CountClinical stage

(mean) CountClinical stage

(mean)

ectum 3 T2 4 T2igmoid colon 4 T2 6 T2olon 16 T2 15 T2

121086420-2-4-6-8-10-12-14-16-18-20

Time from implant (years)

6.00

5.00

4.00

3.00

2.00

1.00

0.00

Nu

mb

er o

f ca

ses

rectal cancer

colon cancer

sigmoid cancer

Fig. 1. Number of patients developing colorectal cancer over time. y

Table 4). However, in multivariate analysis, only D90

aintained statistical significance. In Table 5, univariatenalysis demonstrated that postbrachytherapy rectal polypsere most closely associated with older patient age, areater percent positive biopsies, V100, supplemental XRT,nd hypertension. In multivariate analysis, only patient age,ercent positive biopsies, and hypertension remained statis-ically significant. In Table 6, older patient age, greaterercent positive biopsies, brachytherapy planning volume,100, D90, supplemental XRT, and Pd-103 were univariateredictors for the development of postbrachytherapy sig-oid and colon polyps. In multivariate analysis, patient age,

lanning volume, and supplemental XRT were the bestredictors for postbrachytherapy sigmoid and colon polypormation. When only brachytherapy patients with a mini-um 4-year follow-up were evaluated, the risk factors for

ostbrachytherapy colorectal cancer and polyps remainedhe same as outlined in Tables 4–6 with comparable relativeisks.

DISCUSSION

Because of the ability to successfully eradicate clinicallyocalized prostate cancer with RP, XRT, and brachytherapy,

Table 3. Distribution of postbrachytherapy colorectal polyps

LocationPosttreatment colorectal polyps

(n � 192) (%)

Rectum 27 (14.1)Sigmoid colon 62 (32.3)Colon 103 (53.6)

11109876543210

Time from implant (years)

60

40

20

0

Colon polypSigmoid polypRectal polyp

Nu

mb

er o

f ca

ses

ig. 2. Number of patients developing postimplant colorectal pol-

ps over time.

tiaast(b

dh

(mtsgroccta

APG%PPP

SXIAAPTHD

o1 .

APG%PPP

SXIAAPTHD

52 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 1, 2006

he late effects of therapeutic intervention are being increas-ngly scrutinized. Radiation-induced second malignanciesre a known, but infrequent, complication of radiation ther-py with a latency period of 5–15 years (18). Multipletudies have reported conflicting results regarding the po-ential of XRT to induce treatment-related rectal cancers5–11), and there is no information regarding the impact ofrachytherapy on treatment-related malignancies.The accurate stratification for colorectal cancer risk man-

ates the elucidation of implicated genetic (i.e., familyistory of polyps and cancers) and environmental factors

Table 4. Predictors for postbrachytherap

Parameters Univariate Relative ri

ge at implant (years) 0.453retreatment PSA (ng/mL) 0.838leason score 0.820positive biopsies 0.770

rostate volume (cm3) 0.430lanning volume (cm3) 0.493rostateV100 (% volume) 0.064 1.104D90 (%mPD) 0.013 1.031

tage (2 groups) 0.057 2.478RT 0.188

sotope 0.193DT 0.902DT duration (months) (3 groups) 0.829erineal invasion 0.763obacco 0.350ypertension 0.720iabetes 0.762

Abbreviations: ADT � androgen deprivation therapy; CI � conf the target volume; mPD � minimum peripheral dose; PSA � pr00% of the prescribed dose; XRT � external beam radiotherapy

Table 5. Predictors for postbrachythera

Parameters Univariate Relative ris

ge at implant (years) 0.008 0.936retreatment PSA (ng/mL) 0.423leason score 0.318positive biopsies 0.001 1.022

rostate volume (cm3) 0.401lanning volume (cm3) 0.195rostateV100 (% volume) 0.096 1.100D90 (%mPD) 0.315

tage (2 groups) 0.731RT 0.046 2.407

sotope 0.400DT 0.347DT duration (binned 3 groups) 0.312erineal invasion .0542obacco 0.366ypertension 0.088 1.975iabetes 0.201

Abbreviations as in Table 4.

high body mass index, high fat diet) (12). Because differentalignancies may share the same genetic and environmen-

al influences, it is essential to identify cancers that co-egregate with colorectal malignancies to establish a back-round incidence. For example, Ozden and colleagueseported a 10-year cumulative incidence of prostate cancerf 10.7% in patients with a prior history of colorectalancer, but only 3.8% in patients who underwent colonos-opy without the diagnosis of rectal cancer (12). In addition,he South Wales Cancer Registry reported that patients with

history of colorectal cancer had a significantly increased

ectal cancer by Cox regression analysis

95% CI Multivariate Relative risk 95% CI

0.994/1.2261.007/1.056 0.034 1.034 1.017/1.0530.975/6.301 0.243

e interval; D90 � minimum percentage of the dose covering 90%specific antigen; V100 � percentage of the target volume receiving

tal polyps by Cox regression analysis

95% CI Multivariate Relative risk 95% CI

0.891/0.983 0.012 0.937 0.890/0.986

1.009/1.035 �0.001 1.024 1.010/1.037

0.983/1.232 0.173

1.017/5.695 0.165

0.904/4.315 0.047 2.270 1.011/5.101

y color

sk

fidencostate-

py rec

k

rapc

tagprdSpAtticd(dpahww7str

ltrhf

rdcioto

cadtdcipeorswb

r1iXrwt(aep

APG%PPP

SXIAAPTHD

53Brachytherapy and colorectal cancer ● S. A. GUTMAN et al.

isk of developing prostate cancer (13). Conversely, Mydlond Gerstein reported that 44% of patients with secondrimary malignancies after prostate cancer had colorectalancer (14).

In the retrospective 1973–1994 SEER cohort study, Bax-er and colleagues reported an increased risk of rectal cancerfter definitive XRT when compared with patients under-oing RP (7). Ten years after treatment, 1.0% vs. 0.5% ofatients undergoing XRT and RP, respectively, developedectal cancer (p � 0.0016) with no statistically significantifference in the incidence of rectosigmoid or colon cancers.trengths of the SEER data include the large number ofatients (85,815) and the long follow-up (median 8 years).

major shortcoming of the study, however, is the fact thathe irradiated patients were statistically older than RP pa-ients (67 years vs. 70 years, p � 0.001). Importantly, thenfluence of age on the diagnosis of colorectal cancersannot be understated. Cooper et al. reported that the inci-ence of all colorectal cancers increases steadily with age19). In the SEER study, the absolute relative risk for theevelopment of rectal cancer was more closely related toatient age than any other variable including treatmentpproach. Although the hazard ratio for XRT was 1.70, theazard ratio for patient age (especially �70 years of age)as substantially higher. For rectal cancers, the hazard ratioas 2.12 for men 60–69 years of age and 2.10 for men0–79 years of age. Additional shortcomings of the SEERtudy include the absence of information regarding radiationarget volume, radiation dose, fractionation scheme, andadiation source.

Radiation-induced solid malignancies are generally be-ieved to have a latency period of 5 to 15 years (16–18). Inhe recently published SEER data, no substantial increase inectal cancer was observed for the first 6 years after XRT;owever, a steady increase in incidence was documented

Table 6. Predictors for postbrachytherapy sig

Parameters Univariate Relative ris

ge at implant (years) 0.010 0.971retreatment PSA (ng/mL) 0.909leason score 0.161positive biopsies 0.093 1.005

rostate volume (cm3) 0.291lanning volume (cm3) 0.033 0.016rostateV100 (% volume) �0.001 1.094D90 (% mPD) 0.002 1.013

tage (2 groups) 0.810RT 0.015 1.536

sotope 0.005 1.842DT 0.696DT duration (binned 3 groups) 0.344erineal invasion 0.882obacco 0.645ypertension 0.121iabetes 0.260

Abbreviations as in Table 4.

rom years 6 through 15 (7). In contrast, Johnstone et al. d

eported that in a series of 164 XRT patients, no patienteveloped rectal cancer greater than 10 years after prostateancer diagnosis (10). In our series, 311 patients weremplanted at least 7 years before analysis with the absencef rectal cancer diagnosis greater than 7 years after brachy-herapy (Fig. 1). Continued follow-up with a greater numberf patients is essential to confirm this finding.A Canadian study reported an increased risk of colorectal

ancer in patients undergoing XRT for prostate cancer withrelative risk of 1.21 (8). However, all second cancers

iagnosed more than 2 months after XRT were included inhe analysis. Comparable with our results, it is likely that theiagnosis of colorectal cancer within a few years of prostateancer diagnosis and treatment most likely results fromntense posttreatment surveillance. The inclusion of suchatients in the analyses of XRT-induced cancer will falselylevate the incidence of such events. Since the initiation ofur brachytherapy program, all patients with postbrachythe-apy rectal bleeding undergo colonoscopy and, in addition,ince 2001 all brachytherapy patients undergo colonoscopyithin 18 months of brachytherapy if colonoscopy has noteen performed within 4 years of brachytherapy.In contrast, multiple studies have failed to demonstrate a

elationship between prostatic XRT and rectal cancer (6, 9,1). Specifically, Movsas and colleagues did not detect anncreased risk of second primary malignancies after prostateRT with the vast majority of second malignancies occur-

ing outside the radiation portals (84%) and diagnosedithin 3 years of XRT (97%)—strongly suggesting that

hey were not radiation-related. In addition, only 1 patient0.18%) developed an in-field second malignancy �5 yearsfter XRT. In our study, colorectal cancer was diagnosed withqual frequency before and after brachytherapy for early-stagerostate cancer with comparable stage and colonic geographic

nd colon polyps by Cox regression analysis

95% CI Multivariate Relative risk 95% CI

0.950/0.993 0.002 0.961 0.938/0.985

0.999/1.012

1.001/1.030 0.009 1.019 1.005/1.034

1.044/1.1461.005/1.022 0.175

1.087/2.169 0.017 1.614 1.089/2.3931.201/2.823 0.386

moid a

k

istributions (Fig. 1 and Table 2). Although in multivariate

aceco

cpttasbbrt

tqnopply(i1sosIpopas

dpp

tcwcobiptlrlrcdwbfsphr

radmybc

54 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 1, 2006

nalysis, the development of a postbrachytherapy colorectalancer was highly related to the prostate D90, it is important tomphasize that only 4 of the 25 posttreatment colorectal can-ers were limited to the rectum. As such, the clinical relevancef the prostate D90 is dubious.

The distribution of colorectal cancers in our series isomparable with previously reported distributions in non-rostate cancer populations with no substantial difference inhe distribution between prebrachytherapy and postbrachy-herapy colorectal cancers (7, 28). In our series, 13%, 17%,nd 70% of prebrachytherapy cancers involved the rectum,igmoid colon, and colon, respectively, while the post-rachytherapy distributions were 16%, 24%, and 60% (Ta-le 2). Specifically, Baxter et al. and Ikeda et al. reportedectal cancers in 16% in the RP-alone group and in 31% inhe nonprostate cancer cohorts respectively (7, 28).

Although it is not known whether radiation-induced rec-al cancers evolve via a polyp-to-cancer progression se-uence or a process that involves areas of flat epithelialeoplasia (29), we have assumed that the radiation inductionf colorectal cancers is a result of the polyp-to-cancerrogression scenario. To date, the distribution of colorectalolyps in our series is comparable with the general popu-ation with 14%, 32%, and 54% of postbrachytherapy pol-ps located in the rectum, sigmoid, and colon, respectivelyTable 3). This distribution closely mirrors previous reports,ncluding the study by McCashland et al. who reported1%, 37%, and 52% of polyps to involve the rectum,igmoid, and colon, respectively (28, 30, 31). In addition, ofur 27 rectal polyps, 22 were associated with polyps in theigmoid or colon (or both) with only 5 limited to the rectum.n multivariate analysis, percent prostate positive biopsiesredicted for rectal polyps and may indicate shared geneticr environmental influences (Table 5). Supplemental XRTredicted for postbrachytherapy sigmoid and colon polypsnd as such may ultimately prove to increase the risk of

igmoid and colon cancer (Table 6). Unlike the recent SEER r

REFEREN

tate carcinoma. Cancer 1997;79:1600–1604.

1

1

1

ata (7), supplemental XRT did not impact the risk ofostbrachytherapy rectal cancer or the incidence of rectalolyps.Although our data do not prove whether or not brachy-

herapy with or without supplemental therapies inducesolorectal malignancies, colorectal cancer was diagnosedith equal frequency before and after treatment with a

omparable geographic distribution. In addition, the numberf colorectal cases diagnosed within the first 5 years afterrachytherapy was substantially greater than that diagnosedn the second 5 years, probably a result of intense post–rostate cancer surveillance. Studies without intensive post-reatment surveillance for rectal cancer in all patients areikely to falsely attribute some of these malignancies toadiation. A shortcoming of our study is a maximum fol-ow-up of only 10.8 years and the fact that brachytherapyectal dosimetry was not included because rectal doses werealculated using three different approaches with differentosimetric parameters. Continued follow-up of this cohortill provide additional information regarding the impact ofrachytherapy on colorectal health, including the potentialor radiotherapy-induced malignancies. In the meantime,eries regarding postradiation cancers should address theossibility that some cancers attributable to radiation mayave been present long before radiotherapy could haveesulted in their induction.

CONCLUSION

In patients with clinically localized prostate cancer, colo-ectal cancer was diagnosed with equal frequency beforend after treatment with comparable stage and geographicistributions throughout the rectum and colon. Posttreat-ent colorectal polyps were most likely diagnosed within 4

ears of brachytherapy, and the vast majority were locatedeyond the confines of the rectum. The peak incidence ofolorectal cancer and polyps 1 year after brachytherapy is a

esult of intense post–prostate cancer surveillance.

CES

1. Merrick GS, Wallner KE, Butler WM. Permanent interstitialbrachytherapy for the management of carcinoma of the pros-tate gland. J Urol 2003;169:1643–1652.

2. Potters L, Morganstern C, Calugaru E, et al. 12-year outcomesfollowing permanent prostate brachytherapy in patients withclinically localized prostate cancer. J Urol 2005;173:1562–1566.

3. Merrick GS, Wallner KE, Butler WM. Minimizing prostatebrachytherapy-related morbidity. Urology 2003;62:786–792.

4. Merrick GS, Butler WM, Wallner KEet al. ]?�Androgendeprivation therapy does not impact cause-specific or overallsurvival following permanent prostate brachytherapy. Int JRadiat Oncol Biol Phys. 2006;65:669–677.

5. Brenner DJ, Curtis RE, Hall EJ, et al. Second malignancies inprostate carcinoma patients after radiotherapy compared withsurgery. Cancer 2000;88:398–406.

6. Neugut AI, Ahsan H, Robinson E, et al. Bladder carcinomaand other secondary malignancies after radiotherapy for pros-

7. Baxter NN, Tepper JE, Durham SB, et al. Increased risk ofrectal cancer after prostate radiation: A population-basedstudy. Gastroenterology 2005;128:819–824.

8. Pickles T, Phillips N. The risk of second malignancy in men withprostate cancer treated with or without radiation in British Co-lumbia, 1984–2000. Radiother Oncol 2002;65:145–151.

9. Movsas B, Hanlon AL, Pinover W, et al. Is there an increasedrisk of second primaries following prostate irradiation? Int JRadiat Oncol Biol Phys 1998;41:251–255.

0. Johnstone PAS, Powell CR, Riffenburgh R, et al. Secondprimary malignancies in T1–3N0 prostate cancer patientstreated with radiation therapy with 10-year follow-up. J Urol1998;159:946–949.

1. Kleinerman RA, Liebermann JV, Li FP. Second cancer fol-lowing cancer of the male genital system in Connecticut,1935–82. Natl Cancer Inst Monogr 1985;68:139–147.

2. Ozden N, Saruc M, Smith LM, et al. Increased cumulativeincidence of prostate malignancies in colorectal cancer patients.

Int J Gastroint Cancer 2003;34:49–53.

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

55Brachytherapy and colorectal cancer ● S. A. GUTMAN et al.

3. McCredie M, Macfarlane GJ, Bell J, et al. Second primarycancers after cancer of the colon and rectum in New SouthWales, Australia, 1972–1991. Cancer Epidemiol BiomarkersPrev 1997;6:155–160.

4. Mydlo JH, Gerstein M. Patients with urologic cancer and othernonurologic malignancies: Analysis of a sample and review ofthe literature. Urology 2001;58:864–869.

5. Putnam SD, Cerhan JR, Parker AS, et al. Lifestyle and an-thropometric risk factors for prostate cancer in a cohort ofIowa men. Ann Epidemiol 2000;10:361–369.

6. Wakeford R. The cancer epidemiology of radiation. Oncogene2004;23:6404–6428.

7. Jao SW, Beart RW Jr, Reiman HM, et al. Colon and anorectalcancer after pelvic irradiation. Dis Colon Rectum 1987;30:953–958.

8. Hall EJ, Wuu CS. Radiation-induced second cancers: Theimpact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys2003;56:83–88.

9. Cooper GS, Yuan Z, Landefeld S, et al. A national population-based study of incidence of colorectal cancer and age. Cancer1995;75:775–781.

0. Merrick GS, Butler WM. Modified uniform seed loading forprostate brachytherapy: Rationale, design and evaluation.Tech Urol 2000;6:78–84.

1. Merrick GS, Butler WM, Dorsey AT, et al. The effect ofprostate size and isotope selection on dosimetric quality fol-lowing permanent seed implantation. Tech Urol 2001;7:233–240.

2. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in theprostate/periprostatic region following brachytherapy. Int JRadiat Oncol Biol Phys 2000;46:215–220.

3. Merrick GS, Butler WM, Wallner KE, et al. Extracapsular

radiation dose distribution following permanent prostatebrachytherapy. Am J Clin Oncol 2003;26:E178–E189.

4. Nath R, Anderson LL, Luxton G, et al. Dosimetry of intersti-tial brachytherapy sources: Recommendations of the AAPMRadiation Therapy Committee Task Group No 43. Med Phys1995;22:209–234.

5. Beyer D, Nath R, Butler W, et al. American BrachytherapySociety recommendations for clinical implementation ofNIST-1999 standards for (103) palladium brachytherapy. TheClinical Research Committee of the American BrachytherapySociety. Int J Radiat Oncol Biol Phys 2000;47:273–275.

6. Luse RW, Blasko J, Grimm P. A method for implementing theAmerican Association of Physicists in Medicine Task Group-43dosimetry recommendations for 125-I, transperineal prostate seedimplants on commercial treatment planning systems. Int J RadiatOncol Biol Phys 1997;37:737–741.

7. Kollmeier MA, Stock RG, Stone N. Biochemical outcomesafter prostate brachytherapy with 5-year minimal follow-up:Importance of patient selection and implant quality. Int JRadiat Oncol Biol Phys 2003;57:645–653.

8. Ikeda Y, Mori M, Yoshizumi T, et al. Cancer and adenoma-tous polyp distribution in the colorectum. Am J Gastroenterol1998;94:191–193.

9. Grady WM, Russell K. Ionizing radiation and rectal cancer:Victims of our own success. Gastroenterol 2005;128:1114–1129.

0. McCashland TM, Brand R, Lyden E, et al. Gender differencesin colorectal polyps and tumors. Am J Gastroenterol 2001;96:882–886.

1. Lev R, Healey J. Colon polyp registries and colorectal cancer

control. Cancer Detection and Prevention 1999;23:474–478.