PROSTATE CANCER DETECTION IN VETERANS WITH A HISTORY OFAGENT ORANGE EXPOSURE

MUHAMMAD BEHZAD ZAFAR AND MARTHA K. TERRISFrom the Section of Urology, Veterans Affairs Palo Alto Health Care System, Palo Alto and Department of Urology, Stanford University

Medical Center, Stanford, California

ABSTRACT

Purpose: Agent Orange, a chemical that was widely used in the Vietnam War as a defoliant, iswidely accepted as a health hazard but its potential causative role in prostate cancer has beencontroversial. We evaluated the rate of prostate cancer in veterans referred for prostate biopsywho reported a history of Agent Orange exposure compared to the rate in veterans who deniedsuch exposure.

Materials and Methods: A total of 400 consecutive veterans referred for prostate needle biopsyin a 30-month period completed a survey regarding Agent Orange exposure. Of these 400 patients32 (8%) reported previous exposure to Agent Orange. From the remaining 368 patients whodenied Agent Orange exposure 3 consecutive age matched controls were selected per each patientreporting exposure for a total of 96 age matched controls. Prostate specific antigen, prostatecancer, cancer grade and length of cancer in the biopsy cores were compared in Agent Orangeexposed patients and unexposed controls. To determine whether the patient population referredfor biopsy was skewed by proportionally more exposed and referred than unexposed patientsthose referred for biopsy were compared to the overall adult male veteran population followed atthe outpatient clinics at our facility.

Results: Of the 32 Agent Orange exposed patients 13 (41%) had prostate cancer, while 33 of the96 controls (34.4%) had cancer. There was no correlation of Agent Orange exposure with cancer(r 5 0.06). There was also no statistically significant difference in the 2 groups in regard to PSA(p 5 0.90), cancer (p 5 0.15), proportion of well differentiated cancers (p 5 0.41) or length ofcancer in the biopsy cores (p 5 0.34). Compared with the total adult male veteran populationfollowed on an outpatient basis at our facility an average of 1.07% of those with a history of AgentOrange exposure were referred for prostate biopsy yearly versus 1.33% of unexposed patients.

Conclusions: Agent Orange may have a role in the causation of some types of cancer but weidentified no significant relationship of prostate cancer with Agent Orange exposure in patientsreferred for prostate biopsy.

KEY WORDS: prostate, prostatic neoplasms, dioxins, Vietnam, veterans

Dioxin, a component of the defoliant widely known bythe military code name Agent Orange, has been a majorhealth concern in veterans of the Vietnam War for severaldecades. This herbicide has been proved to be a healthhazard. Several studies have shown its association withvarious types of cancer, including prostate cancer,1–3 whileothers have refuted this association.4, 5 This controversy iscompounded because the implication of Agent Orange asan etiological agent has as much a financial as a scientificimpact. Due to the large number of veterans exposed tothis chemical there is the potential for enormous costs forproviding treatment and compensation to victims, espe-cially for diseases as common as prostate cancer. Previousstudies done in Vietnam veterans had a low likelihood ofdetecting an increased rate of prostate cancer due to therelatively young age of the Vietnam veteran population.This population is now reaching an age at which prostatecancer is more likely, adding potential new information toour understanding of any relationship of Agent Orangeexposure with prostate cancer risk. With this fact in mindwe evaluated the correlation of Agent Orange exposurewith the rate of prostate cancer in patients referred forprostate biopsy.

MATERIALS AND METHODS

We evaluated 400 consecutive veterans 39 to 86 years old(mean age 65.5, median 66) referred for prostate biopsy in a30-month period. Before biopsy each patient completed aquestionnaire regarding Agent Orange exposure and bloodsamples for prostate specific antigen (PSA) determinationwere obtained. All patients underwent transrectal ultra-sound and sextant biopsies6 with additional lateral and/oranterior biopsies as indicated.7 Biopsy specimens were fixedin 10% formalin, sectioned longitudinally, stained with he-matoxylin and eosin, and examined by microscopy. Any can-cer detected was noted as well as the Gleason grade and totallength of the tumor in mm. in the biopsy cores. A Gleasongrade of 314 or less was considered well differentiated andGleason grade 413 or greater was considered poorly differ-entiated.

Of these 400 patients 32 (8%) 50 to 73 years old (mean age60.4, median 59) reported exposure to Agent Orange (table1). An age matched control group of 96 patients was selectedconsecutively from the 368 who denied Agent Orange expo-sure. These age matched controls included 3 patients with abirth date within 12 months of each of the 32 Agent Orangeexposed patients. Controls were 49 to 73 years old (mean age60.6, median 59).

To evaluate the referral base from which the patients pre-senting for prostate biopsy were selected we searched theAccepted for publication February 9, 2001.

0022-5347/01/1661-0100/0THE JOURNAL OF UROLOGY® Vol. 166, 100–103, July 2001Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.® Printed in U.S.A.

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ambulatory care database at our facility. This database in-cludes the answer of each veteran to a query regarding thehistory of Agent Orange exposure, which is a routine compo-nent of the registration process at our facility. All adult maleveteran outpatient visits to any clinics at our facility werecounted for the fiscal years 1998 through 2000, correspond-ing to the period during which prostate biopsy referrals wereevaluated. Only individual patients were counted, that ismultiple visits by an individual were not counted as separateentries. An average of 33,608 men (range 32,151 to 34,405) 18to 105 years old (mean age 57.1) presented yearly as outpa-tients during this time. An average of 1,194.3 men (3.3%) 38to 85 years old (mean age 53.3) yearly had a history of AgentOrange exposure (table 2). Tests for statistical significancewere performed with Student’s 2-tailed t test with statisticalsignificance considered at p ,0.05. Correlation coefficientswere generated using the Pearson rank correlation with astrong correlation considered at .0.6.

RESULTS

In the 400 patients referred for biopsy mean pre-procedurePSA was 15.44 ng./ml. (median 7, range 0.3 to 727). Of thesepatients 170 (43%) had prostate cancer on biopsy. In the 32Agent Orange exposed patients mean pre-procedure PSA was8.4 ng./ml. (median 6.6, range 1.4 to 48.7). Of the AgentOrange exposed patients 13 (41%) had prostate cancer, ofwhom 11 (85%) had well differentiated disease with Gleasongrade 314 or less. Mean pre-procedure PSA in the 96 agematched controls was 8.2 ng./ml. (median 5.7, range 0.5 to55.2). Of the 96 controls 33 (34.4%) had prostate cancer, ofwhom 24 (72.7%) had well differentiated disease.

There was no statistically significant difference in PSA(p 5 0.9), cancer (p 5 0.15), cancer grade (p 5 0.41) or lengthof cancer in the biopsy cores (p 5 0.34) in the Agent Orangeexposed patients and controls (table 1). There was also nocorrelation of Agent Orange exposure with the detection ofprostate cancer in this referral population (r 5 0.06).

To determine whether Agent Orange may effect age ofonset despite the lack of an effect on the overall prostatecancer detection rate we evaluated younger subpopulationsof patients. Of the patients 60 years or younger, cancer was

detected in 5 of 17 (29%) with and in 10 of 24 (42%) withoutAgent Orange exposure. Of the patients 50 years or youngercancer was identified in 1 of 11 (9.1%) with and in 10 of 30(33.3%) without Agent Orange exposure.

We compared the total adult male veteran population fol-lowed as outpatients at our facility and noted that an averageof 1.07% and 1.33% of patients with and without a history ofAgent Orange exposure, respectively, were referred for pros-tate biopsy yearly. The overall group of 400 men referred forbiopsy was significantly older than the outpatient population(p 5 0.0003). The 32 exposed patients referred for biopsywere not significantly different in age compared with theveteran outpatient population (p 5 0.07) but they were sig-nificantly younger than the overall group of 400 referred forbiopsy (p 5 0.01). There was no statistically significant dif-ference in the Agent Orange exposure rate when stratified byage in the 400 patients referred for prostate biopsy and theaverage yearly male veteran population (p 5 0.2). Table 2lists exposure rates and age distributions.

DISCUSSION

Agent Orange is the code name for a mixture of 2,4,5-T(2,4,5-trichlorophenoxyacetic acid, molecular weight 545.4kg./m.3) and 2,4-D (2,4-dichloro phenoxyacetic acid, molecu-lar weight 485.1 kg./m.3). Associated with the 2,4,5-T moietyis the impurity 2,3,7,8-tetrachlorodibenzo-p-dioxin, alsoknown as dioxin. To our knowledge the exact mechanism ofaction of any of these chemicals is not known. However,current research indicates several hypotheses.

The mechanism of action of 2,4-D probably involves thedisruption of thiol homeostasis.8 It is also proposed to behepatotoxic by disrupting glutathione homeostasis. It hasbeen suggested that 2,4,5-T may enter metabolic pathwaysinvolving acetyl-coenzyme A, resulting in altered metabolismand cholinergic transmission.9 Other effects being re-searched are the induction of genetic mutations and forma-tion of DNA adducts.

Of these chemicals the best studied is dioxin. The arylhydrocarbon receptor, a cytoplasmic protein expressed inalmost every cell and organ of the body, largely mediates itsbiochemical and toxic effects. Ligand binding with dioxin

TABLE 1. Comparison of Agent Orange exposed patients and age matched, unexposed patients referred for prostate biopsy

Group No.Pts.

Mean Age(range)

Mean Ng./Ml.PSA (range)

No.ProstateCa (%)

MeanBiopsy

CaLength(cm.)

No. PoorlyDifferentiated

Ca (%)*

Overall 655 65.5 (39–86) 15.4 (0.3–727) 282 (43.1) 5.4 212 (32.4)Exposed pts. 52 60.4 (50–73) 8.4 (1.4–48.7) 21 (40.4) 3.8 3 (14.3)Controls 156 60.6 (49–73) 8.2 (0.5–55.2) 54 (34.6) 4.4 15 (27.8)p Value 0.9 0.9 0.15 0.34 0.41

* Gleason grade 413 or greater.

TABLE 2. Comparison of Agent Orange exposure in the general adult male Veterans Affairs clinical population and those referred forprostate biopsy yearly from 1998 to 2000

Age RangeMean No. Outpts. Mean No. Biopsy Referrals

p ValueAll Men Exposure (%) Overall Exposure (%)

Younger than40

3,704 0 0 0 Not significant

40–44 2,530 18 (0.7) 0 0 Not significant45–49 3,791 294 (7.4) 4.3 0 Not significant50–54 5,208 577 (11.2) 17.3 4.7 (26.9) 0.000355–59 2,888 138 (4.7) 22.3 4.3 (19.4) 0.07 3 1025

60–64 2,973 52 (1.7) 50.7 1.7 (3.3) Not significant65–69 3,598 68 (1.9) 54.7 3.3 (6.1) 0.000270–74 3,584 30 (0.8) 47 3.3 (7.1) 0.01 3 1029

Older than 75 5,333 16 (0.3) 22 0 Not significant

Totals 33,608 1,194 (3.6) 218.3 17.4 (7.9) 0.03 3 1028

Mean Age 57 53.3 65.5 60.4 0.0003

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transforms the aryl hydrocarbon receptor into a form withhigher DNA binding affinity. This form translocates into thenucleus, where it attaches with aryl hydrocarbon nucleartranslocator protein. The complex binds to specific sequencesin the regulatory regions of target genes called arylhydrocarbon-responsive elements to influence patterns ofgene expression.10, 11

In 1977 Hardell introduced the idea that soft tissue sar-coma is associated with exposure to defoliants such as AgentOrange.12 Axelson et al drew similar conclusions in a subse-quent series13 but Pierce and Ruger suggested that thesestudies were fundamentally flawed.14 Others have detectedno association of herbicide exposure with cancer.4, 5 A groupof 27 scientists from 11 countries convened by the Interna-tional Agency for Research on Cancer to review evidence forthe potential carcinogenicity of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans concluded that2,3,7,8-dioxin is carcinogenic to humans.15

The Agent Orange Act of 1991 enacted on February 6, 1991directed the Secretary of Veteran Affairs to request the Na-tional Academy of Sciences to review and evaluate all infor-mation regarding the health effects of exposure to AgentOrange and other herbicides used in the Vietnam War. As aresult, the Institute of Medicine (IOM) of the National Acad-emy of Sciences established a committee to review thesehealth effects. In several reports the IOM committee haspresented sufficient evidence that soft tissue sarcoma,Hodgkin’s disease, nonHodgkin’s lymphoma and chloracneare associated with Agent Orange exposure.10, 16, 17 Healthoutcomes with limited or suggestive evidence of an associa-tion with Agent Orange exposure are considered by the IOMcommittee to include prostate and respiratory cancer, multi-ple myeloma, porphyria cutanca tarda, acute and subacutetransient peripheral neuropathy, and spina bifida in childrenof veterans. Illnesses listed by the IOM committee with in-adequate or insufficient evidence of an association withAgent Orange exposure include hepatobiliary cancer, nasal/nasopharyngeal cancer, leukemia, and cancer of the bone,breast, female reproductive system, skin, kidney, bladderand testis. Diseases classified by the IOM committee withlimited or suggestive evidence of no association with AgentOrange exposure include brain tumors and gastrointestinalcancer.

Several studies have specifically focused on prostate can-cer, including evaluations of occupational exposure18, 19 aswell as assessments of Vietnam veterans.20–22 However, theyshow inconclusive evidence of any relationship of Agent Or-ange with prostate cancer. Thus, Agent Orange exposure isconsidered to be a possible risk factor for prostate cancer. Amajor obstacle when establishing or refuting a relationship isthe inability to access the level of exposure to Agent Orangein Vietnam veterans. To date all successful studies withsignificant results for cancer caused by Agent Orange expo-sure have been based on factory workers in whom the level ofexposure was quantitatively measured,3 which is not possiblein veterans. Also, studies of Vietnam veterans have had a lowlikelihood of detecting an increased risk of prostate cancer ifthere is one, because of the relatively young age of the vet-erans. This population is now entering the age range inwhich prostate cancer diagnosis is more likely. Time sinceexposure is another potential bias that to our knowledge hasnot been completely evaluated for Agent Orange. The inter-val since exposure is fairly narrow in our patient populationat between 25 and 30 years, thus, it is impossible to correlatewith cancer occurrence. We further refined our analysis byevaluating only patients referred after prostate cancerscreening by primary care providers. This population is po-tentially biased by a possible lower threshold of primary careproviders for referring veterans with a history of Agent Or-ange exposure. However, comparing those referred for biopsyto the whole outpatient population revealed no statistically

significant difference in the Agent Orange exposure rate, asstratified by age group. In fact, an average of 1.07% of ex-posed patients at our facility were referred yearly for pros-tate biopsy compared to 1.33% of unexposed patients. Multi-variate analysis of Agent Orange exposure with otherpotential risk factors, such as race, family history, dietaryhabits and previous vasectomy, may show the influence ofAgent Orange as a contributing factor for prostate cancerrather than as a primary carcinogen.

CONCLUSIONS

We observed that 13 of 32 patients (41%) with a history ofAgent Orange exposure had prostate cancer, while 33 of 96controls (34.4%) had cancer. We did not identify an increasedrate of prostate cancer in Agent Orange exposed veterans butthis population is still relatively young with a mean age of60.4 years and continued followup may potentially showsome differences. We may more confidently conclude thatprostate cancer does not present at an earlier age in AgentOrange exposed individuals and a history of such exposuredoes not lower the threshold of primary care providers forreferring men for prostate biopsy.

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