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Is Testicular Cancer Related to Gulf War Deployment? Evidence From a Pilot Population-Based Study of Gulf War Era Veterans and Cancer Registries

Posted on: Thursday, 24 February 2005, 03:00 CST

The possible relationship between military deployment and the subsequent increase in cancer rates has been prominent since the Vietnam War. The objective of this study was to investigate whether any form of cancer was increased among veterans deployed to the Persian Gulf in the 1991 conflict. This study matched data from central cancer registries in the District of Columbia and New Jersey with the records for 1.4 million Gulf War era veterans, i.e., 621,902 veterans who arrived in the Persian Gulf before March 1, 1991, and 746,248 non-Gulf veterans. Using a proportional incidence ratio, testicular cancer was found to be the only significantly increased malignancy among deployed Persian Gulf War veterans. The increase became apparent 2 to 3 years after the Persian Gulf War and peaked 4 to 5 years afterward. Our data and those of investigators studying Vietnam veterans suggest that testicular cancer may be related to military deployment.

Introduction

Interest in the possible effects of deployment on subsequent increases in cancer rates has been prominent since the Vietnam War. In 1994, after conflicting studies were evaluated, the Institute of Medicine published a report linking certain forms of cancer to Agent Orange exposure.1 In 1998, the decision was made to add Hodgkin's disease to the 1994 list, which already considered non-Hodgkin's lymphoma, chloracne, and soft tissue sarcoma as having sufficient evidence to indicate a positive association with Agent Orange exposure.2 In addition, the Institute of Medicine noted some suggestive evidence for links with respiratory cancer, prostate cancer, and myeloma.2 The more recent development of the North American Association of Central Cancer Registries, which has facilitated the use of standardized procedures in cancer registries in each of the 50 states and the District of Columbia,3 has allowed the possible determination of national cancer rates in various study groups. The impetus from the Presidential Advisory Committee on Gulf War Veterans' Illnesses4 to develop long-term studies investigating cancer rates among Persian Gulf War veterans and the success of the acquired immunodeficiency syndrome (AIDS)-cancer records matching program in investigating cancer patterns among AIDS patients5,6 led us to investigate whether cancer patterns differed among those who were deployed compared to those who were not.

Methods

Files obtained from the Defense Manpower Data Center included data for 697,000 veterans who arrived in the Persian Gulf during the study period (Aug. 2, 1990 to March 1, 1991) and 746,248 non-Gulf region veteran control subjects. The former group represents the entire population deployed, whereas the latter consists of a stratified random sample of all military personnel who served during the conflict but were not deployed to the Gulf region. Both groups included personnel on active duty, in the reserves, and in the National Guard. The details of selection for these two study groups and their demographic and military characteristics are described in detail elsewhere.7,8 The database contains names, Social Security numbers, demographic data, and military service information for the 1.4 million veterans. The study group was selected to exclude individuals who arrived in the Persian Gulf after the end of hostilities to allow a focus on those with potentially greater exposure to harmful environmental agents. In the control group, equal numbers of subjects were selected from units that were activated and not sent to the Persian Gulf and units that were not activated at all. Race/ethnicity, gender, and age distributions for the deployed and nondeployed subjects are shown in Table I.

The matching procedure involved the central cancer registries of New Jersey and the District of Columbia. The District of Columbia Cancer Registry was chosen because of proximity to the study investigators, and the New Jersey State Cancer Registry was chosen because it was the closest registry with experience with the AIDS- Cancer Match.5,6

Identification of military personnel who received a diagnosis of cancer between 1991 and 1999 was accomplished through record linkage of the veterans database with files supplied by the central cancer registries. Before participation, each central cancer registry conducted ethical reviews. In addition, Institutional Review Board approval was obtained from the George Washington University and the State of New Jersey. For confidentiality reasons, the matching procedures were performed at the registry offices, either by registry personnel or under their supervision. All personal identifiers were deleted from the matched records before the records were removed from the registry offices for data analysis.

The New Jersey registry matching was performed with matching software (Automatch; Match Ware Technologies, Burtonsville, Maryland) used by that registry. Automatch9-11 implements a probabilistic matching algorithm that weighs the likelihood of subject identity on the basis of identical or nearidentical information in the veterans and cancer registries. The matching variables included Social security number, name, race, gender, and dates of birth and death.

TABLE I

CHARACTERISTICS OF CANCER-MATCHED VETERANS AND ALL VETERANS

The District of Columbia registry did not have available matching software, such as Automatch. Instead, our George Washington University-based team wrote a SAS program (SAS Institute, Gary, North Carolina) to identify potential matching records on the basis of the same fields as the New Jersey registry matching. Social security numbers were available for all records in the veterans database but not all cancer registry records. For the first pass, exact Social security number matches were a necessary but not sufficient criterion for judging records as potential matches. A second match pass was conducted for registry records with missing Social security numbers. There an exact match of birth dates was necessary but not sufficient for judgment as a potential match. Data from each potential match were viewed and discussed by at least four individuals (including cancer registry personnel) to classify the match quality as "exact,""uncertain," or "unlikely." In all cases, a consensus on the match quality was obtained without difficulty.

For each of the linked records, the type of cancer was determined on the basis of International Classification of Diseases for Oncology, second Edition, primary site codes and histology codes for Hodgkin's and non-Hodgkin's lymphoma. The number of cancers at each site, relative to the total number of cancers (or the total number of cancers among male patients, if the cancer was gender specific), and the histology codes for the lymphomas were examined descriptively to determine whether any particular form of cancer was occurring in higher numbers in the Gulf-deployed group compared with the nondeployed group. For each cancer type meeting this criterion, a crude proportional incidence ratio (PIR; referred to as proportionate mortality rate or proportional mortality ratio in mortality studies) and 95% confidence interval (CI) were calculated for the proportional incidence of that specific cancer type among all cancers in the Gulf-deployed group compared with the proportional incidence in the nondeployed group.

To control for potential confounding, a logistic regression analysis was conducted to predict the specific cancer (against all other cancers) from deployment status and central registry and demographic variables. In addition, age-specific PIRs were calculated by dividing, within each age group, the observed number of cases of the specific cancer by the expected number. The expected number was based on the relative proportion of that specific cancer found in the Surveillance, Epidemiology, and End Results (SEER) incidence database for the years 1991-1995. Data were extracted with SEER Stat 4.0 software.12 An overall standardized incidence ratio was also calculated.

Results

The SAS match procedure yielded 324 matches for the District of Columbia registry, of which one was judged to be uncertain. Many of the matches were for non-District of Columbia residents who were diagnosed in the District of Columbia. The New Jersey Cancer Registry Automatch system yielded 137 matches, of which two were judged to be uncertain. Those deemed uncertain were dropped from the analysis. Table I shows the demographic characteristics for the matches from the two registries, categorized according to Gulf/non- Gulf status. Racial distributions appeared fairly similar across the states, as well as between the Gulf-deployed and nondeployed. However, among the cancer matches within each of the two states, the Gulf-deployed group was more often male and less than 30 years of age (Table I). In an examination of the proportional incidence according to cancer site in the District of Columbia sample, three cancer types appeared to fit the criterion of a higher proportional incidence in the Gulf-deployed group compared with the nondeployed group, namely, testicular cancer, non-Hodgkin's lymphoma, and brain cancer. Of these three, only testicular cancer showed a higher relative proportion in the New Jersey Gulf-deployed sample. On the \basis of the pooled District of Columbia and New Jersey data, testicular cancer had a significantly higher crude proportional incidence among the deployed male subjects (n = 17 deployed and 11 nondeployed; PIR, 3.05; 95% CI, 1.47-6.35). However, neither non- Hodgkin's lymphoma (n = 73 deployed and 138 nondeployed; PIR, 1.04; 95% CI, 0.85-1.23) nor brain cancer (n = 9 deployed and 12 nondeployed; PIR, 1.48; 95% CI, 0.64-3.43) showed significant evidence of higher proportional cancer incidence among the deployed subjects, compared with the nondeployed subjects.

Because testicular cancer is known to have a higher incidence among young Caucasian men,13 a logistic regression analysis, applied only to the 358 male subjects with cancer, included the following covariates in addition to the state of residence and deployment status: race (Caucasian/non-Caucasian), age, and age squared. Age squared was included because of the nonlinear relationship between age and first cancer. Results of the logistic regression analysis showed a weakened effect of deployment status (adjusted PIR, 2.33; 95% CI, 0.95-5.70), compared with the crude proportional incidence. The proportion of male veterans with testicular cancer, stratified according to age, for each central registry and deployment status is shown in Table II. The difference in testicular cancer proportions according to deployment status was pronounced for the 25- to 29- year-old and 30-to 34-year-old groups.

TABLE II

PROPORTION OF ALL CANCERS AMONG MALE PATIENTS CLASSIFIED AS TESTICULAR CANCER, ACCORDING TO AGE, REGISTRY STATE, AND GULF WAR DEPLOYMENT STATUS

Table III shows the calculations for the observed number of testicular cancers among Caucasian male subjects compared with the number expected for this group from seeR data according to age group for the deployed and nondeployed subjects. The observed/expected ratios were elevated for the deployed age groups of 25 to 29 years and 30 to 34 years, whereas the nondeployed age groups of 30 to 34 years and 35 to 39 years had elevated observed/expected ratios. The overall standardized incidence ratio for the deployed group was 1.42, compared with 0.94 for the nondeployed group.

To provide possible insight into latency, the testicular cancer proportions were examined according to the year of diagnosis. Table IV shows the relative proportions of cancers classified as testicular at each year of diagnosis for the Gulf-deployed and nondeployed groups. The proportions for the nondeployed group remained fairly constant from 1991 through 1998, but the values for the Gulf-deployed group peaked in 1995-1996 and were considerably higher from 1993 to 1994 through 1995 to 1996.

Discussion

The methods in our matching program provided an objective analysis of deployed and nondeployed Persian Gulf War era veterans in two population-based registries that had not been used in earlier studies of cancer patterns among veterans. The results, which showed that testicular cancer was the only cancer significantly more common among deployed vs. nondeployed veterans, support the link between deployment in the Persian Gulf War and testicular cancer. Earlier studies also addressed the possible relationship between military activities and testicular cancer, particularly among Navy personnel working as aviation support equipment technicians, enginemen, or construction mechanics,14 as well as those with military service in Vietnam,15,16 particularly those in the Navy.16 The Vietnam studies were strongly supported by monitoring of deployed vs. nondeployed military war dogs,17 and the initial interpretation was that exposure to Agent Orange was responsible for the malignancies. A subsequent study16 Indicated, however, that the health effects spread well beyond the area where Agent Orange was used. Initial studies focusing on the association between deployment in the Persian Gulf and the subsequent incidence of testicular cancer yielded varying results and interpretations.

TABLE III

OBSERVED AND EXPECTED NUMBERS OF TESTICULAR CANCER AND OBSERVED/ EXPECTED RATIO FOR GULF VS. NON-GULF VETERANS (CAUCASIAN MALE SUBJECTS ONLY)

TABLE IV

PROPORTION OF ALL CANCERS AMONG MALE PATIENTS CLASSIFIED AS TESTICULAR CANCER, ACCORDING TO YEAR OF DIAGNOSIS AND GULF WAR DEPLOYMENT STATUS

Gray et al.18 noted an increased risk of hospitalization for testicular cancer among deployed vs. nondeployed regular, active- duty, Persian Gulf War servicemen shortly after their return from the Persian Gulf. The follow-up period was only 26 months, and the higher rates were noted in the immediate postdeployment period. Knoke et al.19 had similar results in their study of regular, active- duty servicemen in the Persian Gulf from August 1991 through March 31, 1996. They noted an excess of testicular cancer among deployed veterans shortly after return, and they suggested that this transient increase resulted from delayed diagnosis because of deployment, rather than being an actual effect of deployment. As noted by those authors, a limitation of their study was the restriction to men on active duty. Our study, involving all Persian Gulf War era veterans, including those in the reserves, had the advantage of a larger number of subjects. Another analysis of cancer patterns among deployed vs. nondeployed Massachusetts Vietnam veterans noted higher rates of testicular cancer and non-Hodgkin's lymphoma for the deployed group20,21 but the deployed veterans were younger than the nondeployed control subjects and, with adjustment for age, the higher rates found for the younger group were not significant.

Regarding a possible rationale for testicular cancer as an occupational malignancy, it has been noted that a number of studies have suggested exposure to chemicals, but with somewhat inconsistent results.22 Swerdlow et al.22 suggested exposure to dimethylformamide and heavy metal pigments, particularly chromate-based dyes, as being responsible for the reports of clusters of testicular cancer among aircraft repairmen23 and Navy personnel associated with technical engineering and construction,13 oil and gas extraction,24 and several other occupations.25-27 All of these links make military exposure to a variety of industrial products an area of concern. Although our data on concurrent studies suggest that deployed Persian Gulf War veterans were more intensively exposed to petroleum products than were nondeployed veterans, there is currently no documented evidence that these specific types of exposures occurred at a higher rate for those deployed to the Persian Gulf War.

In addition to possible occupational exposures, this study provides suggestive data on the latent period between putative exposures and testicular cancer. We noted a paucity of cases until 2 to 3 years after deployment, a finding of particular interest because the cases of testicular cancer in the case-control study of Tarone et al.15 occurred at least 4 years after deployment to Vietnam. Our data are in marked contrast to earlier studies18,19 that suggested that the increased number of testicular cancer cases among Persian Gulf War veterans was attributable to delays in diagnosis because of deployment. Our approach to matching deployment files with cancer registry data may be useful for studying latent periods between exposures and cancer for a number of malignancies, because the period between an exposure and subsequent cancer often varies. For adult T cell leukemia/lymphoma, for which perinatal infection is more likely to result in cancer than exposure later in life, the usual latent period is apparently at least 40 years, somewhat greater among infected Japanese than people living in the Caribbean basin.28-30 Shorter latent periods have been noted for other malignancies, such as chemotherapy and/or radiotherapy for non- Hodgkin's lymphoma, and there is some evidence that short intensive exposure to carcinogens may produce cancer more quickly than longer low-dose exposures.31,32 case-control studies to investigate occupational and other exposures should be undertaken if elevated testicular cancer rates continue to be supported by matching programs with other state cancer registries.

The larger number of cases from the District of Columbia Cancer Registry, compared with the much larger population base of New Jersey, was of interest and appears to reflect the methods used by the cancer registries in identifying cases. All cases seen in District of Columbia hospitals were reported to the District of Columbia Cancer Registry; cases from Walter Reed Army Medical Center were included even if the veterans resided outside the District of Columbia. The data from the District of Columbia registry also contained a large proportion of non-District of Columbia residents. In the interest of maintaining a larger sample, these cases were not removed. The chance of duplicate cases was very low because of the geographic distance between the two registries. When matches are performed for neighboring states (such as Maryland and Virginia), the non-District of Columbia resident cases will be removed, to avoid the duplication of cases.

Conclusions

This study identifies testicular cancer as a possible subsequent outcome of deployment to the Persian Gulf. The use of cancer registry incidence data rather than mortality data is particularly important for malignancies such as testicular cancer, which has such a high cure rate. Although these findings are preliminary, approaches such as this matching effort, when expanded to the national level over an extended period of time, may provide important opportunities to understand the impact of exposure to a variety of risk factors on the subsequent risk of developing cancer.

Acknowledgments

We thank Toshi Abe and his colleagues at the New Jersey Cancer Registry for their assistance with this project.

References

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2. Institute of Medicine: Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC, National Academy Press, 1998.

3. North American Association of Central Cancer Registries: Accomplishments Related to Mission Goals and Objectives. Springfield, IL, North American Association of Central Cancer Registries, 2000. Available at http://www.naaccr.org.

4. Presidential Advisory Committee on Gulf War Veterans' Illnesses: Final Report. Washington, DC, U.S. Government Printing Office, 1996.

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11. Match Ware Technologies: Automatch User's Manual, Versions 3.0 and 4.1. Burtonsville, MD, Match Ware Technologies, 1996.

12. Surveillance, Epidemiology, and End Results Program: Surveillance, Epidemiology, and End Results Program Public-Use Data (1973-1998). Bethesda, MD, National Cancer Institute, 2001.

13. Schotlenfeld D: Testicular cancer. In: Cancer Epidemiology and Prevention, Ed 2, pp 1207-19. Edited by Schotlenfeld D, Fraumeni J. New York, Oxford University Press, 1996.

14. Garland FC, Gorham ED, Garland CF, et al: TesUcular cancer in US Navy personnel. Am J Epidemiol 1988; 127: 411-4.

15. Tarone RE, Hayes HM, Hoover RN, et al: Service in Vietnam and risk of testicular cancer. J Natl Cancer fast 1991; 83: 1497-9.

16. Bullman TA, Watanabe KK, Kang HK: Risk of testicular cancer associated with surrogate measures of Agent Orange exposure among Vietnam veterans on the Agent Orange Registry. Ann Epidemiol 1994; 4: 11-16.

17. Hayes HM, Tarone RE, casey HW, et al: Excess of seminomas observed in Vietnam service U.S. military working dogs. J Natl Cancer fast 1990; 82: 1042-6.

18. Gray GC, Coate BD, Anderson CM, et al: The postwar hospitalisation experience of US veterans of the Persian Gulf War. N Engl J Med 1996; 335: 1505-13.

19. Knoke JD, Gray GC, Garland FC: Testicular cancer and Persian Gulf War service. Epidemiology 1998; 9: 648-53.

20. Clapp RW, Cupples LA, Colton T, et al: Cancer surveillance of veterans in Massachusetts USA, 1982-1988. Int J Epidemiol 1991; 20: 7-12.

21. Clapp RW: Update of cancer surveillance of veterans in Massachusetts, USA. Int J Epidemiol 1997; 26: 679-81.

22. Swerdlow AJ, Douglas AJ, Huttly SRA, et al: Cancer of the testis, socioeconomic status, and occupation. Br J fad Med 1991; 48: 670-4.

23. Ducatman AM1 Conwill DE, Crawl J: Germ cell tumors of the testicle among aircraft repairmen. J Urol 1986; 136: 834-6.

24. Mills PK, Newell GR, Johnson DE: Testicular cancer association with employment in agriculture and oil and natural gas extraction. Lancet 1984; 1: 207-9.

25. Wong O, Brocker W, Davis HV, et al: Mortality of workers potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB, and DDT. Br J tad Med 1984; 41: 15-24.

26. Levin SM, Baker DB, Landrigan PJ, et al: Testicular cancer in leather tanners exposed to dimethylformamide. Lancet 1987; 2: 1153.

27. Guberan E, Usel M, Raymond L, et al: Disability, mortality, and incidence of cancer among Geneva painters and electricians: a historical prospective study. Br J Ind Med 1989; 46: 16-23.

28. Shimoyama M, Members of the Lymphoma Study Group: Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-Iymphoma. Br J Haematol 1991; 79: 428-37.

29. Hanchard B, Gibbs WN, Lofters W, et al: Adult T-cell leukemia/ lymphoma (ATL) in Jamaica. In: Human Retrovirology: HTLV, pp 173- 83. Edited by Blattner WA. New York, Raven Press, 1990.

30. Levine PH, Manns A, Jaffe ES, et al: The effect of ethnic differences on the pattern of HTLV-I associated T-cell leukemia/ lymphoma (HATL) in the United States. Int J Cancer 1994; 56: 177- 81.

31. Levine PH, Hoover RN: The emerging epidemic of non-Hodgkin's lymphoma: current knowledge regarding etiological factors. Cancer Res 1992; 52(Suppl): 5245s-5374s.

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Guarantor: Paul H. Levine, MD

Contributors: Paul H. Levine, MD*; Heather A. Young, PhD*; Samuel J. Simmens, PhD*; Danielle Rentz, MPH*; Vincent E. Kofie, PhD[dagger]; Clare M. Mahan, PhD[double dagger]; Han K. Kang, DPH[double dagger]

* Department of Epidemiology and Biostatistics, School of Public Health and Health Services, George Washington University, Ross Hall, Suite 118, 2300 I Street NW, Washington, DC 20037.

[dagger] District of Columbia Department of Health, 825 North Capitol Street N.E., Washington, DC 20002.

[double dagger] Environmental Epidemiology Service, Department of Veterans Affairs, 1120 20th Street N.W., Suite 950, Washington, DC 20036.

This manuscript was received for review in May 2003 and was accepted for publication in November 2003.

Copyright Association of Military Surgeons of the United States Feb 2005

Source: Military Medicine

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