In this issue of Cancer, Chamie and colleagues have presented a timely article characterizing the relative risk of prostate cancer in Vietnam War veterans exposed to Agent Orange compared with their unexposed counterparts.1 In 1998, the National Academy of Science concluded that “limited/suggestive evidence” existed of an association between Agent Orange and prostate cancer.2 The majority of data linking Agent Orange exposure to an increased risk of prostate cancer has come from farmers and forestry workers exposed to herbicides and dioxins.3-5 Initial studies evaluating the relation between Agent Orange exposure and prostate cancer in Vietnam veterans yielded conflicting results and were limited by small sample sizes and the lack of quantification of Agent Orange exposure, as mentioned by the authors.6-8 Continued publication of updated results is necessary as veterans exposed to Agent Orange reach an age at which they are more likely to be screened and diagnosed with prostate cancer. Prior studies performed when these veterans were younger men may have been less likely to detect a link between Agent Orange exposure and increased risk of prostate cancer because of a lack of an appropriate cohort. More recent studies by Akthar et al9 and Pavuk et al10 did not find a difference in the risk of prostate cancer between comparison veterans (those in Southeast Asia but not Vietnam) and those serving in Vietnam during the same time period as a whole, but when the results were reviewed more closely, these investigators found a higher risk of prostate cancer in Operation Ranch Hand veterans serving during the time periods with heaviest spraying and longest duration of spraying and those veterans with the highest levels of quantified exposure based on serum dioxin levels compared with controls and the comparison group. The current article by Chamie et al suggests an even more ubiquitous link in their analysis of a more contemporary series.
On the basis of the current Veterans Health Administration Handbook,11 veterans who served in the Republic of Vietnam between 1962 and 1975 (regardless of length of service), any veteran who served in Korea during 1968 or 1969, or any other veteran who may have been exposed to dioxin based on locations specified at http://www1.va.gov/agentorange/ are entitled to an Agent Orange Health Registry Examination. However, participation in the Agent Orange examination program does not constitute a formal claim for compensation for an illness related to Agent Orange. Claims for compensation must be filed separately and do not necessarily require an Agent Orange Health Registry Examination if adequate documentation of illness is provided from private sector medical care. The Registry Examination includes a full history and physical, including documentation of civilian exposure to possible toxic agents. Veterans are offered a digital rectal examination and prostate-specific antigen (PSA) screening after the risks, benefits, and controversy surrounding such testing is explained to them. It has been our experience that many veterans do not report exposure history and forego the inconvenience associated with the time-consuming Registry Examination until they are diagnosed with an Agent Orange-related illness, at which point they decide to seek compensation or medical coverage or have Agent Orange-related illnesses documented in the private sector. The authors excluded 7 patients who changed their reporting of Agent Orange exposure after being diagnosed with prostate cancer. Other patients may have documented Agent Orange-related prostate cancer based on private sector diagnosis but were classified as “unexposed” because of lack of a Registry Examination. Another bias in this study is the finding that only those who served in Vietnam were included in the “exposed” group, despite the finding that veterans who served in Korea in 1968 and 1969 are eligible for the same benefits and examimations related to Agent Orange exposure. It is possible that veterans who served in Korea were included in the “unexposed” group, resulting in a weakening of the correlation of Agent Orange exposure and increased risk of prostate cancer.
Another possible source of bias or error in this study is the finding that occupational exposure history to dioxin and dioxin-like compounds outside of military activity was not included in the analysis and could be a significant confounding variable. Farming is a common occupation associated with a high dioxin exposure4, 5 and likely comprises a large number of the “unexposed” veterans treated in the farm-intensive Sacramento Valley, from which the current patient sample originated.
There are a multitude of unexpected findings in this study. An interesting finding in this study is that only 71.5% of those reporting exposure were screened with a PSA test. On the basis of the registry guidelines, one would expect this to be closer to 100%. In those with prostate cancer, the authors also found a higher rate of family history of prostate cancer in the unexposed group. This suggests that individuals in the unexposed group who are reporting a family history of cancer are more aggressively screened and diagnosed, whereas those reporting Agent Orange exposure were screened aggressively regardless of family history. Higher stage disease, similar PSA screening rates, similar biopsy rates, and similar referral for urologic evaluation between the 2 groups is suggested by the authors to provide evidence that those reporting exposure are not more aggressively screened compared with their counterparts. This is contrary to our personal experience8 and may reflect changes in awareness in the years since our study.
Agent Orange (more specifically, dioxin) is more tumor promoter than mutagen and displays dose-dependent effects.2, 12-13 Most theories involve dioxin binding to an aryl hydrocarbon receptor, which then translocates to the nucleus and attaches to the aryl hydrocarbon nuclear translocator protein, which allows it to bind to the regulatory regions of target genes. Oncogenic response in laboratory animals has been shown to depend on age, sex, species, dose, and route of administration.14-16 The authors identified higher rates of advanced disease and Gleason grade in the exposed group. A potential explanation could be that those with this more aggressive disease may have been those with the highest levels of exposure. The authors report that quantification of dioxin levels may not be justified for all patients reporting exposure because of current budgetary constraints and significant associated cost. Although we agree that it is impractical and exorbitant to do this for everyone reporting exposure, we do believe that further study at least on a small scale is warranted with quantification of dioxin levels to estimate exposure and then to explore the relation between levels and stage and grade of disease. This would help to clarify whether a dose response exists, and if so, it would further help to support the link between Agent Orange exposure and an increased risk of prostate cancer.
The authors identified a significantly higher proportion of African-American men in the exposed group (22.3% vs 19.0%; P <.001) and a trend toward a higher proportion of those with prostate cancer in the exposed group compared with the unexposed group (33.9% vs 29.0% P = .46). Black men made up 23% of the ground troops in Vietnam despite comprising only 9% of the Armed Forces and were more likely to have extensive patrols in the jungles as they contributed to more than half of the front line.17-18 In Operation Ranch Hand veterans, ground troops accounted for a significantly higher proportion (76.2%) of individuals with the highest quantified levels of dioxin compared with the low level (42%) and background level groups (27.3%). Therefore, it stands to reason that African-American men were more likely to be exposed and to have higher levels of exposure.
It is possible that the differences between the exposed and unexposed reported in the current study may not be as great when biases are considered. Despite these biases, the relation between prostate cancer and Agent Orange in this study is quite impressive. The authors should be commended for the timeliness of this study and its contribution to the growing amount of support for the theory that Agent Orange exposure plays a role in prostate cancer pathogenesis. At a time when many Vietnam veterans with possible exposure to Agent Orange are reaching the age at which they are at increased risk for prostate cancer, primary care physicians and urologists should recognize this interaction and consider more aggressive screening, especially in light of those with a history of exposure who presented with more advanced disease in this study and in studies by Kamradt et al6 and Giri et al.7 The findings of this study also serve to further warrant continued research on risk and outcomes of prostate cancer in individuals with a history of Agent Orange exposure.