Agent Orange exposure increases veterans' risk of aggressive recurrence of prostate cancer

Veterans exposed to Agent Orange are at increased risk of aggressive recurrence of prostate cancer, researchers report.

A study of 1,495 veterans who underwent radical prostatectomy to remove their cancerous prostates showed that the 206 exposed to Agent Orange had nearly a 50 percent increased risk of their cancer recurring despite the fact that their cancer seemed relatively nonaggressive at the time of surgery. And, their cancer came back with a vengeance: the time it took the prostate specific antigen, or PSA, level to double – an indicator of aggressiveness – was eight months versus more than 18 months in non-exposed veterans.

"There is something about the biology of these cancers that are associated with prior Agent Orange exposure that is causing them to be more aggressive. We need to get the word out," says Dr. Martha Terris, chief of urology at the Charlie Norwood VA Medical Center in Augusta and professor of urology at the Medical College of Georgia School of Medicine.

Dr. Terris, corresponding author on the study published in the May issue of British Journal of Urology International, says she wants her colleagues following prostate cancer patients with Agent Orange exposure to know those patients may need more meticulous scrutiny and so-called salvage therapy quickly if their prostate cancer returns. "Not only are their recurrence rates higher but their cancers are coming back and growing much faster when they do come back," the Georgia Cancer Coalition Distinguished Scholar says.

The PSA of prostate cancer patients is typically measured every three months for two years after surgery then every six months for life. After surgery to remove the diseased prostate, the PSA should be zero, but any prostate cancer cells left behind continue to make PSA, a red flag of recurrence, Dr. Terris says. The PSA often "percolates along" so physicians tend to watch it for a while to determine if additional therapy is needed. However in patients with Agent Orange exposure, radiation or hormone therapy to kill remaining cells may need to be done sooner rather than later, she says.

Increasing evidence is emerging that exposure to Agent Orange, a herbicide and defoliant used during the Vietnam War, increases risk for a variety of health problems, including prostate cancer, although the exact mechanism is unclear. Dioxin, its known carcinogen, also is found in herbicides and pesticides used by U.S. farmers, forestry and chemical plant workers who studies have shown to have an increased cancer risk. Scientists suspect dioxin activates regulatory regions of genes to enable the uncontrolled cell division that is a cancer hallmark.

Dr. Terris led a separate study of 1,653 veterans at VA medical centers in five cities between 1990 and 2006 that also showed recurrence rates were higher and recurring cancers were more aggressive with Agent Orange exposure. Dr. Sagar R. Shah, MCG urology resident, presented the findings at the 2007 annual meeting of the American Urological Association.

This new study – which includes the VA Medical Center in Augusta, Veterans Affairs Greater Los Angeles Healthcare System, Veterans Affairs Palo Alto Healthcare System and six affiliated medical schools – included new patients as well as longer follow up on many of the original study patients. As with the previous study, prostate cancer seemed to have a similar course in blacks and whites, but Agent Orange exposure was more common in blacks, who were more likely to be ground troops in Vietnam.

Plenty of questions remain, such as what happens to patients whose primary treatment is standard radiation or brachytherapy, where rice-size radiation pellets are implanted in the prostate, rather than surgery, Dr. Terris says.

She also wants to know whether the veterans' degree of exposure is related to the severity of their cancer. Everyone has some dioxin exposure; "Even if you never set foot in Vietnam or outside the United States," she says. So she is now measuring levels in the body fat – which is like a repository for what the body has been exposed to – to determine how levels correlate to their cancer severity.

Prostate cancer is the most common cancer in men and trails lung cancer as the second leading cause of cancer death.

The study was funded by the Department of Veterans Affairs, the National Institutes of Health, the Georgia Cancer Coalition, the Department of Defense Prostate Cancer Research Program and the American Urological Association/Astellas Rising Star in Urology Award.

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Geographical Ties to 1991 Gulf War ALS Cases Probed

Researchers from Duke University, the University of Cincinnati (UC) and the Durham Veterans Administration Medical Center are hoping to find a geographical pattern to help explain why 1991 Gulf War veterans contracted the fatal neurological disease amyotrophic lateral sclerosis (ALS) at twice the normal rate during the decade after the conflict.

By layering military records of troop locations onto Gulf-area maps, "we've found there were some areas of service where there appears to be an elevated risk," said Marie Lynn Miranda, an associate professor at Duke's Nicholas School of the Environment whose group uses geographic information systems (GIS) to study environmental health problems.

Also known as Lou Gehrig's Disease because it crippled and ultimately killed that baseball great in 1941, ALS causes cellular degeneration in the central nervous system. Its cause is unknown.

“There are no reports on the occurrence of ALS among veterans of other conflicts," the researchers wrote. "There is only a single report that suggests ALS may arise from environmental exposures associated with military service, per se." The cases assessed by Miranda and her colleagues occurred within a group of people who are expected to be at low risk for ALS, because they're mostly under the age of 45.

Miranda is the first author of a report on an initial analysis now published online in the research journal NeuroToxicology. The work was funded by the Department of Veterans Affairs Cooperative Studies Program.

The report’s senior author is Ronnie Horner, professor and director of the department of public health at Cincinnati, who led research that first documented twice-normal ALS rates among vets of the first Persian Gulf War in an article published in the September 2003 issue of the journal Neurology.

Horner's group is now assessing possible exposures vets might have had in the Gulf region that could explain the higher ALS rates its 2003 study found.

"As one of the largest contemporary set of cases, it presents a real opportunity to identify clues as to the cause of ALS not only for veterans of the first Gulf War but, perhaps, for ALS generally," Horner said. UC researchers are coordinating their investigations with those of researchers at the Durham, N.C. Veterans Medical Center and nearby Duke Medical Center.

Another UC-led study, published in the July 2008 issue of the journal Neuroepidemiology, found that the risk for developing ALS has now decreased among 1991 Gulf War vets. That suggests that the cause or causes of the ALS had something to do with their deployment in the region between August 1990 and July 1991.

Of the 135 cases diagnosed among the vets within 11 years after the war, only three had a family history of the disease. The small numbers might indicate that there is an environmental cause for ALS, the authors added.

“In the one-year period of military operations, some deployed military personnel experienced numerous exposures to multiple, potentially neurotoxic agents,” Miranda and coauthors wrote in the new report. “If the array of possible candidate environmental exposures could be reduced, it may be possible to identify or at least focus inquiry on specific potential causative agents.”

To narrow down the possibilities, Miranda and fellow investigators used GIS analysis, which allows researchers to layer different kinds of information onto maps to deduce potential risks.

They began by searching Department of Veterans Affairs and Department of Defense records as well as other sources to identify military personnel diagnosed with ALS after 1991. Department of Defense data also allowed the researchers to identify the military units these veterans with ALS served in during their deployment to the Persian Gulfregion.

In a separate analysis, the researchers identified troop units known to have been exposed to emissions from a munitions storage area at Khamisayah, Iraq. Those munitions were destroyed by U.S. forces in March 1991, and a United Nations commission later found many rockets there had been loaded for chemical warfare.

A previous Defense Department modeling study deduced that "some 90,000 veterans may have been exposed to low levels of nerve agent" at Khamisayah, the new report said.

The GIS mapping revealed that “there were some areas where there appeared to be an elevated risk,” Miranda said. To narrow down the possibilities, she and co-investigators then used statistical methods that assess the “best guess about the likelihood that space matters” for each grid of Gulf territory, she added.

Applying those statistics, the likelihood of a spatial connection with ALS development “climbed as high as 91 percent” in some grid cells, she said, most notably in a region southeast of Khamisayah. But Miranda cautioned that she will need to do additional analyses that add “time” to “place” before she can be more specific.

For instance, the researchers will want to know whether the ALS victim’s units were in the path of emissions from Khamisayah on a specific day. Miranda and her colleagues are also interested in examining environmental exposures that may be associated with smoke plumes from oil well fires.

Other authors of the new NeuroToxicology report include Miranda’s Nicholas School colleagues M. Alicia Overstreet Galeano and Eric Tassone as well as Kelli Allen, a research health scientist at the Durham VA Medical Center and a Duke assistant research professor of medicine.