(UroToday.com) The 2023 AUA annual meeting included a bladder cancer session, featuring a presentation by Dr. Stephen Williams discussing a nationwide cohort study assessing agent orange exposure and risk of bladder cancer. From 1962 to 1971, the US military sprayed herbicides over Vietnam to destroy the jungle canopy concealing opposition forces. Agent Orange is a 50:50 mixture of 2,4-dichloro phenoxy acetic acid (2,4-D) and 2,4,5-trichloro peroxyacetic acid (2,4,5-T), and exposure among Veterans has been previously associated with increased risk of prostate cancer, non-melanoma skin cancer, and other malignancies.
The plausibility that Agent Orange may be linked with cancer is supported by a body of evidence that Agent Orange disturbs cellular processes leading to carcinogenesis. However, to date, limited data exist regarding the link between Agent Orange and bladder cancer risk and the Institute of Medicine (IOM) concluded the interplay between Agent Orange exposure and bladder cancer outcomes is an area of needed research. Dr. Williams and colleagues examined the relationship between Agent Orange exposure and bladder cancer risk in Vietnam Veterans.
This study was a nationwide Veterans Affairs (VA) retrospective cohort study to determine bladder cancer risk according to Agent Orange exposure. A total of 25,144,713 Veterans were identified in the VA from 2001-2019. Due to limited numbers of female patients exposed to agent orange, the study was limited to males. Agent Orange exposed patients were matched on a 1:3 basis by age, gender, race, military branch, and year of service entry to non-Agent Orange exposed patients. Risk of bladder cancer was measured by incidence and aggressiveness by muscle-invasion status using natural language processing. Multivariable Cox proportional-hazards regression was used to test the association between Agent Orange and bladder cancer incidence with time zero being entry into the VA system. Multivariable logistic regression was used to test the association between Agent Orange and aggressiveness among men with bladder cancer.
After inclusion and exclusion criteria, there were 629,907 (25.0%) patients with Agent Orange exposure and 1,888,019 (75.0%) matched patients without Agent Orange exposure:
All patients from 2000-2020 with a CTP code for TURBT (n = 76,060) were selected from the VA database. A sample of 600 patients (with 2,337 full-text notes) who had a TURBT and confirmed pathology results were selected for NLP model development and validation.
Agent Orange exposure was associated with significantly increased risk of bladder cancer, though effect was very slight (HR 1.03, 95% CI 1.01-1.05):
When stratified by median age at VA entry, Agent Orange was not associated with significant bladder cancer risk among older patients (above the median) but was associated with increased bladder cancer risk among younger patients (below the median: HR 1.07, 95% CI 1.04-1.10). Among veterans diagnosed with bladder cancer (n = 50,781), Agent Orange was associated with lower risk of muscle-invasive bladder cancer (OR 0.91, 95% CI, 0.85-0.98).
Dr. Williams noted the following limitations of this study:
- Male only cohort
- VA electronic health record generalizability
- Selection bias and misclassification bias (ie. Agent Orange exposure, CCI classification at VA entry) when using large population-based data
- Lack of biological assessment of Agent Orange exposure
- Unmeasured confounding
- Over-powered to detected differences (ie. can detect differences which are not clinically meaningful)
Dr. Williams concluded his presentation by discussing a nationwide cohort study assessing agent orange exposure and risk of bladder cancer with the following take-home messages:
- In the largest case matched study among Vietnam Veterans to date, there was an increased risk of bladder cancer, but not bladder cancer aggressiveness, among Agent Orange exposed Veterans, though the increased risk was small
- These findings suggest a link between Agent Orange exposure and risk of bladder cancer, though the clinical relevance of this is unclear
Presented by: Stephen B. Williams, MD, University of Texas Medical Branch, Galveston, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023
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Agent Orange and Bladder Cancer: Insights from a Study on 25 Million Veterans - Stephen Williams