Health Stream Literature Summary - Issue 56 - December 2009

Arsenic exposure predicts bladder cancer survival in a US population.
Kwong RC, Karagas MR, Kelsey KT et al. (2009) World Journal of Urology.
doi: 10.1007/s00345-009-0477-y

Chronic arsenic exposure has been associated with a number of types of cancer, including bladder cancer. However, arsenic compounds have been used historically as medicines and studies conducted in the 1990s suggested that inorganic trivalent arsenic may be a useful therapeutic agent for treatment of blood-related cancers including leukaemia, multiple myeloma and lymphoma. Clinical trials are currently underway to assess the efficacy of arsenic for solid tumours including bladder cancer. This study explored the relationship between inorganic arsenic exposure from contaminated drinking water and bladder cancer survival in a large population-based study in New Hampshire. In this region of the US around 40% of residents drink water from private wells, many of which contain arsenic.

All bladder cancer cases diagnosed among New Hampshire residents and registered with the state cancer registry from 1 July 1994 to 31 December 2001 were eligible. There were 832 bladder cancer cases interviewed, representing 85% of eligible cases identified. Sociodemographic, water consumption and lifestyle information was collected by interview. Tumour tissue samples were reviewed to assess tumour histology, stage and grade. Cause of death information was only available on cases that died prior to June 2006 due to the lag time for inclusion in the national death registry. Of the 298 total deaths, 87 were classified as attributable to bladder cancer. Death from other causes or unknown causes were excluded from the analysis of bladder cancer cause-specific mortality.

At the time of interview of cases, samples of toenail clippings were collected and analysed for arsenic and other trace elements and water samples were collected from the current household's drinking water supply and analysed for arsenic. Groups were created for high versus low arsenic exposure analysis using the 75th percentile as a cutoff, which was equivalent to a toenail arsenic level of 0.12 g/g or 0.74 micro g/L in household drinking water. Low arsenic exposure was used as the reference group (less than or equal to 25th or 0.057 micro g/g toenail, 0.11 micro g/L drinking water). Arsenic consumption was calculated by multiplying the drinking water arsenic concentration at home by the number of glasses the subject reported consuming from the questionnaire.

There were 534 surviving cases and 71% of these were male. Of the 250 deceased cases, 84% were male. The majority (75%) of participants had stage Ta or T1 tumours when diagnosed and 12% had stage T2 or higher. The median survival time for these groups was 8 and 6 years, respectively. A total of 33% were current smokers and 49% former smokers at the time of diagnosis. Cox-proportional hazard regression analysis was performed comparing high arsenic exposure (greater than 75th percentile) to the low exposure (less than or equal to 25th), grouped by toenail arsenic level. A significant hazard ratio (HR) of 0.5 (95% CI 0.4-0.8) was found, indicating that those with higher arsenic exposure had more prolonged survival after adjustment for age, sex, smoking status, stage, grade and therapy. A dose-response relationship was seen for better survival with high toenail arsenic levels (p-trend = 0.004) (Log-rank p value less than 0.001). Cox-regression analysis using high versus low arsenic consumption (calculated as arsenic concentration in well water times number of glasses consumed) showed a similar trend with HR 0.7 (95% CI 0.5-1.1). There was a suggestion also of a slightly improved survival with household drinking water arsenic level above the current US MCL (greater than 10 micro g/L), compared to lower levels, but the confidence intervals were wide [HR 0.7 (95% CI 0.3-1.5)]. High toenail arsenic levels were associated with longer survival HR 0.5 (95% CI 0.3-1.1) compared to low arsenic levels. The effect of high versus low toenail arsenic level on overall survival did not differ strongly between non-invasive and invasive tumours. Logistic regression analysis with adjustment for age, gender and smoking showed that high toenail arsenic levels decreased the odds of being diagnosed with a tumour of stage I or higher [OR 0.7 (95% CI 0.5-0.90)] compared to having low arsenic exposure.

The reduced hazard ratio for survival associated with high toenail arsenic exposure was found among the cases who had a history of smoking [overall survival HR 0.5 (95% CI 0.3-0.7); bladder cancer survival HR 0.4 (95% CI 0.2-0.9)], in contrast to the non-smokers [overall survival HR 1.2 (95% CI 0.4-3.9); bladder cancer survival 1.4 (95% CI 0.3-6.7)]. The interaction between high toenail arsenic and smoking was not statistically significant. Drinking water arsenic levels were associated with similar differences on the basis of smoking status. This study found a decreased risk of overall death for patients exposed to higher amounts of arsenic through drinking water, with a non-significant similar trend for cause-specific mortality. The authors suggest several possible explanations including differences in the biology of arsenic-related tumours, direct effects of arsenic on tumour growth, interaction between arsenic and cancer treatments.

Comment Arsenic levels in drinking water this study were much lower than encountered in regions of the world (eg Taiwan, Bangladesh) where there is strong evidence of arsenic-induced cancers. Most of the bladder cancer cases in this study are likely to be attributable to other causes (eg smoking) rather than arsenic exposure.

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