ADT FOR PROSTATE CANCER MAY INCREASE COLORECTAL CANCER RISK

November 10, 2010 — Men with prostate cancer who are taking androgen-deprivation therapy (ADT) might be at increased risk for colorectal cancer, according to a new analysis of data from more than 100,000 patients in the United States.

After adjustment for a number of potential variables, there was a 30% to 40% increased rate of colorectal cancer among men who were using ADT, compared with those who were not.

The new finding is reported in the November 10 issue of the Journal of the National Cancer Institute. An accompanying editorial suggests that "an elevated risk of colorectal cancer may be an additional consideration to weigh in the risk vs benefit profile" of this therapy.

ADT is already associated with a risk for heart disease and diabetes, and the US Food and Drug Administration recently mandated that warnings to this effect appear on all these products. This might be related to other adverse effects, the researchers speculate, because hyperinsulinemia and diabetes are known risk factors for colorectal cancer.

Strong Evidence of Link

The study provides "strong evidence to link ADT in the setting of prostate cancer to an increased risk of colorectal cancer," say the authors.

The researchers, led by Silke Gillessen, MD, MS, from the University of Michigan in Ann Arbor, analyzed data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database. They identified 107,859 men who were 67 years or older and had been diagnosed with prostate cancer between January 1, 1993 and December 31, 2002.

About half of these men (n = 55,901; 51.8%) received ADT during the study period, mostly in the form of gonadotrophin-releasing hormones (GnRH) agonists, although a small proportion (n = 5804; 5.4%) underwent orchidectomy.

As of 2004, colorectal cancer had been diagnosed in 2035 (1.9%) of these men.

When the team calculated unadjusted incident rates of colorectal cancer, the incidence was highest in men who had undergone orchiectomy (6.3 cancers per 1000 person-years), intermediate among those receiving GnRH agonist therapy (4.4 cancers per 1000 person-years), and lowest among those who had not been treated with ADT (3.7 cancers per 1000 person-years).

There was a statistically significant dose-response relation that suggests causality, the researchers note. There was a gradient of increasing risk for colorectal cancer in men who received just 13 to 24 months of GnRH agonist therapy (adjusted hazard ratio [HR], 1.19), in men who received 25 months or more of GnRH agonist therapy (adjusted HR, 1.31), and in men who underwent orchiectomy (adjusted HR, 1.37).

The finding is biologically plausible, the researchers explain. Androgen receptors have been found on both healthy and malignant colon tissue. In various animal studies, androgens have been shown to protect against colon carcinogenesis, whereas androgen ablation promotes it.

This raises the question of whether men who are androgen deficient are at increased risk for colorectal cancer. "Androgen deficiency is now recognized as a relatively common occurrence in the male general population," the researchers write; they suggest that clinical trials exploring testosterone replacement in the population should include colorectal cancer as an outcome.

Potential Confounders

Lifestyle and dietary factors play a role in colorectal cancer and could have confounded the results, suggest the authors of an accompanying editorial, Jennifer Lin, PhD, from the Brigham and Women's Hospital and Edward Giovannucci, MD, ScD, from the Harvard School of Public Health, both in Boston, Massachusetts.

In the study population, the patients receiving ADT were more likely to have had more advanced prostate cancer, so conceivably they could have been less physically active, spending less time participating in outdoor activities, and hence have lower vitamin D levels. All of these factors have been associated with an increased risk for colorectal cancer, they note. Obesity might also play a role; obese men tend to have lower androgen levels.

The finding of an elevated risk for colorectal cancer with ADT adds another factor to consider when weighing the risks and benefits of this treatment approach, the editorialists write. "It also reinforces the need for routine screening for colorectal cancer and the adoption of lifestyle practices such as physical activity that may help to counter some of the drawbacks of antiandrogen therapies," they add.

The researchers have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online November 10, 2010. Abstract