New Risk With ADT in Prostate Cancer: Kidney Injury

Acute Injury Has High Mortality

Nick Mulcahy

July 16, 2013

There is yet another reason for clinicians to be careful about the use of androgen-deprivation therapy (ADT) in men with nonmetastatic prostate cancer, according to a new research.

In the study of more than 10,000 men with prostate cancer, the therapy, which has been tied to diabetes, heart disease, stroke, and other conditions, was significantly associated with an increased risk for acute kidney injury (AKI). This serious adverse event has a mortality rate of 50%, according to other research.

In their study, published in the July 17 issue of JAMA, Laurent Azoulay, PhD, from the Center for Clinical Epidemiology at the Jewish General Hospital in Montreal, and colleagues report that the current use of any ADT more than doubled the risk for AKI, compared with never use (odds ratio [OR], 2.48).

The risk was especially heightened for combination therapies and estrogens (OR, ≥4).

"Clinicians should exercise caution and not indiscriminately prescribe ADT to all men with progressive prostate cancer," Dr. Azoulay told Medscape Medical News in an email.

"There is no question that this therapy has a place in the treatment of patients with metastatic disease," he noted. However, the trend of using ADT in earlier-stage disease is controversial, in part, because of an unclear survival benefit, he explained.

Which patients with earlier-stage disease are good bets for ADT? "It comes down to identifying the group of patients for whom the benefits outweigh the risks," said Dr. Azoulay.

The first and only case report of AKI associated with ADT (the oral antiandrogen flutamide) was published in 2002 by Turkish clinicians (Med Oncol. 2002;19:117-119). The study by Dr. Azoulay and colleagues is the first observational study of AKI and ADT use.

So why has it taken 11 years for an observational study to flush out this serious adverse event?

Dr. Azoulay said that AKI is a "rare event" and was not detected in randomized controlled clinical trials. Also, other adverse outcomes, such as diabetes, "have received much of the focus in recent years."

Although ADT has been used to treat prostate cancer since 1941, research into adverse events has only recently caught up with its use, Dr. Azoulay explained.

He and his colleagues have done some of that work. The group previously reported that oral antiandrogen therapy and bilateral orchiectomy are associated with increased risks for stroke and transient ischemic attack (Eur Urol. 2011;60:1244-1250). Other researchers have reported that the current use of gonadotropin-releasing hormone (GnRH) agonists is associated with increased risks for incident diabetes and coronary heart disease.

In their study, Dr. Azoulay's team found that the association between ADT and AKI is mainly driven by 4 types of ADT: combined androgen blockade consisting of GnRH agonists with oral antiandrogens (OR, 4.50), estrogens (OR, 4.00), other combination therapies (OR, 4.04), and GnRH agonists (OR, 1.93).

ADT reduces testosterone levels, which leads to a hypogonadal condition marked by metabolic changes such as dyslipidemia, hyperglycemia, and an increase in fat mass, the researchers report.

"With respect to the renal system, hyperglycemia and dyslipidemia may disrupt glomerular function by expanding and thickening the interstitial tubular membrane," they note, explaining the possible mechanism of damaging action.

The study findings are not definitive, said Robert Dreicer, MD, from the Department of Solid Tumor Oncology at the Cleveland Clinic in Ohio, who was not involved in the study.

"Although provocative, these findings remain hypothesis-generating, and given that no [previous] study has addressed this issue, they must be replicated in other settings," he writes in a review published online July 17 in NEJM Journal Watch.

Dr. Dreicer also encourages limited use of ADT in prostate cancer. "Our current understanding of the risks associated with androgen-deprivation therapy should preclude its routine use in patients with prostate-specific antigen (PSA)-only disease, especially in those with prolonged PSA doubling times."

Case–Control Analysis

The researchers reviewed data from the Clinical Practice Research Datalink in the United Kingdom on 10,250 men newly diagnosed with nonmetastatic prostate cancer from 1997 to 2008. They found 232 incident cases of AKI during follow-up, which continued until 2009. Cases were randomly matched to 2721 controls on the basis of age, calendar year of prostate cancer diagnosis, and duration of follow-up.

The men were categorized into 1 of 6 mutually exclusive treatment groups: GnRH agonists (leuprolide, goserelin, triptorelin); oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide); combined androgen blockade (GnRH agonists plus oral antiandrogens); bilateral orchiectomy; estrogens; or a combination of the above therapies.

As noted, combination therapies and estrogens were especially associated with increased risk.

Overall, the incidence rate for AKI in the study population was 5.5 per 1000 person-years, which is much higher than the 1.8 per 1000 person-years seen in the general population, the researchers point out.

The odds ratio of AKI with current use, compared with never use, was highest during the first year of therapy. Although the ratios decreased with longer durations, they remained statistically significant for up to 3 years and for 3 years and beyond.

Dr. Azoulay and colleagues point out that the database provided patient lifestyle information on factors such as smoking, alcohol use, and body mass index, which allowed them to adjust for these potential confounders. For participating patients, the data also had to include up to a year of medical history prior to the prostate cancer diagnosis.

The data in this study were acquired with a grant from Prostate Cancer Canada. A number of the study authors report financial ties with industry, as detailed in the paper. Dr. Dreicer reports financial relationships with Dendreon, Eli Lilly, Endo Pharmaceuticals, Ferring, Janssen, Millennium, Novartis, Janssen, and Progenics.

JAMA. 2013;310:289-296. Abstract

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