Intermittent ablation plus 5-ARI slows tumor growth

Vancouver, British Columbia-A combination of intermittent androgen ablation and finasteride (Proscar) appears to slow tumor growth and improve survival time compared with continuous androgen ablation (CAA) and intermittent androgen ablation (IAA) strategies, according to findings of an animal study conducted at Northwestern University, Chicago. Researchers found that mice treated with IAA plus finasteride were three to five times more likely to survive for 70 days from start of treatment than were those in the other treatment groups.

CAA and IAA are commonly used in patients with prostate cancer.

"Previous work from our lab showed that, following castration, a hormonal environment high in testosterone and low in dihydrotestosterone (DHT) induces expression of androgen-response genes that are primarily growth inhibitory," explained Scott Eggener, MD, currently a fellow in urologic oncology at Memorial Sloan-Kettering Cancer Center, New York.

Speaking here at the International Study of Intermittent Therapy for Cancer of the Prostate meeting, Dr. Eggener described a study testing the hypothesis that finasteride, a type II 5-alpha-reductase inhibitor that increases testosterone and decreases DHT, would improve tumor growth characteristics when administered during the intermittent ablation off-cycle.

Lower DHT levels

Nude mice were castrated and injected with LNCaP cells to induce tumors of 0.5 cm to 1.0 cm. Surgical orchiectomy followed, and 2 weeks later, 110 mice were randomized into one of four arms based on tumor size: CAA, CAA plus finasteride implanted as a pellet, IAA, and IAA plus finasteride pellets during the off-cycle.

In mice treated with IAA, the cycling treatment pattern consisted of 14 days of castration followed by 14 days of androgen re-introduction. The CAA, CAA with finasteride, and IAA groups showed no difference in tumor volume after one cycle, whereas mice treated with IAA and finasteride exhibited approximately 25% of the growth compared with other treatments. Few mice were able to complete a second cycle, but of those that did, the IAA with finasteride group showed markedly decreased tumor growth, regardless of the size of the tumor at the time of randomization.

"We were happy to find out the use of finasteride during the off-cycle of intermittent androgen ablation appears to induce favorable tumor growth characteristics and prolong survival, at least in an animal model," Dr. Eggener said.

Prolonged off-cycle tested

Researchers also carried out a one-time pellet implantation on the mice, rather than cyclic therapy, to test a prolonged off-cycle. Again, mice treated with IAA plus finasteride survived the longest.

Within the tumors, DHT levels were much lower when finasteride was present.

"This shows that [finasteride] is not only causing differences in serum androgen levels, but also at the level of the tumor itself," said Dr. Eggener.

Researchers also found the mild increase in serum testosterone caused by finasteride in the intermittent ablation plus finasteride group and subsequent conversion of testosterone to estrogen was not responsible for any of the observed changes in tumor volume.

"However, we were surprised to find out that serum PSA really had a poor correlation with tumor volume in our model, suggesting our LNCaP cell line contained an androgen-independent component," Dr. Eggener said.

He noted that, although rare, this finding has been noted in other studies. Multiple clinical trials of IAA are ongoing.

Finasteride was provided by Merck and Co. to Dr. Zhou Wang for use in the animal studies.