Results from the National Cancer Institute's (NCI) first large-scale prostate cancer prevention trial (Figure 1) have been released a year earlier than expected, showing that prostate cancer can, at least in part, be prevented by the drug finasteride. But, as is usually the case with research, while one critical question has been answered, others have been formed.
Figure 1
"This is the first intervention that is proven to reduce a man's risk of prostate cancer," said Ian Thompson, MD, professor and chief of the division of urology at the University of Texas Health Sciences Center, and the principal investigator for the nearly 19,000-man Prostate Cancer Prevention Trial (PCPT). Data from the trial showed that men who took finasteride for seven years were 25% less likely to develop prostate cancer than men taking a placebo; 18.4% of men taking finasteride developed prostate cancer vs. 24.4% of men taking placebo. Men on finasteride reported more sexual side effects, such as impotence, and fewer urinary side effects compared to men on placebo.
However, those men taking finasteride who did develop prostate cancer seem to have more high-grade disease, which can be more aggressive, although researchers aren't convinced that what they see is truly high-grade disease. Of the men on placebo, 5.1% developed high-grade prostate cancer. For men on finasteride, 6.4% developed high-grade prostate cancer. Almost 98% of all the prostate cancers diagnosed during the trial were early-stage disease.
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The reason men on finasteride had more high-grade tumors is currently unknown; the
researchers are studying several possibilities. The drug, like other hormonal agents, affects the appearance of prostate cancer cells, and this may lead to a false estimate of tumor grade. Or if high-grade tumors are unaffected by finasteride, but the rest of the prostate shrinks from the drug, the biopsy may reveal more of the high-grade tumor that is present. Another possible explanation being examined is whether finasteride truly causes more aggressive tumors to develop.
"Although a larger percentage of men taking finasteride had tumors that appeared to be more aggressive to a pathologist, we do not know if those tumors will act biologically aggressive," said Leslie Ford, MD, associate director for clinical research in NCI's Division of Cancer Prevention. "We will follow these men long-term to determine whether a cancer that looks high grade in a man taking finasteride correlates medically with aggressive disease."
The PCPT began in 1993, based on both the association of male hormones with prostate cancer risk, and the fact that men with inherited deficiencies in the enzyme that makes the most active form of testosterone (dihydrotestosterone [DHT]) don't get prostate cancer. Finasteride inhibits the enzyme that transforms testosterone into DHT, shrinks the prostate and lessens urinary symptoms of benign prostatic hypertrophy (BPH), which lead to its current Food and Drug Administration (FDA) approved indication. Finasteride is sold as Proscar® in 5 mg-doses to treat BPH (it is also sold in a 1 mg-dose as Propecia® to treat hair loss). The PCPT used the 5-mg dose.
The PCPT included men >= 55 only if their prostate specific antigen (PSA) level was < 3.0 ng/ml and they had a negative digital rectal exam (DRE). They were then randomized to finasteride or placebo and had yearly follow up exams including PSA and DRE-if these tests or any symptoms suggested the need for follow up, a biopsy was recommended. If the biopsy was negative, the men continued on the trial. At the end of seven years, the men were required to have a biopsy to check for disease. About half of the cancers were found during regular surveillance and half were found by end-of-study biopsy.
This process allowed PCPT researchers to collect a treasury of biological data that is being used to both decipher the initial study findings and to pursue other molecular-level research on the cause and prevention of prostate cancer. "The men who participated in the PCPT have left behind an incredible legacy of blood samples, prostate tissue, and tumor samples," said Dr. Ford. "And we have assembled a world-class group of scientists to explore the disease on a molecular level."
Additional studies will focus on:
- How variations in the genes for 5-alpha reductase, the androgen receptor, and enzymes that control androgen metabolism affect prostate cancer risk
- How variations in genes affect how finasteride works in the body and how people respond to the drug (pharmacogenomics)
- How levels of insulin-like growth factors, substances that stimulate cell division in many organs including the prostate, affect development of prostate cancer
- The role of diet in prostate cancer risk
- How oxidative damage, DNA repair mechanisms, and inflammation affect prostate cancer development
In the meantime, the question becomes a more pragmatic one for men who are concerned about their risk of developing prostate cancer. "Decisions to initiative preventive therapies are always complex and involve trade-offs of benefits and risks," said Dr. Ford, "whether it's aspirin, cholesterol-lowering drugs, or finasteride. Finasteride may not be right for every man. Fortunately, the decision is not acute and not irreversible, and men and their doctors can take time to review the data and make an informed choice."
In addition, the FDA must first change the indication for finasteride to allow it to be marketed for cancer prevention, and any review of data will take months. The data were released online by the
New England Journal of Medicine on June 24, 2003 and appeared in the July 17, 2003 print journal.
"The Influence of Finasteride on the Development of Prostate Cancer," appeared in the July 17, 2003 issue of the New England Journal of Medicine, along with an editorial, "The Prevention of Prostate Cancer-the Dilemma Continues." Please visit the Web site (http://content.nejm.org/) to view both of these articles.
