The Prostate Cancer Prevention Trial, a randomized placebo-controlled study involving nearly 19,000 men at 221 sites over 10 years, has shown that men who took the drug finasteride reduced their risk of getting prostate cancer by about 25%.
Health officials hailed the trials resultsthe first demonstration of a drugs ability to prevent this common and widely feared diseaseas a resounding success for chemoprevention. But the findings also brought some surprises, including a large caveat for men deciding whether to use finasteride.
The National Cancer Institute-sponsored trial, which began enrolling patients in January 1994, was halted 15 months early after a monitoring committee ruled that the already-robust findings were unlikely to change with further study. Still, 86% of enrolled men completed their 7 years on finasteride or placebo. The results appeared in the online New England Journal of Medicine on June 24 and will appear in the July 17 print edition.
Coordinated by the Southwest Oncology Group, the trial enrolled men 55 years old and older with no evidence of prostate cancer. The treatment group took 5 mg of finasteride daily, the same dose at which the drug was approved by the U.S. Food and Drug Administration, and marketed by Merck & Co. as Proscar, to treat the urinary obstruction of benign prostatic hyperplasia. (Merck also sells finasteride at a 1-mg dose as Propecia to treat male pattern baldness.)
The trial was designed with statistical power to detect a 25% reduction in prostate cancer incidence. So in one respect, the investigators expectations were right on target. But instead of the expected 6% of men in the placebo group that they estimated would be diagnosed with prostate cancer, four times that many24.4% of the placebo group, or 1,147 of the 4,692 men with data available for final analysishad such a diagnosis. By comparison, 18.4% of men taking finasteride (803 of 4,368 with final data) had a prostate cancer diagnosis. Five men in each group died from prostate cancer.
"There was a lot more prostate cancer than we expected," said Leslie Ford, M.D., associate director for clinical research in NCIs Division of Cancer Prevention. But, she added, autopsy studies show prostate cancer in a much higher proportion of men than are diagnosed through symptoms or screening, and thus, the 6% estimatewhich had been based on general population rateswas likely too low given the intensive scrutiny the participants received.
This level of surveillanceall participants were recommended for needle biopsy if they had a prostate-specific antigen (PSA) reading over 4 ng/ml, an abnormal digital rectal exam, or completed 7 years in the trial without a prostate cancer diagnosisled Peter Scardino, M.D., to express skepticism in interpreting the study results.
In an accompanying editorial, Scardino, chairman of urology at Memorial Sloan-Kettering Cancer Center in New York, stated that "The high rate of detection of cancer in both groups ... raises serious concern about the clinical significance of the cancers that were detected and of the reduction achieved with finasteride treatment."
Offering biopsy to all men, he wrote, "is destined to lead to the overdetection of histologically identified cancers of little clinical significance. We do not know the malignant potential of such cancers and have no evidence that any benefit would be worth the risk associated with treatment."
The other surprise findingand the one to give pause to men considering the drugwas that 37% of cancers found among men in the finasteride group had a Gleason grade of 7 to 10, compared with 22.2% of those in the placebo group. Overall, 5.1% of men on placebo and 6.4% of those on finasteride had high-grade tumors. Based on a pathologists assessment of how abnormal the cells appear, the Gleason scale is an attempt to estimate the aggressiveness of a tumor; scores of 7 or above suggest tumors more likely to spread outside the gland.
Considering this increase in the number of high-grade tumors, Scardino concluded that "on balance, finasteride does not appear to be an attractive agent for the chemoprevention of prostate cancer."
Although the trials investigators acknowledged the same concerns that Scardino raised, they expressed greater optimism about the drugs potential. For one thing, the increase in high-grade tumors has several possible explanations. The most worrisome would be if finasteride actually induces these aggressive cancers because of its mechanism of action: blocking the conversion of testosterone to the more potent dihydrotestosterone. This scenario is plausible because cancers in men with low testosterone levels tend to have higher Gleason grades and worse outcomes. However, there is also evidence that androgen deprivation causes changes that simply mimic the characteristics of high-grade tumors. A third possibility relates to the fact that finasteride shrinks the prostate gland, but tumors that do not respond to the drug remain unaffected. Thus, these portions of the glandwhich are also likely to be more abnormal or "high-grade" in appearancemay show up more prominently in biopsy. The authors pointed out, however, that about 98% of the cancers in each group were clinically localized.
"We know that hormones affect the appearance of prostate cancer cells," Ford said. "So we can speculate on whether these are truly high-grade tumors or just a change in the way they look under the microscope. But long-term follow-up is the only thing thats going to answer the question." The investigators plan to track all participants diagnosed with prostate cancer, and "mortality will be the ultimate endpoint," Ford added.
Ian Thompson, M.D., principal investigator of the trial and chief of urology at the University of Texas Health Sciences Center, San Antonio, challenged the notion that finasteride mostly prevents clinically insignificant cancers.
"A man with a Gleason 6 prostate cancer ... has a measurable risk of dying of his disease if left untreated," Thompson said. "So although many of those men may never die from the disease, they frequently enter into treatment, because at this point in time we cant determine [which cancers will be fatal]. To be able to take that man away from the [doctors] office and say he never has to sit across the table from me and have this discussion is a remarkable benefit. We cant forget the fact that there is no good prostate cancer."
Beyond the current findings, the blood and tissue specimens collected during the trial "are really going to be a treasure for understanding the role of the androgen receptor and androgens in the development of prostate cancer, as well as how finasteride interacts with that," Ford said. "The bottom line is trying to determine which men are actually at risk for developing prostate cancer, and narrowing down who might benefit from finasteride." Additional studies are planned to examine the role of diet, oxidative stress, and insulin-like growth factor, she said.
For now, a mans decision about whether to take finasteride for prostate cancer preventionassuming FDA approval for that indicationis likely to be based on medical history and personal preference. Thompson said men should discuss the options with their physicians, and those at elevated risk of prostate cancersuch as African Americans and men with a family history of the diseasemight decide to take the drug, along with men who are concerned about the risk for other reasons. And even finasteride skeptic Scardino agrees that men whose urinary symptoms are helped by the drug need not discontinue it based on this trials results, so long as they are carefully monitored. On the other hand, men concerned about sexual functioning might put more value on the studys finding that erectile dysfunction and loss of libido were slightly higher in the finasteride group.
Despite the caveats, Ford said, "Its an absolutely positive study in that weve never before been able to say on a scientifically sound basis that we can demonstrate a reduction in the occurrence of prostate cancer. Where, when, how, and who is it best for? are always the questions that follow."
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