Journal of the National Cancer Institute Advance Access originally published online on August 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(16):1132-1133; doi:10.1093/jnci/djn300
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© Oxford University Press 2008.
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Preventing Prostate Cancer: New Analyses Put Finasteride Back on the Map
In 2003, when investigators from the National Cancer Institute and the Southwest Oncology Group published initial results from the Prostate Cancer Prevention Trial (PCPT), an anomaly arose.
The study found that the drug finasteride reduced the relative risk of a prostate cancer diagnosis by about 25%. That is, 24.4% of men taking placebo were diagnosed with prostate cancer, whereas 18.4% of men taking finasteride got the diagnosis. Alone, that finding would have been a major advance in prostate cancer prevention.
But at the same time, the study data showed an increase in high-grade cancers in men taking finasteride. Those cancers are the most troubling because they tend to grow and spread quickly.
The results confounded study investigators and stymied the adoption of finasteride—which is approved by the U.S. Food and Drug Administration to treat benign prostate hyperplasia—for prostate cancer prevention.
Later, some prostate cancer experts suggested another downside to finasteride. The drug may have prevented only insignificant tumors, they said—cancers that would never kill.
"People said, ‘You’re preventing inconsequential tumors and you’re potentially causing high-grade cancers.’ So people basically walked away from the results of the trial," said PCPT principal investigator Ian Thompson, M.D., chair of the department of urology at the University of Texas Health Science Center at San Antonio.
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Now, 5 years after the initial report, three new analyses suggest that the 2003 findings underestimated the benefits of finasteride and overestimated its risks. The new analyses dismiss the two main concerns surrounding finasteride for prostate cancer prevention, Thompson said. Therefore, they are the "most important papers to come out of the study. They wrap it all up, and they show that [finasteride] is a home run," he said.
With the new analyses in place, the PCPT now "proves that we can actually prevent this disease," said Christopher Logothetis, M.D., director of the genitourinary program at the University of Texas M. D. Anderson Cancer Center in Houston. Logothetis was not involved in the original study or the new analyses.
High-grade Tumors Explained
Two of the new articles, published online May 18 in Cancer Prevention Research, address concerns that finasteride causes an increase in high-grade cancers. Both draw on information gathered after the initial 2003 publication.
In the PCPT, 19,000 men aged 55 years and older received either finasteride or a placebo for 7 years. All men were then scheduled for end-of-study biopsies to determine whether they had prostate cancer. Study participants also underwent biopsies if they had an abnormal digital rectal exam or a high reading on a prostate-specific antigen (PSA) blood test performed during annual visits. Biopsy samples of men with tumors were graded according to the widely used Gleason criteria. Tumors with Gleason scores of 7–10 were considered "high grade".
But because biopsies sample only small sections of the prostate, assigning a Gleason score to the biopsy specimen is an inexact science, said Howard Parnes, M.D., chief of the prostate and urologic cancer research group in the division of cancer prevention at NCI. "What many people didn’t fully grasp with the [2003] publication is that all the concern about grade was derived from biopsy data, which should always be taken with a grain of salt," said Parnes, who was involved in the PCPT and one of the new analyses.
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Instead, the "gold standard" for assigning a Gleason grade requires an examination of the entire prostate after surgical removal. Pathologist Scott Lucia, M.D., of the University of Colorado School of Medicine in Denver and colleagues did just that, closely grading 500 prostates surgically removed from PCPT participants. In a 2007 JNCI publication (99:1375–83), the pathologists reported that participants taking finasteride had smaller prostate gland volumes than participants taking placebo. In other words, finasteride, by shrinking the prostate, made it easier to find high-grade cancers on biopsy. Lucia and colleagues still found more high-grade tumors in radical prostatectomy specimens from men taking finasteride, but this excess was much lower than the excess seen in the original PCPT results. "It's clear [that the original results] overestimated the rates of high-grade disease," Parnes said. "The excess high-grade disease reported in 2003 is explained at least in part by the bias introduced by the drug we were testing." That bias—a smaller prostate—made it more likely that a biopsy would find high-grade tumors.
The two new analyses take the biopsy bias results and mathematically extend them to the entire PCPT cohort. One of the analyses, from Parnes and two NCI colleagues, concludes that "the rate of true high-grade disease may have been lower in the finasteride arm" than in the placebo arm. The second analysis, from Mary Redman, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle and colleagues, including Thompson, reaches a stronger conclusion. The Redman analysis estimates a 27% reduction in relative risk of high-grade prostate cancer in the finasteride arm compared with the placebo arm. That is, 8.2% of men in the placebo arm would have been diagnosed with high-grade prostate cancer (if they all had had prostatectomies), compared with 6% in the finasteride arm, according to the model.
"I’m not exactly a fan of [mathematical] modeling, but just simply accounting for [finasteride's effect] on tumor detection makes the high-grade disease issue go away," Thompson said.
Clinically Significant Tumors
The third new report from Lucia, Thompson, and colleagues eliminates the second concern about finasteride for prostate cancer prevention—that it prevents only inconsequential tumors, Thompson said. For this study, also published May 18 online in Cancer Prevention Research, pathologists reexamined biopsy cores from every PCPT participant found to have prostate cancer. Using criteria developed by Jonathan Epstein, M.D., a pathologist at Johns Hopkins Medical Institutions in Baltimore, Lucia and colleagues determined whether each tumor was "clinically significant"—meaning that treatment would most likely be recommended. The Epstein criteria include clinical stage and extent of the tumor and a measure called PSA density, which averages PSA over the size of the prostate. The report found that 75% of cancers found in the placebo group were clinically significant; these are the tumors that finasteride helps prevent, Thompson said.
Although the PCPT cannot answer whether preventing such tumors saves lives, preventing them does reduce the frequency of prostate cancer treatment and the adverse effects the treatments carry, he said. About 90% of men with clinically significant tumors opt for surgery, radiation, or some other treatment. Such treatments often cause sexual, urinary, and bowel problems.
"It is a bit of a strange prevention argument," Logothetis said, "because we’re arguing that if it's bad enough for you to operate on, it's bad enough for me to prevent. We can’t say we’ve avoided cancers that otherwise would have killed people. But we can say we’ve avoided cancers that people consider significant enough to treat."
The NCI does not make any treatment or prevention recommendations. But in light of the new analyses and previous studies that show that finasteride increases the accuracy of PSA testing (JNCI 2006;98:1104–1105), Parnes said that men with enlarged prostates, men worried about prostate cancer, and men committed to annual screening for the disease make good candidates for the drug.
Said Logothetis, "In patients with a family history [of prostate cancer], in patients fearful of a diagnosis, it seems safe and reasonable to offer it as an option."
Not every urologist is enthusiastic, however. Derek Raghavan, M.D., Ph.D., of the Cleveland Clinic said that although the new data "move the pendulum" toward finasteride's being a safe chemopreventive, he still wants to see more data. "I’m worried about the guy with no family history of prostate cancer who goes to his doctor and gets a handful of finasteride and is just sent on his way with no follow-up," Raghavan said. But he added that men with risk factors—such as being black or having a family history of prostate cancer—are good candidates for finasteride.
Seven companies manufacture finasteride. But the drug's generic status makes it unlikely that any of them will ask the FDA to approve it for prostate cancer prevention, Thompson said. "It's the worst possible scenario. If one company spends $3 million to get the new indication, the other six companies get the benefit. I call it a tragic tale of success. It's driving me absolutely bonkers."
A second drug, still on patent, may have better odds of becoming the first FDA-approved drug for prostate cancer prevention. But that's far from certain. Marketed by GlaxoSmithKline as Avodart, dutasteride works similarly to finasteride and is approved to treat benign prostate hyperplasia. An 8,000-man trial sponsored by GlaxoSmithKline is evaluating the drug's ability to reduce the incidence of prostate cancer. Enrollment in the trial is complete, and the company expects data in 2010. Dutasteride is on patent until 2013, although one generic drug maker, Barr Laboratories, has challenged the patent in court. The case is pending.
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