Aspirin therapy for people at high risk of heart disease may be the ideal model for preventing disease with pharmaceuticals: It is effective, inexpensive, and has few side effects. However, cancer chemoprevention is a newer concept and far more complicated. The drugs tested so far tend to be more expensive and have more serious side effects than aspirin, and their acceptance by doctors and patients has been slow.
Only a few chemoprevention drugs have so far completed phase III clinical trials. In 1998, the National Surgical Adjuvant Breast and Bowel Project (NSABP) completed its P-1 study of tamoxifen for the prevention of breast cancer in women at high risk. The drug was shown to reduce breast cancer incidence by about 50% compared with placebo and was approved by the U.S. Food and Drug Administration for breast cancer prevention later that year. In 2000, celecoxib (Celebrex) was shown to inhibit polyp development in people with familial adenomatous polyposis, a genetic disease that, when left untreated, confers a nearly 100% risk of colon cancer. And last year, results from the Prostate Cancer Prevention Trial (PCPT) showed that finasteride reduced biopsy-detected prostate cancer incidence by about 25% compared with placebo.
Six years after publication of the NSABP P-1 study, tamoxifen is slowly becoming more popular. In a study that appeared earlier this year in Cancer, 42% of women who came to the Lynn Sage Breast Program in Chicago and were offered the drug after being deemed eligible decided to take it. An earlier study, published in 2001 in the Annals of Surgical Oncology, found that only two of 43 patients who qualified for the drug elected to take it. Fear of the drug's side effects was the most common reason for declining the drug.
Finasteride, however, has been slower to catch on, according to anecdotal evidence. For example, at a recent urology meeting where physicians in the audience at one lecture were asked if they had written a prescription for finasteride for the purpose of prostate cancer prevention, only a few raised their hands, said Ian M. Thompson, M.D., of the Department of Urology at the University of Texas Health Science Center at San Antonio, who attended the meeting.
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Thompson, who led the PCPT, attributes the slow uptake of finasteride to its side effects. Besides an increase in sexual side effects, such as decreased sexual potency and loss of libido, the finasteride group in the trial also had a greater number of high-grade tumors.
As part of a follow-up study, which Thompson expects to be finished by the end of this year, his team is examining radical prostatectomy samples from the men diagnosed with high-grade prostate cancer in both the finasteride and placebo groups to see if there are differences in the tumors themselves. High-grade tumors may not be more common in finasteride users, Thompson said, but simply easier to find because the drug shrinks the prostate.
For tamoxifen, users must not only overcome fear of that drug's side effectswhich include an increased risk of endometrial cancer, stroke, and pulmonary embolismbut also realize that its first duty was as a cancer drug, and there can be hesitancy in prescribing it for healthy women, according to D. Lawrence Wickerham, M.D., associate chairman of the NSABP.
One important missing piece of the chemoprevention puzzle has been adequate surrogate endpoints for clinical studies. Unlike studies of the prevention of heart disease that can use the well-established surrogate endpoint of cholesterol level for some classes of drugs, in cancer research, surrogate endpointssuch as cancer incidence or premalignant conditionsdo not necessarily correspond to prevention of cancer deaths.
"The challenge is, how do we really know that treating that premalignant lesion reduces the likelihood that it will develop into cancer?" said Scott M. Lippman, M.D., professor of cancer prevention and cancer medicine at the University of Texas M. D. Anderson Cancer Center in Houston. "There is a lack of a cholesterol-like endpoint" in cancer research, said Lippman.
Price is another barrier to cancer chemoprevention. Unlike aspirin, which costs only pennies per day, these drugs are much more expensive. The average wholesale price for generic tamoxifen is $3.79 per 20 mg pill (the dose tested in the NSABP P-1 trial), according to First Databank, although several studies have concluded that the drug is cost-effective not only because of its health benefitswhich include a reduction in hip fractures in addition to the preventive effect on breast cancerbut also because the drug needs to be taken for only 5 years.
For finasteride, however, researchers do not yet know how long the drug needs to be taken to get the most benefit from it, and it does not fare well in at least one cost-effectiveness analysis. Steven B. Zeliadt, Ph.D., a postdoctoral fellow at the Fred Hutchinson Cancer Research Center in Seattle, presented a poster at the American Society of Clinical Oncology meeting in June that showed the calculated cost-effectiveness of finasteride. Based on a price of $2.22 per pill (as available on drugstore.com; the average wholesale price is higher), finasteride use costs $1,660,000 per life-year gained and $200,000 per quality-adjusted life-year gained. (Researchers generally consider a cost of $50,000 to $100,000 per year gained to be the cutoff for cost-effectiveness. See sidebar below.)
Even when Zeliadt assumed that there was no effect on high-grade tumors, the drug still cost $290,000 per life-year gained and $130,000 per quality-adjusted life-year gained. The calculations did not approach the cost-effectiveness threshold until the price of the drug was reduced by half.
The numbers were even more staggering when Zeliadt calculated the overall net costs for the entire U.S. population, which take into account both the cost of the drug and the reduction in prostate cancers and benign prostatic hyperplasias. Assuming that about 60% of adult men would be eligible for the drug and about half would take it, Zeliadt calculated that finasteride, at its present price, would cost a total of $2.2 billion per year for men in the United States aged 55 to 64 and an additional $1.2 billion per year for men aged 65 to 80.
"It's just so expensive to prescribe any preventive intervention," said Zeliadt, in part because the natural history of cancer is so long and the disease can take decades to develop.
The disconnect between when the drugs are taken by patients and when cancer appears also affects how physicians approach these drugs. "You have population-based analyses that say this works, but when you sit down with a patient you can't guarantee that he needs it," said Thompson.
In addition, disease prevention may not be as ingrained in the medical community as treatment. "I don't know if it's a lack of interest or a lack of expertise in prevention," Thompson said. "We have to change our health care delivery system. We do a lousy job at prevention."
But tamoxifen and finasteride are just the first generation of chemoprevention drugs, and there are several other drugs that are now in phase III clinical trials. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is recruiting 32,000 men to test selenium and vitamin E alone and in combination for the reduction of prostate cancer risk. And in men at high risk of prostate cancer, Merck is testing rofecoxib (Vioxx, a COX-2 inhibitor) and GlaxoSmithKline is testing dutasteride (Avodart, a second-generation version of finasteride).
The Study of Tamoxifen and Raloxifene (STAR), which completed its accrual of more than 19,000 patients this past June, seeks to compare the effectiveness of tamoxifen and raloxifene, an osteoporosis drug that may have fewer side effects than tamoxifen, for prevention of breast cancer in women at elevated risk. And the NSABP has just started recruiting patients who have undergone surgery for stage I colon cancer for their P-3 trial, which will test celecoxib (Celebrex) for the prevention of polyp development.
Chemoprevention "is clearly something that is here to stay," said Wickerham. "The history of medicine certainly tells us that the greatest gains come not from treatment but from prevention."
Related News Article in JNCI
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