Mew,
This needs to go into Finasteride Studies, I don’t have authority to post on that forum. Scroll down to the chart TABLE 4 where it says medical events and side effects
The Influence of Finasteride on the Development of Prostate Cancer
Ian M. Thompson, M.D., Phyllis J. Goodman, M.S., Catherine M. Tangen, Dr.P.H., M. Scott Lucia, M.D., Gary J. Miller, M.D., Ph.D., Leslie G. Ford, M.D., Michael M. Lieber, M.D., R. Duane Cespedes, M.D., James N. Atkins, M.D., Scott M. Lippman, M.D., Susie M. Carlin, B.A., Anne Ryan, R.N., Connie M. Szczepanek, R.N., B.S.N., John J. Crowley, Ph.D. and Charles A. Coltman Jr., M.D.
N Engl J Med 2003; 349:215-224July 17, 2003
Rates of Nonadherence
The rate of nonadherence, estimated as the percentage of days of treatment missed in men who had a diagnosis of prostate cancer or an end-of-study biopsy, was 14.7 percent in the finasteride group and 10.8 percent in the placebo group. The rate of nonadherence in the finasteride group, as indicated by a dihydrotestosterone level of more than 16 ng per milliliter, was 14.5 percent, and the drop-in rate in the placebo group, as indicated by a dihydrotestosterone level of 16 ng per milliliter or lower, was 6.5 percent.
A total of 36.8 percent of men in the finasteride group and 28.9 percent in the placebo group temporarily discontinued treatment at some time during the study for reasons other than death or an interim diagnosis of prostate cancer (P<0.001 for the comparison between groups). The yearly rate of temporary discontinuation of treatment was highest during the men’s first year in the study (10.0 percent in the finasteride group and 6.3 percent in the placebo group) and decreased steadily, so that by year 5, the rate was 3.6 percent in the finasteride group and 3.4 percent in the placebo group. Side effects of finasteride represented the primary reason for the difference in the proportion of men who temporarily discontinued treatment (1722 of 9423 men in the finasteride group [18.3 percent] vs. 931 of 9457 men in the placebo group [9.8 percent]).
Medical Events and Side Effects
Medical events and side effects (Table 4Table 4
Medical Events and Side Effects.) were graded according to the toxicity criteria of the Southwest Oncology Group.8 These events and side effects were reported by the men during directed interviews over the course of their treatment. Reduced volume of ejaculate, erectile dysfunction, loss of libido, and gynecomastia were more common in the finasteride group than in the placebo group (P<0.001 for all comparisons), whereas urinary urgency, urinary frequency, or both; prostatitis; urinary tract infection; and urinary retention were more common among men in the placebo group (P<0.001 for all comparisons). There was no significant difference in the number of deaths between the two groups: five men in each group died from prostate cancer.
Biopsy Results
Table 5Table 5
Gleason Scores for Prostate Cancers Detected. shows Gleason scores assigned by the central pathology laboratory for all biopsies. There was a higher proportion of tumors with Gleason scores of 7, 8, 9, or 10 in the finasteride group (280 of 757 graded tumors [37.0 percent], or 6.4 percent of the 4368 men included in the analysis) than in the placebo group (237 of 1068 graded tumors [22.2 percent], or 5.1 percent of the 4692 men included in the analysis; P<0.001 for the comparison between groups in terms of the percentage of graded tumors; relative risk of a high-grade tumor, 1.67 [95 percent confidence interval, 1.44 to 1.93]; P=0.005 for the comparison between groups in terms of the percentage of all men; relative risk, 1.27 [95 percent confidence interval, 1.07 to 1.50]). To understand the risk of high-grade disease from the perspectives of a man considering taking finasteride and of a man who is found to have prostate cancer, we report these data in two ways. The rate of high-grade disease among men in whom prostate cancer was diagnosed on a biopsy performed for cause was 188 of 393 men in the finasteride group (47.8 percent) and 148 of 504 men in the placebo group (29.4 percent; P<0.001; relative risk, 1.62 [95 percent confidence interval, 1.37 to 1.93]); the rate among all men who underwent biopsy for cause was 188 of 1639 men in the finasteride group (11.5 percent) and 148 of 1934 men in the placebo group (7.7 percent; P<0.001; relative risk, 1.50 [95 percent confidence interval, 1.22 to 1.84]).
Prostate volume was determined at the time of biopsy. The median volume among men in the finasteride group was 25.5 cm3, as compared with 33.6 cm3 among men in the placebo group (a 24.1 percent relative difference). There was no significant difference between the two groups in the number of biopsy specimens obtained: sextant biopsy was performed in 81.5 percent of men in the finasteride group and 81.0 percent of men in the placebo group. Most prostate cancers detected during the trial were clinically localized. A total of 97.7 percent of cancers in men in the finasteride group were classified as T1 or T2, as were 98.4 percent of those in men in the placebo group. Of the tumors found on end-of-study biopsies that were not performed for cause, 21.1 percent were in men who had a concurrent PSA level between 2.6 and 3.9 ng per milliliter. Of the remaining tumors found on end-of-study biopsies that were not performed for cause in men with a concurrent PSA level of 2.5 ng per milliliter or less, 15.4 percent had a Gleason grade of 7, 8, 9, or 10.
Discussion
The lifetime risk of prostate cancer in the United States is 16.7 percent, and 28,900 men are expected to die of this disease in 2003.9 This high rate and the unpredictable biology of prostate cancer make prevention of the disease an appealing strategy. Finasteride is an attractive chemopreventive agent, because it inhibits the conversion of testosterone to the more potent androgen dihydrotestosterone within the prostate and has low toxicity. At the inception of our study, finasteride became available for the treatment of benign prostatic hyperplasia (as Proscar [Merck]), and since then, it has been approved for the treatment of male pattern baldness (Propecia [Merck]). Although it is used by millions of men for these indications, little is known about its long-term effects on the prostate.
We faced a challenge in designing our study, because of the effect of finasteride on the PSA level, measurement of which is the primary method of screening for prostate cancer. For this reason, we planned to perform a prostate biopsy at the end of the study.6 We recognized the possibility that there would be an increased number of positive biopsies among men who received finasteride, because a proportionately greater volume of gland would be sampled from smaller glands.10,11 This effect could introduce a bias against any evidence of benefit from finasteride.
Every attempt was made to ensure that an equal proportion of men in each group was evaluated for prostate cancer; this was the logic behind the initial doubling of PSA values for men in the finasteride group and the later increase by a factor of 2.3 at the beginning of each participant’s fourth year in the study.5 An additional difference in the rate of evaluation for prostate cancer between the two groups was a different number of abnormal digital rectal examinations (1845 in the finasteride group vs. 2090 in the placebo group) (Table 3) and transurethral resections of the prostate. In addition, more men in the finasteride group than in the placebo group were categorized as having refused the end-of-study biopsy (25.4 percent vs. 22.8 percent, P<0.001), most likely because of the higher rate of temporary discontinuation of treatment in a group of men less committed to the study requirements. Although the difference between the groups in the overall rate of ascertainment of prostate-cancer status of 3.4 percentage points (59.6 in the finasteride group vs. 63.0 percent in the placebo group) was statistically significant, we believe that this difference by itself is unlikely to have contributed substantially to the difference in the rate of detection of prostate cancer.
Seven years of finasteride treatment resulted in a 24.8 percent reduction in the prevalence of prostate cancer during that period. There was a reduction in relative risk among men who underwent a prostate biopsy before seven years and among men who underwent biopsy at the end of the study. The risk reductions were similar in subgroups defined according to age, race or ethnic group, family history of prostate cancer, and stratum of PSA level at randomization.
Decreases in sexual potency, libido, and ejaculate volume were frequently reported over the course of the trial, as would be expected in men in this age group who were followed for seven years with repeated queries regarding these symptoms.12 These side effects were more common in the finasteride group. Urinary symptoms or events related to benign prostatic hyperplasia were less common among men receiving finasteride — a finding that is consistent with a previous report.13
High-grade disease was noted in 6.4 percent of the men in the finasteride group, as compared with 5.1 percent of those in the placebo group. A difference in the rate of high-grade disease was seen within the first year of the study. One possible explanation for this difference is a grading bias: histologic changes that mimic those of high-grade disease are caused by androgen-deprivation therapy.14-18 There are, however, differences of opinion as to whether this effect occurs with finasteride. It is possible that finasteride induces high-grade tumors by reducing the level of intracellular dihydrotestosterone within the prostate. There is evidence that the prostate tumors that develop in men with low testosterone levels have higher Gleason grades and worse outcomes than the prostate cancers that develop in men with normal testosterone levels.19-21 It is also possible that finasteride selects for high-grade tumors by selectively inhibiting low-grade tumors. Long-term follow-up in these men and further laboratory research will be required to determine the reason for the association between finasteride and high-grade prostate cancer.
The tumors that were detected on biopsies performed for cause were clinically similar to those that are detected in clinical practice by screening of the PSA level and digital rectal examination. The clinical significance of cancers found in the end-of-study biopsies (those not performed for cause) is unknown. Of the men with such diagnoses, 21.1 percent had PSA levels between 2.6 and 3.9 ng per milliliter. Clinically significant tumors are as common among men with PSA levels in this range as they are among men with PSA levels between 4.0 and 10.0 ng per milliliter.22 Of the remaining tumors found in men with PSA levels of 2.5 ng per milliliter or less, 15.4 percent had high-grade cancer.
The overall cancer detection rate of 24.4 percent in the placebo group is a matter of concern, because the eligibility criteria for enrollment in the study selected for low-risk men with an expected lifetime incidence of prostate cancer of 16.7 percent and a rate of death from prostate cancer of 3 to 4 percent. The rate of 24.4 percent suggests the possibility of overdiagnosis of disease.
The study raises two interrelated questions: did finasteride prevent or treat prostate cancer,23 and did finasteride prevent or delay24,25 the appearance of prostate cancer? These issues are important for the field of cancer prevention. The early difference in the incidence of prostate cancer between the two groups suggests that finasteride may have treated subclinical, microscopical cancer early in the study, and the fact that the difference continued to increase suggests that it prevented or delayed the onset of cancer. In either case, the effect is beneficial.23-25
Physicians can use these results to counsel men regarding the use of finasteride. It is important to stress that finasteride reduced the risk of prostate cancer in a clinical trial marked by frequent monitoring for disease and was associated with an increased risk of diagnosis of high-grade prostate cancer. For a man considering using this medication, the greater absolute reduction in the risk of prostate cancer must be weighed against the smaller absolute increase in the risk of high-grade disease.
There is also the matter of side effects: the incidence of adverse effects on sexual function was higher with finasteride, but the finasteride group had a lower incidence of urinary symptoms and complications than the placebo group. Using published information on the outcomes of prostate-cancer treatment, men can weigh these trade-offs in the context of their own priorities regarding the avoidance of prostate cancer as well as their urinary and sexual function to reach a personal decision regarding finasteride use.26-28 As more is learned from the molecular biology of prostate cancer about the risk of aggressive disease, data from this and other studies will help to refine the appropriate use of interventions such as finasteride.