What’s new in prostate cancer screening and prevention?
ABSTRACTProstate cancer is extremely common but causes death in only a minority of men in whom it develops, facts that raise issues regarding screening and treatment morbidity. Two large trials of screening with prostate-specific antigen (PSA) measurements came to seemingly opposite conclusions. Furthermore, a large trial of selenium and vitamin E found that these agents have no value as preventive agents.
KEY POINTS
- An elevated PSA level lacks specificity as a test for prostate cancer, but PSA measurements can be useful in combination with clinical risk factors or to measure changes in PSA over time.
- Rather than relying on PSA screening alone, we should stratify the risk of prostate cancer on the basis of race, age, PSA level, family history, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride (Proscar). A simple online tool is available to do this.
- There is no PSA level below which the risk of cancer is zero.
- Finasteride has been found in a randomized trial to decrease the risk of prostate cancer, but vitamin E and selenium supplements have failed to show a benefit.
Limitations of PSA screening
PSA screening has low specificity. PSA is more sensitive than digital rectal examination, but most men with “elevated” PSA do not have prostate cancer. Nevertheless, although it is not a perfect screening test, it is still the best cancer marker that we have.
In the Prostate Cancer Prevention Trial (PCPT),10 finasteride (Proscar) decreased the incidence of prostate cancer by about 25% over 7 years. But there were also lessons to be learned from the placebo group, which underwent PSA testing every year and prostate biopsy at the end of the study.
We used to think the cutoff PSA level that had high sensitivity and specificity for finding cancer was 4 ng/mL. However, in the PCPT, 6.6% of men with PSA levels below 0.5 ng/mL were found to have cancer, and 12.5% of those cancers were high-grade. Of those with PSA levels of 3.1 to 4.0 ng/mL, 26.9% had cancer, and 25.0% of the cancers were high-grade. These data demonstrate that there is no PSA level below which risk of cancer is zero, and that there is no PSA cutoff with sufficient sensitivity and specificity to be clinically useful.
The PCPT risk calculator (https://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp) is a wonderful tool that came out of that study. It uses seven variables—race, age, PSA level, family history of prostate cancer, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride—and calculates the patient’s risk of harboring prostate cancer and, more important, the risk of having high-grade prostate cancer. This tool allows estimation of individual risk and helps identify who is at risk of cancer that may require therapy.
Other factors can affect PSA levels. Men with a higher body mass index have lower PSA levels. The reason is not clear; it may be a hormonal effect, or heavier men may simply have higher blood volume, which may dilute the PSA. Furthermore, there are genetic differences that make some men secrete more PSA, but this effect is probably not clinically important. And a study by Hamilton et al11 suggested that statin drugs lower PSA levels. As these findings are confirmed, in the future it may be necessary to adjust PSA levels to account for their effects before deciding on the need for biopsy.
Two new, conflicting studies
Two large trials of PSA screening, published simultaneously in March 2009, came to opposite conclusions.
The European Randomized Study of Screening for Prostate Cancer2 randomized 162,243 men between the ages of 55 and 69 to undergo PSA screening at an average of once every 4 years or to a control group. Most of the participating centers used a PSA level of 3.0 ng/mL as an indication for biopsy. At an average follow-up time of 8.8 years, 214 men had died of prostate cancer in the screening group, compared with 326 in the control group, for an adjusted rate ratio of 0.80 (95% confidence interval [CI] 0.65–0.98, P = .04). In other words, screening decreased the risk of death from prostate cancer by 20%.
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,1 conducted in the United States, came to the opposite conclusion, ie, that there is no benefit from PSA screening. This study was smaller, with 76,693 men between ages 55 and 74 randomly assigned to receive PSA testing every year for 6 years and digital rectal examination for 4 years, or usual care. A PSA level of more than 4.0 ng/mL was considered to be positive for prostate cancer. At 7 years, of those who reported undergoing no more than one PSA test at baseline, 48 men had died of prostate cancer in the screening group, compared with 41 in the control group (rate ratio 1.16, 95% CI 0.76–1.76).
Why were the findings different? The PLCO investigators offered several possible explanations for their negative results. The PSA threshold of 4 ng/mL that was used in that study may not be effective. More than half the men in the control group actually had a PSA test in the first 6 years of the study, potentially diluting any effect of testing. (This was the most worrisome flaw in the study, in my opinion.) About 44% of the men in the study had already had one or more PSA tests at baseline, which would have eliminated cancers detectable on screening from the study, and not all men who were advised to undergo biopsy actually did so. The follow-up time may not yet be long enough for the benefit to be apparent. Most important, in their opinion, treatment for prostate cancer improved during the time of the trial, so that fewer men than expected died of prostate cancer in both groups.
Improvements to PSA screening
Derivatives of PSA have been used in an attempt to improve its performance characteristics for detecting cancer.
PSA density, defined as serum PSA divided by prostate volume, has some predictive power but requires performance of transrectal ultrasonography. It is therefore not a good screening test in the primary care setting.
PSA velocity or doubling time, based on the rate of change over time, is predictive of prostate cancer, but is highly dependent on the absolute value of PSA and does not add independent information to the variables defined in the PCPT risk calculator or other standard predictive variables.12
A PSA level between the ages of 44 and 50 may predict the lifetime risk of prostate cancer, according to a study by Lilja et al13 in Sweden. This finding suggests that we should measure PSA early in life and screen men who have higher values more frequently or with better strategies. This recommendation has been adopted by the American Urological Association, which released updated screening guidelines in April 2009 (available at www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf).
New markers under study
A number of new biological markers probably will improve our ability to detect prostate cancer, although they are not yet ready for widespread use.
Urinary PCA3. Prostate cancer gene 3 (PCA3) codes for a messenger RNA that is highly overexpressed in the urine of men with prostate cancer. Urine is collected after prostate massage. Marks et al14 reported that PCA3 scores predicted biopsy outcomes in men with serum PSA levels of 2.5 ng/mL or higher.
Serum EPCA-2 (early prostate cancer antigen 2) is another candidate marker undergoing study.
Gene fusions, specifically of TRMPSS2 and the ETS gene family, are detectable in high levels in the urine of some men with prostate cancer, and appear to be very promising markers for detection.
Metabolomics is a technique that uses mass spectroscopy to detect the metabolic signature of cancer. Sreekumar et al15 identified sarcosine as a potential marker of prostate cancer using this technique.
