Balancing treatment vs. risk
By Peter D. Sershon, MD, FACS
From Minnesota Healthcare News
Physicians, patients, and health regulatory groups such as the U.S. Preventive Services Task Force continue to question, evaluate, and revise the recommendations for prostate cancer screening, diagnosis, and management. Recent advances attempt to balance risk of treatment against the risk of enabling clinically significant disease to progress to an incurable metastatic state.
Prostate cancer screening
Despite the continuing controversy, prostate-specific antigen (PSA) and digital rectal exam (DRE) remain simple, cost effective, and minimally invasive screening tools for prostate cancer—and the only ways to screen for clinically significant prostate cancer while it is still localized to the prostate. The American Urological Association (AUA) fully supports prostate cancer screening. Its PSA screening guidelines are available for review at www.auanet.org/education/guidelines/prostate-cancer-detection.cfm.
However, we know PSA results may also be elevated by benign prostate growth, inflammation, and even transiently by ejaculation. Using the following recommendations can decrease the number of unnecessary evaluations for prostate cancer.
If a patient has a PSA less than 10 ng/ml, no new voiding symptoms, a normal urinalysis, and a normal DRE, wait two to four weeks and then repeat the PSA. Ask the patient not to ejaculate for at least two to three days prior to the repeat test. Recent studies have confirmed at least 25 percent of these patients will have their PSAs drop back to normal ranges and will not require evaluation. If the DRE is abnormal or the PSA value is very high, don’t repeat the test but refer the patient to a urologist for evaluation.
Treat a presumed infection first
If there are new voiding symptoms suggesting a urinary tract infection, or a urinalysis suggesting infection even if no symptoms are present, treat with an appropriate antibiotic for at least two weeks, then repeat the PSA at one month. Using antibiotics to reduce the PSA value is not indicated if there are no new voiding symptoms or abnormal urine.
Note: Do not get a PSA if the patient has an obvious infection, because it will likely be elevated.
There are several U.S. Food and Drug Administration (FDA)-approved blood and urine biomarkers that attempt to stratify risk of a patient harboring a clinically significant prostate cancer (see Figure 1). In men with an abnormal PSA, biomarkers can provide a high negative predictive value. If the test is negative, then the risk of prostate cancer is considered low. Biomarkers are used most frequently in patients who have already had one negative prostate biopsy. Be judicious using these tests in men who would benefit from treatment if they do have a clinically significant cancer, but the tests can be helpful with a patient who refuses a prostate biopsy, as long as he accepts the risk of missing cancer. As technology improves, we expect a surge in biomarker use over the next several years, which we hope will safely reduce the need for prostate biopsies.
Prostate cancer diagnosis
The current standard of care for prostate cancer detection is a prostate mapping biopsy using a transrectal ultrasound probe to visualize mapping sites. Tissue diagnosis gives critical information on cancer volume and grade, which currently cannot be reliably obtained by imaging or biomarkers. However, mapping biopsies can miss clinically significant lesions up to 20 percent of the time, especially with a larger prostate or a cancer in an anterior prostate location. Therefore, many patients have endured repeat prostate biopsies, due to either a continued rise in PSA or a high index of suspicion.
Several developing avenues aim to improve accuracy and reduce the need for repeat prostate biopsies. At this time, none should be considered a replacement for the initial transrectal ultrasound biopsy.
Multiparametric MRI of the prostate
Technological improvement in the MRI of the prostate has enabled the radiologist to evaluate lesions within the prostate better. All suspicious areas can now be marked out on the MRI images and then scored for risk of clinical significance. The higher the score (PI-RAD 1 through 5), the higher the risk of a clinically significant cancer (Gleason grade 7 and higher). Reading and scoring a multiparametric MRI of the prostate has a significant learning curve and a very high intra-observer variability, so it is critical that the radiologist involved has the experience to interpret it correctly.
MRI/ultrasound fusion biopsy
Another diagnostic advance in MRI technology is the new ability to fuse the MRI with the standard transrectal ultrasound, creating a “fusion biopsy,” so that suspicious areas marked by the radiologist on the MRI, can be biopsied under ultrasound guidance in the office. The MRI/ultrasound fusion enables us to biopsy suspicious areas outside of the standard mapping biopsy template accurately, decreasing the risk of missing a significant lesion. Conversely, negative MRIs, or negative biopsies from suspicious areas on an MRI, mean the risk of harboring a significant cancer outside of the more common prostate cancer locations is low. Currently, in Minnesota, the fusion biopsy technology is only available at Metro Urology and Mayo Clinic.
Blood and urine biomarkers
While blood and urine biomarkers (see Figure 1) attempt to avoid the need for a repeat prostate biopsy, no biomarker result can currently attain the same level of certainty as tissue analysis. In the near future, some form of blood or urine analysis will routinely be used to stratify patients for prostate cancer risk.
Prostate cancer management
From the early days of PSA screening, there has been a reasonable concern about prostate cancer overtreatment. Yet, undertreatment could lead to incurable metastatic disease in men with excellent survival and quality of life outside of their prostate cancer. Active surveillance and focal therapy may minimize overtreatment for men with low-risk prostate cancer.
There are multiple, well-established guidelines available for prostate cancer risk assessment, all formulated to give the physician and patient confidence that the patient’s specific cancer can be managed with surveillance. At Metro Urology, we most commonly use the National Comprehensive Cancer Network (NCCN) guideline, which assesses risk based on age, life expectancy, PSA values, and pathologic features of biopsy, including Gleason grade and tumor volume. However, clinical risk assessment can underestimate tumor aggressiveness in 30 percent of patients, which in the past has led to the underutilization of active surveillance.
Now, in addition to repeating prostate biopsy within one to two years and carefully following serial PSA values, two new developments have improved the ability to place patients on active surveillance safely.
Tissue biomarkers. There are several FDA-approved tissue biomarkers (see Figure 1) that analyze tumor gene variants on the biopsy specimen to predict risk. Each biomarker has a different predictive capability and uses percent risk in the reports, so the physician must still determine the appropriate threshold at which to trigger treatment for each patient.
MRI of the prostate. Patients who did not have an MRI prior to diagnosis may benefit from imaging if they are deemed at risk for having a more aggressive cancer than noted on a biopsy. The MRI can also be used to designate candidates for focal therapy.
Even with these predictive improvements, the most important step is still repeating the prostate biopsy at the appropriate time to assess for change in tumor volume and Gleason grade.
Treatment for localized prostate cancer has traditionally been “whole gland,” most often involving radical prostatectomy or radiation therapy. Many patients have high-risk disease and require this management. In addition, prostate cancer is almost always multi-focal, although different lesions within the same gland can have different risks of progression.
Now, the advent of MRI-targeted biopsies is enabling us to predict, in some patients, which cancer sites within the prostate may be clinically significant. We can then direct focal energy at these lesions using real-time imaging, sparing the rest of the gland. This minimizes treatment risks and side effects of whole gland treatment, while achieving the same efficacy in survival and metastatic progression. Current FDA-approved energy sources include cryotherapy and high-intensity focused ultrasound (HIFU). A focal therapy treatment protocol, using carefully selected patients, is currently underway at Metro Urology.
If current trends continue, personalized risk factor protocols for prostate cancer will be developed and established, and the use of some variant of biomarker or genomic analysis will identify patients who require evaluation and treatment. Debates over mass screenings and concerns about management will become irrelevant. Until then, we must use the tools available to minimize the risk of both over- and undertreatment of prostate cancer for each individual patient.
Peter D. Sershon, MD, FACS, is a board-certified urologic surgeon with Metropolitan Urologic Specialists. He is chief of surgery and director of the Robotic Surgery Program at United Hospital in St. Paul. He sees patients in St. Paul, Woodbury, and at the Apple Valley Medical Center in Apple Valley.