Expert On Call

Q: If I have just done a rectal examination, is PSA testing still valid?

A: There have been several prospective trials that looked at the effect of a digital rectal examination (DRE) upon PSA levels. In none of the studies did DRE cause meaningful elevations of PSA that would change the category of PSA from normal to high-risk. The only exception was that larger increases in PSA were seen in men with elevated PSA to start out with; since these men would be referred anyhow, the modest elevation in PSA seen post-DRE would have no clinical impact. Having undergone a DRE should not change the utility of PSA screening.

Q: A 66-year-old man is reluctant to consult urology in reference to his elevated PSA. His PSA level has risen over the last 16 years of screening from 2.0. to 4.1, and he is already recognized as having benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) that are well controlled on tamsulosin (Flomax) 0.4 mg QD. During no year was the rate of PSA increase greater than 0.4 ng/ml/yr. Is there any alternative to referral at this point? The patient says he has a neighbor who incurred urinary incontinence post-prostatectomy, and he would rather NOT consult urology.

A: The absolute PSA threshold for suggestion of urologic consultation is a matter of controversy. Most primary care literature suggests referral at a level of 4.0 ng/mL, although some urology literature suggests consultation even at a level of 2.5 ng/mL. In any case, the patient has exceeded either threshold. On the other hand, he has had a slow and steady increase in his PSA, at no time exceeding the recognized PSA velocity threshold of 0.75 ng/ml/year. Two metrics might mitigate the need for consultation: PSA density and % free PSA. When PSA density is appropriate (ie, the amount of PSA is commensurate with gland size), and when % free PSA is high (especially > 25%), likelihood of benignity is strong. Because none of these additional metrics rules out malignancy with 100% accuracy, some clinicians will still prefer referral, but each additional metric that supports a non-malignant cause for PSA elevation reduces likelihood of malignancy.

Q: I saw a young man who is now concerned about his PSA at age 45 because his dad died of prostate cancer at age 49. We began screening him at age 44, when his PSA was 1.2. Over the past year, his PSA has risen to 2.3. Is there reason for concern?

A: Unless the patient has some inflammatory condition of the prostate (eg, prostatitis), or has undergone genitourinary instrumentation (eg, cystoscopy), the rate of rise of his PSA is concerning. 'Normal' prostate growth can increase PSA simply by benign growth as much as 0.50-0.60 ng/ml/year, but increases in PSA more than 0.75 ng/ml/year suggest a non-benign etiology. Because this patient has at least a doubling of risk due to family history, consultation is especially appropriate. It is NOT appropriate to wait until the total PSA level crosses a particular threshold (eg, 4.0) prior to referral. The rate of rise is the concern.

Q: What does the term PSA velocity refer to?

A: PSA velocity describes the rate of change in a man's PSA level. The PSA blood test is very helpful in making an early diagnosis of prostate cancer but it is not a perfect test. The PSA can be elevated from prostate cancer, prostate enlargement, or prostatic inflammation. Urologists use the rate of rise in PSA to help determine the likelihood that a rising PSA is due to cancer. In general, for a man over 60, a PSA rise greater than 0.75 ng/ml/yr suggests a significant chance of prostate cancer while a rise at a rate below 0.75 ng/ml/yr suggests benign causes are more likely. For men under 60, the cutpoint is 0.50 ng/ml/yr. PSA velocity is not always correct and the result must be used in the context of the individual patient's situation.

Q: What is the age cutoff for recommending radical prostatectomy for treatment of prostate cancer?

A: There is no absolute age cutoff or threshold above which radical prostatectomy cannot be done. In general, as a man gets older, the risks of prostate surgery increases and other treatment options, such as radiation, are recommended. Factors that go into the decision are a man's age, health status, general physical condition, the stage and grade of his cancer, previous surgery, and the patient's wishes. Robotic radical prostatectomy greatly reduces the blood loss and overall risks of radical prostatectomy and as a result surgery is being done on older men with good results.

Q: Age-specific PSA levels result in a higher positive predictive value (PPV) and fewer biopsies in older men, and more biopsies in younger men. PSA should be less than 2.5, < 3.5, < 4.5, and < 6.5 ng/ml for men in their 40s, 50s, 60s, and 70s respectively. How can PSA velocity be used to increase specificity for PSA?

A: PSA velocity is defined as a change in PSA over a year's time. PSA velocity > 0.75 ng/ml/yr is abnormal and requires referral to a urologist for consideration of a biopsy. Reliability of PSA velocity increases when 3 values are obtained over a period of 18 months, and lastly, some authors feel that for younger-aged men a lower PSV velocity may be applicable (0.4 ng/ml/yr).

Reference:

Gomella L. The 5-minute Urology Consult. Philadelphia, PA: Lippincott Williams and Wilkins; 2000.

Q: I have heard that chemoprevention aims to reduce both incidence and mortality of prostate cancer through the use of agents that interfere with or delay the carcinogenic process. What are some of the agents studied for chemoprevention of prostate cancer?

A: The following have been studied as chemoprevention agents to reduce prostate cancer risks:

• 5-a-reductase inhibitors (finasteride and dutasteride)
• Statins (a class of compounds used to reduce cholesterol)
• Nonsteroidal antiinflammatory drugs (NSAIDs)
• Selenium
• Vitamins E and D
• Lycopene
• Allium vegetables (garlic, scallions, onions, chives, and leeks)
• Soy/isoflavones
• Green tea polyphenols

The following table is adapted from a review by Colli and Amling summarizing the strength of evidence for various agents studied.

Chemoprevention Agents Studied for Prostate Cancer
 

Reference:
Colli JL, Amling CL. Chemoprevention of prostate cancer: what can be recommended to patients? Curr Urol Reports. 2009;10:165-171.

Q: I have a patient who is a 50-year-old African American male with no family history of prostate cancer. What can I tell him about why prostate cancer is more common with a higher death rate in African American men than white men?

A: The primary risk factors for prostate cancer are age, race/ethnicity, and family history. Based on US data from 2001-2005, prostate cancer incidence is 156.7 per 100,000 for whites and 248.5 per 100,000 for African Americans. This represents a 58% increase compared with white men. The underlying reason is a topic of great interest and debate. Contributing factors may include access to care, attitude about care, socioeconomic and educational issues, fear, aversion to screening procedures, differences in the type and aggressiveness of treatment, diet, and genetic factors. Barriers such as socioeconomic status, education, and access to care are intertwined. It is complicated, but the current younger generation of African American men seems more amenable to screening for prostate cancer and taking better care of themselves in general.

References:

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M. Cancer Statistics, 2009. CA Cancer J Clin. 2009;59:225-249.

Freedland S, Isaacs W. Explaining racial differences in prostate cancer in the United States: sociology or biology? Prostate. 2005;62(3):243-252.

Reynolds D. Prostate cancer screening in African American men: barriers and methods for improvement. Am J Men's Heath. 2008;2(2):172-177.

Q: September was designated as "Prostate Cancer Awareness Month," which promoted screening for prostate cancer. Why is there so much controversy about prostate cancer screening?

A: This is a very complicated question that has generated a lot of controversy. While there is general agreement that PSA screening allows for early detection of prostate cancer, we still do not have definitive evidence that screening reduces prostate cancer mortality. Improvement in mortality for prostate cancer may be related in large part to the efficacy of current treatment strategies.

Overdiagnosis and overtreatment are associated with pain, discomfort, anxiety, as well as the costs of screening, biopsy, and treatment. Erectile dysfunction, urinary incontinence, and bowel dysfunction are adverse effects associated with prostate cancer treatment. Men with small non-invasive, clinically insignificant cancers may never become symptomatic or have progression to a life-threatening point before death from other causes. There is clearly a need to be able to distinguish the non-aggressive from the aggressive prostate cancer.

The American Cancer Society (ACS), the US Preventive Services Task Force (USPSTF), and the American Urological Association (AUA) each have different recommendations regarding prostate cancer screening. This confuses the issue of screening for both physicians and patients. The ACS recommendation states that "health care providers discuss the potential benefits and limitations of prostate cancer early detection testing with men and offer the PSA blood test and the digital rectal examination annually, beginning at age 50, to men who are at average risk of prostate cancer and who have a life expectancy of at least 10 years. Those men who indicate a preference for testing following this discussion should be tested. Men at high risk of developing prostate cancer (African Americans or men with a close relative diagnosed with prostate cancer before the age of 65) should have this discussion with their provider beginning at age 45. Men at even higher risk (because they have several close relatives diagnosed with prostate cancer at an early age) should have this discussion with their provider at age 40." The USPSTF recommendation regarding screening for prostate cancer states "Current evidence is insufficient to assess the balance of benefits and harms of screening for prostate cancer in men younger than age 75 years. Do not screen for prostate cancer in men age 75 years or older." Additionally the task force suggests, "Given the uncertainties and controversies surrounding prostate cancer screening in men younger than age 75 years, a clinician should not order the PSA test without first discussing with the patient the potential but uncertain benefits and the known harms of prostate cancer screening and treatment. Men should be informed of the gaps in the evidence and should be assisted in considering their personal preferences before deciding whether to be tested." The AUA provided updated guidelines regarding PSA screening earlier this year, including the lowering of the age for obtaining a baseline PSA to 40 years. The AUA emphasizes that a thoughtful and broad approach to PSA is important. Included in their recommendation is the elimination of a single threshold PSA value to prompt prostate biopsy. Instead, the organization advocates that the decision to biopsy should be based primarily on PSA and DRE results, but also with consideration of free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history, and comorbidities. Because the results of recent studies suggest that prostate cancer screening leads to overdetection and overtreatment for some patients, the AUA suggests that "men be informed of the risks and benefits of prostate cancer screening before biopsy and the option of active surveillance in lieu of immediate treatment for certain men newly diagnosed with prostate cancer."

Improvements are clearly needed in the detection of potentially lethal prostate cancers. A new promising biomarker for the detection of prostate cancer is being studied extensively. This new biomarker may assist with prostate cancer diagnosis and biopsy decisions, monitoring patients following treatment, and perhaps help to identify clinically insignificant tumors. In the meantime, each patient will have to discuss the risks, benefits, and potential complications of screening and treatment with his physician based on his risk factors as outlined above.

References:

Smith R, Cokkinides V, Brawley O. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009;59:27-41.

US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191.

Carroll P, Albertsen P, Greene K, et al. Prostate-specific antigen best practices statement: 2009 update. http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf. Accessed Sept 2009.

Q: Can prostatitis develop into prostate cancer?

A: There are no data in the literature to suggest that prostatitis is a precursor for the development of prostate cancer.

Q: What were the results of the SELECT trial?

A: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, placebo-controlled trial, with 35,533 men randomized to supplementation with selenium (200 micrograms/day from L-selenomethionine), vitamin E (400 international units/day), selenium + vitamin E, or placebo for a minimum of 7 years and a maximum of 12 years. Men participating in the study were ≥ 50 years (African American) or ≥ 55 years for other ethnicities, with baseline PSA ≤ 4 ng/mL, and normal DRE. The primary study endpoint was clinical incidence of prostate cancer, with prostate biopsy performed based on PSA or DRE as determined by study physicians. End of study biopsies were not required. Selenium/vitamin E supplementation was discontinued per recommendation of the Data Safety Monitoring Committee following a second interim analysis in August 2008. Data collected through October 28, 2008 with a median follow-up of 5.46 years indicate that there was no benefit associated with selenium or vitamin E (alone or in combination) for prostate cancer in this study population. Hazard ratios compared with placebo were 1.04 (99% CI 0.87-1.24, P = 0.62) for selenium; 1.13 (99% CI 0.95-1.35, P = 0.06) for vitamin E; and 1.05 (99% CI 0.88-1.25, P = 0.52) for selenium + vitamin E. Vitamin E supplementation was associated with a nonsignificant increased risk for prostate cancer and selenium was associated with a nonsignificant increase in the risk for type 2 diabetes.

References:

Lippman S, Klein E, Goodman P, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers. The selenium and vitamin E cancer prevention trial (SELECT). JAMA. 2009;301:39-51.

Q: What is the difference between finasteride and dutasteride?

A: Finasteride and dutasteride are 5-alpha reductase inhibitors (5-ARIs) FDA-approved for the treatment of symptomatic benign prostatic hyperplasia. Dutasteride inhibits both type 1 and type 2 5-alpha reductase (5-AR), whereas finasteride is a selective type 2 5-AR inhibitor. Finasteride has a serum half-life of ~6 to 8 hours, while dutasteride has a serum half-life of 5 weeks. Both finasteride and dutasteride reduce serum dihydrotestosterone, by 70 and > 90%, respectively. Treatment with finasteride results in a reduction in prostate volume by approximately 18%, and dutasteride treatment results in a 26% reduction in prostate volume.

Both finasteride and dutasteride have been studied for prostate cancer risk reduction in large clinical trials. The PCPT was a 7-year, double-blind, placebo-controlled study in which healthy men ≥ 55 years with a baseline PSA ≤ 3.0 ng/mL and normal DRE (N = 18,882) were randomized to treatment with placebo or finasteride (5 mg daily). The men were monitored annually with DRE and PSA tests, and biopsy was recommended for abnormal DRE or PSA ≥ 4 ng/mL. The primary study endpoint was the prevalence of prostate cancer during the 7 years of the trial. Prostate cancer was detected in 18.4% of men treated with finasteride and in 24.4% of men who received placebo treatment; there was a 24.8% reduction in prostate cancer prevalence with finasteride (P < 0.001). The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a 4-year, multicenter, international, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of dutasteride (0.5 mg daily) in men with higher risk for the development of prostate cancer as compared with the study population of the PCPT. Men randomized (N = 8200) to dutasteride or placebo in the REDUCE trial were between 50 and 75 years, with a baseline PSA of 2.5 to 10 ng/mL for men 50 to 60 years or 3.0 to 10.0 ng/mL for men > 60 years, and a single negative biopsy within 6 months of enrollment. Clinical assessments and PSA determinations were performed every 6 months. The primary study endpoint was biopsy-detectable prostate cancer at 2 and 4 years of treatment. Prostate cancer incidence for the first 2 years of the trial was 17.2% and 13.4% for placebo and dutasteride arms, respectively. At 4 years, cumulative prostate cancer incidence was 29.6% and 22.9%, for placebo and dutasteride groups, respectively. This difference between treatment groups over 4 years represents a 23.5% relative risk reduction (P < 0.001). While PCPT and the REDUCE trials differed in study duration and patient entry criteria, the overall relative risk reduction associated with 5-ARI treatment was similar in magnitude for the 2 studies.

References:

Andriole G. Overview of pivotal studies for prostate cancer risk reduction, past and present. Urology. 2009;73(5A):36-43.
Thompson IM, Goodman P, Tangen C, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-224.
Andriole G, Bostwick D, Brawley O, et al. Further analysis from the REDUCE prostate cancer risk reduction trial. American Urological Association Annual Meeting. Chicago, IL. April 28, 2009. LBA1.

Q: When should you refer a patient to a urologist for further evaluation?

A: Referral to a urologist should occur when the PSA is outside the normal age specific range or there is an abnormal PSA velocity. If a family physician or internist detects an abnormality on rectal examination this patient should be referred for transrectal ultrasound and prostate needle biopsy. For patients who have started therapy with either finasteride or dutasteride, if there is not a 50% reduction in PSA after six months, these patients should be referred for possible prostate biopsy. In addition, all patients who have failed medical management for benign prostatic hyperplasia should be sent to a urologist for further evaluation.

Q: What are the common risk factors for prostate cancer?

A: There are three major risk factors associated with prostate cancer: age, race, and family history. Approximately 64% of prostate cancer is detected between the ages of 55 and 74. We do know that as age increases, the autopsy prevalence of prostate cancer increases as well. Race is also a major risk factor for prostate cancer. There is a 58% higher incidence of prostate cancer in African-American men when compared with white men. In addition, prostate cancer mortality is also higher in African-American men. Family history is also associated with a greater risk of prostate cancer. There is a strong familial clustering in families with early onset prostate cancer. The relative risk of prostate cancer is 2.16 if a father or brother is diagnosed with prostate cancer under the age of sixty years old. This risk increases to 2.3 if both a father and one brother develop prostate cancer.

References:

Wein A, et al. eds. Campbell-Walsh Urology. 9^th ed. Philadelphia, PA: Saunders Elsevier, 2007.

Fleshner N, Lawrentschuk N. Risk of developing prostate cancer in the future: overview of prognostic biomarkers. Urology. 2009;73(S5A):21-27.