CHAPTER 44 Diagnosis and Staging of Prostate Cancer
What is the US Preventive Services Task Force (USPSTF) recommendation for prostate specific antigen (PSA) screening in 2012 and describe its significance?
They recommend against prostate-specific antigen-based screening and gave it a “D” recommendation. USPSTF concludes that there is moderate or high certainity that prostate screening harms outweigh the benefits.
Discuss the studies used as the basis for the USPSTF level D recommendation including the associated morbidities.
• The USPSTF recommendation for not screening is the fact that there is no reduction in all-cause mortality in the PLCO (Prostate, Lung, Colon and Ovary) trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) study showed only a modest overall survival benefit.
• You have to screen 1000 people and diagnose 37 individuals with prostate cancer in order to prevent one death from prostate cancer.
• The USPSTF sees that risk versus benefit from screening leads to erectile dysfunction and urinary incontinence, which is as high as 20% to 30% in men who undergo therapy with no reduction in all-cause mortality.
The basis for the American Urologic Association for continued screening are based on what scientific data?
• Since widespread screening was initiated in 1992, there has been a 44% reduction in prostate cancer-specific deaths, of which 50% to 75% are attributed to prostate cancer screening. In addition, there has been 75% reduction in the number of men presenting initially with metastatic prostate cancer. There are also a number of trials such as those done in Tyrol—Austria and Goteborg—Sweden that suggest a 50% or better cancer-specific survival benefit in screened populations.
• The PLCO and ERSPC trials were highly flawed with over 50% of men in the control group getting PSA testing either before or during the trial. The test period for these studies was less than 10 years (7 and 9 years) when initially reported, and there were significant protocol violations where up to 70% of the men in the screened group who had an elevated PSA did not get the required biopsies.
The identification and molecular analysis of prostate circulating tumor cells (CTC) has potential in the following areas:
• Early prostate cancer detection
• Selection of cancer therapy
• Monitoring chemotherapy
• Determining surgical intervention
• All of the above
True/False: Quantification of circulating prostate tumor cells for monitoring chemotherapy of hormone refractory prostate cancer is FDA approved.
True.
What does the Prolaris test for in prostate cancer, and what is its significance?
• It tests for quantitative measures of RNA expression levels of multiple genes that are related to tumor cell division and progression.
• The significance of this test is that it can assess an individual’s relative risk of mortality from prostate cancer within 10 years with a hazard ratio (HR) value of 1.67 in a multivariate analysis.
Discuss the clinical utility of the PCA3 test in the management of a patient with a PSA positive and negative biopsy.
The PCA3 test has a sensitivity of 62% and a specificity of approximately 90%. Thus, this test is useful in combination with PSA when deciding regarding repeat biopsy or initial biopsy of patients at risk for prostate cancer. In the receiver operating characteristic (ROC), the area under the curve increases 0.2 to 0.7 compared to PSA 0.5. Thus the accuracy of this test is improved when compared to the PSA test.
Discuss the current role of CTC.
CTC may be used to predict survival outcome in prostate cancer and can provide insight into patients with metastatic disease. CTCs may be more useful in monitoring patients with bone metastasis because they are more frequently elevated than in patients with visceral disease.
What PCA3 values are useful for the clinical management of patients with prostate cancer?
PCA3 score threshold of 20 may have the highest utility for selecting men with clinically insignificant prostate cancer while a PCA3 score of 50 may be used to identify men who are at significant risk for prostate cancer and are candidates for a radical prostatectomy.
What is pro-PSA?
[—2] pro-PSA, a truncated form of pro-PSA is the most specific cancer form, and is most preferentially expressed in cancer epithelium. There is evidence to suggest that percentage of pro-PSA over free PSA improves the specificity of both tPSA and fPSA.
What is prostate health index (PHI)?
Phi is defined as ([–2] pro-PSA/fPSA) X 
tPSA.
Laparoscopic pelvic lymphadenectomy prior to treatment is typically reserved for patients with what criteria?
Gleason score greater than 8, extraprostatic extension on digital rectal examination (DRE), PSA greater than 20 ng/mL, or suspicion of enlarged lymph nodes on radiologic evaluation.
In what groups of prostate cancer patients is a bone scan recommended?
In patients with PSA greater than 20 ng/mL, a Gleason score of 8 to 10, clinical stage T3 or T4, or clinical symptoms of bone metastasis.
What is the D’Amico stratification of prostate cancer?
• Low-risk patients are those with clinical stage T1 to T2a, PSA 10 ng/mL or less, and Gleason score of 6 or less.
• Intermediate stage patients are those with stage T2b, PSA greater than 10 ng/mL but less than 20 ng/mL, or Gleason score of 7.
• High-risk patients include those with T2c, PSA greater than 20 ng/mL, or Gleason score 8 to 10.
What other factors other than Gleason score determinations on prostate biopsies are used for risk prediction?
The number of positive cores, the percentage of tumor involvement of those positive cores, the presence or absence of bilateral involvement, and the presence of perineural invasion all have some predictive value. Even worse prognosis is associated with seminal vesicle invasion. A new biomarker EN2 may be useful for defining tumor volume (Pandha et al., 2012). PCA3 has been shown in preliminary studies to correlate with tumor volume as well as capsular invasion and penetration.
What information should be related to a patient prior to PSA screening?
PSA screening should be limited to those individuals with a life expectancy of greater than 10 years. Patients should be informed that even though their PSA is elevated, this may not indicate that they have cancer and the chance of finding cancer based on PSA alone in an unscreened population is less than 25%. In addition, the patient should be informed that a positive biopsy based on an elevated PSA or clinical findings does not necessarily indicate the patient will be recommended for surgery or definitive radiation, but may be considered a good candidate for active surveillance. Information regarding the future management should be a joint decision between the patient and physician considering the risk versus benefit for each individual patient at each decision point.
Describe the PIVOT trial and how its conclusions affect PSA screenings since it does not appear to show any benefit from surgical intervention in localized prostate cancer.
The Prostate Intervention versus Observation Trial followed 2 groups of men with localized prostate cancer and good performance status. One group received radical prostatectomies, the other just observation. After 10 years, there was no significant difference in overall survival between the 2 groups. The study has been criticized for several reasons. The median age was 67 where, according to the Actuary Office of the Social Security Administration, the current average life expectancy would be slightly more than 17 years while in this study of mostly VA patients, the median life expectancy was only 10 years. A careful review of the data also shows that there was a trend beginning to show a cancer-specific benefit to treatment beginning at 10 years, but only a longer follow-up will be able to show this.
What are the current recommendations for screening for prostate cancer in American men?
To date, there is no consensus on screening for prostate cancer in American men. The American Urological Association currently recommends initiating screening at age 50 for white men with no family history of prostate cancer and age 45 for black men with no family history of the disease. In men with a first-degree relative with the disease, initiation of screening should begin at age 45 for whites and at age 40 for blacks. AUA recommends checking baseline PSA at age 40 for all men.
What is considered a “normal” PSA?
Normal PSA ranges have been determined to be 0 to 4 ng/mL. Age-specific normal reference ranges and acceptable rates of change in the PSA value over time (PSA velocity) have been delineated and may enhance the identification of individuals at risk for the disease.
What are the age-specific normal reference ranges for PSA?
• For men aged 40 to 49 years, the normal reference range is 0 to 2.5 ng/mL.
• For men aged 50 to 59 years, the normal reference range is 0 to 3.5 ng/mL.
• For men aged 60 to 69 years, the normal reference range is 0 to 4.5 ng/mL.
• For men aged 70 to 79 years, the normal reference range is 0 to 6.5 ng/mL.
So which is better, the normal range or the age-specific range?
It isn’t yet clear exactly what the optimal range should be. If the criteria are too strict, curable cancers will not be detected. If too liberal, too many unnecessary biopsies will be done. While the 0 to 4.0 range has proved very effective, age-related adjustments seem reasonable. For age 65 and above, a PSA range of 0 to 4.0 can be used, and for age 64 and younger, a PSA range of 0 to 2.5 has been suggested.
What is the current suggested PSA cut-off level for men aging 65 years and younger being screened for prostate cancer?
2.5 is the current threshold level for men 65 years of age and younger.
What percentage of the cancers detected in prostate screenings are estimated to be clinically insignificant?
Less than 7%.
At what point should routine prostate cancer screenings (DREs and PSA determinations) be stopped?
The consensus opinion is that there is a declining benefit of treatment of screening detected prostate cancer with advancing age and that men with less than a 10-year life expectancy, usually age 75, should probably not undergo routine prostate cancer or PSA screenings.
What is the normal function of PSA?
PSA is a protease whose normal function is to help liquify the semen. It also liquify cervical mucus to help passage of sperm.
When was PSA approved for prostate cancer screening by the FDA?
1994.
What percentage of prostate cancers are found in men with “normal” PSA levels?
Approximately 20%.
What is PSA velocity?
PSA velocity is the rate of change of serum PSA over time. Studies have indicated that the acceptable rate of change in PSA over 12 months is <0.75 ng/mL for PSA levels between 4 and 10 ng/mL. Changes that exceed this rate are considered abnormal and should be carefully considered by the interpreting physician. An individual should have several PSA determinations over time intervals to provide for correct interpretation.
What types of events can adversely affect PSA results?
A number of factors will affect the accuracy of PSA results. A vigorous DRE, urinary retention, passage of a Foley catheter, acute prostatitis, recent prostate biopsy, and any maneuver that “manipulates” the gland will falsely elevate the PSA. Interpretation of serum PSA results following any of these events should be delayed for 21 days to allow sufficient time for resolution of the false elevation of the PSA.
What is the serum half-life of PSA?
Published reports have documented the serum half-life of PSA to be 2.2 ± 0.8 days and 3.3 ±0.1 days depending upon the testing method used. Based on these data, one should wait at least 21 days following manipulation of the gland to allow for a sufficient number of half-lives to yield a reliable result before drawing a serum PSA.
What is free PSA and what is the significance of free PSA?
PSA is a glycoprotein produced by the prostatic epithelial cells and once in the serum approximately 40% is bound to α2-macroglobulin and is unmeasurable. The remaining fraction of PSA is bound to αr-antichymotrypsin or circulates free in the serum and both are measurable by commercial techniques. Conclusive studies have indicated that individuals with prostate cancer tend to have a lower percent free PSA, and cut-off limits have been assigned to this value. A free PSA less than 25% is considered to be a prognostic factor for prostate cancer. Levels of 10% or less are associated with a 50% incidence of prostate cancer.
Can free PSA be used to assess the relative risk for carcinoma of the prostate in all men?
No. The utility of free PSA is restricted to men with a total PSA between 4 and 10 ng/mL. There have been no definitive studies that indicate an application of free PSA to individuals with a total PSA less than 4 ng/mL. If the total PSA is less than 4.0 ng/mL, one may employ the age-specific reference ranges for PSA and PSA velocity to better assess an individual’s risk for disease.
Can the serum PSA level reliably predict pathological stage?
No. The serum PSA level alone cannot be used to reliably predict the pathological stage of disease. Approximately 70% to 80% of patients with locally advanced prostate cancer have a serum PSA levels > 10 ng/mL. The Gleason biopsy score may have more predictive value in predicting the extent of disease.
You are sent an individual with an elevated PSA for evaluation. He has no symptoms or clinical findings suggesting BPH, LUTS, or prostatitis. What should be your next step?
Rather than rush directly into a prostate biopsy, consider the patients age, general state of health, medications, and state of mind. If he is anxious about prostate cancer and demands a biopsy, it may be best to do so for his anxiety. For most patients, it is often best to repeat the PSA level after a 30-day course of antibiotics. A decision about a possible biopsy can be made at that time. In many cases, the PSA returns to baseline avoiding a potentially painful biopsy.
A 54-year-old man with an enlarged prostate on rectal examination has a serum PSA of 3.6 ng/mL and a free PSA of 45%. There is no family history of prostate cancer. How would you counsel him about his risk for prostate cancer?
Autopsy studies from 1954 indicate that the overall risk for prostate cancer in 50-year-old men is 30%. This individual has BPH by examination and although his free PSA is over 25%, which is consistent with the diagnosis of BPH, his total PSA is less than 4.0 ng/mL and therefore the free PSA may not have much bearing. This patient’s current risk for indolent disease should parallel the age-matched general population. A reasonable course of follow-up may consist of serial PSA measurements to track his PSA velocity.
What is the role for DRE in assessing patients at risk for prostate cancer?
Data reported in the literature indicate that DRE alone detects less than 1.7% of all diagnosed prostate cancers even when there is a high index of suspicion of glandular abnormalities. However, DRE does provide useful information about the size and potential resectability of the prostate in individuals with prostate pathology. It may also detect asymmetry that could suggest a tumor.
What is the accuracy of clinical staging based on DRE?
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