What Every Doctor Who Treats Male Patients Should Know
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PCRI Insights May, 2005 vol. 8, no. 2
Stephen B. Strum, MD, FACP, Medical Oncologist Specializing in Prostate Cancer and Donna Pogliano, Prostate Cancer Advocate

Clinical Practice Prostate Cancer Diagnosis Guidelines

Starting at forty years of age, every man should have an annual PSA (prostate-specific antigen) test and a DRE (digital rectal examination). Men at risk due to a family history of prostate cancer (brothers, fathers)1-3, men with a family history of breast cancer (mothers, sisters, aunts)1,4-6 and African-American men should begin annual screening at age 35. A PSA of 2.0 and over at any age should be investigated to rule out prostate cancer.

A first step in investigation of a PSA elevated at 2.0 or above should be a free-PSA percentage test.

• A free-PSA percentage of more than 25% is associated with a low risk of prostate cancer.

• A free-PSA percentage of less than 15% is associated with a higher risk of prostate cancer7.

An elevated PSA and a correspondingly low free PSA percentage can be caused by prostatitis, which is a benign rather than a malignant condition. If prostatitis symptoms are noted and/or if expressed prostatic secretions are consistent with prostatitis, four to six weeks of Cipro® or similar antibiotic should be prescribed prior to recommending a biopsy. At the end of the Cipro therapy, a repeat PSA determination should be made. If there is significant lowering of the PSA, an element of prostatitis is likely to be present. The PSA value after antibiotic therapy will more aptly reflect the status of the patient in the situation where a diagnosis of prostate cancer is subsequently established.

BPH (benign prostate hyperplasia) does not cause a low free PSA percentage. It may cause an elevated PSA, however. Therefore, in the case of an elevated PSA but a high free PSA percentage (equal to or greater than 25%), an estimate of gland volume by DRE or via transrectal ultrasound of the prostate may reveal findings consistent with a diagnosis of BPH. A general rule of thumb is that an accurate gland volume (best determined by transrectal ultrasound of the prostate) x 0.066 will equal the amount of benign-related PSA.
Therefore, assuming only the presence of BPH, a 60-gram or 60 cubic centimeter prostate is entitled to secrete approximately 3.96 ng of PSA into the blood.

PSA velocity (PSAV) and PSA doubling time (PSADT) are important markers that can indicate the existence of prostate cancer. Blood sampling for PSA determinations, done at least three months apart, and by the same laboratory using the same testing procedure, are necessary to establish PSAV and PSADT. The validity of such determinations is increased if such testing involves at least three determinations over an 18-month span of time. However, a progressive and serial increase in PSA values should raise concern that prostate cancer is present and that a greater degree of vigilance is mandatory.

• A PSAV that exceeds 0.75 ng/ml/yr is associated with a higher probability of PC.8

• A PSADT of less than 12 years is associated with a higher probability of PC.

PSA readings that bounce up and down are more indicative of a benign process than a malignant process. A PSA that shows a persistent rise over time, particularly three consecutive rises three months apart, is suspicious for prostate cancer regardless of the PSA level. Any amount of PSA in excess of the measured benign-related PSA should be considered to have been produced by a malignant process until proven otherwise.

Recently, an additional new screening tool has become available. Bostwick Laboratories now offers the uPM3 test, the first urine-based genetic test for prostate cancer. uPM3 is based on PCA3, a specific gene that is profusely expressed in prostate cancer tissue. On average, the amount of PCA3 is 34 times greater in malignant prostate tissue than it is in benign prostate tissue. No other human tissues have ever been shown to produce PCA3. The uPM3 test predicts cancer as confirmed by prostate biopsy with 81% accuracy, compared to 47% accuracy for PSA. Therefore, after an elevated PSA, further investigations might reasonably include uPM3 testing to enhance the accuracy of diagnosis. Systematic biopsy of the prostate under ultrasound guidance, however, remains the definitive diagnostic procedure when clinical and/or laboratory findings indicate the possibility of prostate cancer.

An approach using biological detection techniques such as those described above would eliminate advanced presentations of PC. Annual screening in this manner presents us with an opportunity to detect localized PC in over 95% of men.9 Such statistics offer an outstanding chance for a curative approach to this disease.

An approach involving these profiling techniques allows the patient-physician team to discern the three major types of PC manifestation using the analogy of the tortoise, the hare and the raven (see Figure 1).

PC Biology Made Simple
Figure 1. PC Biology Made Simple.  Prostate cancer can be thought of as being indolent, intermediate or aggressive. The indolent subtype (the tortoise) is slow moving and slow growing and rarely leaves the prostate gland. It can be rationally managed by active objectified surveillance.10 The intermediate subtype (the hare), without proper attention and treatment can escape the confines of the prostate and result in morbidity and mortality. The aggressive, sinister and often lethal subtype (the raven) is fortunately uncommon and is associated with high mortality but perhaps with more aggressive monitoring and preventive strategy we can minimize this biologic presentation.

The tortoise represents the very slow growing presentation of prostate cancer that may be monitored using active objectified surveillance (so-called watchful waiting) as opposed to the garden variety prostate cancer case (the hare), for which local treatment typically results in long-term biological eradication of disease. Most importantly, attention to PSA kinetics accomplished by monitoring the PSA and PSA derivatives such as free-PSA percentage, PSADT, PSAV and other calculations, should result in an almost total disappearance of the highly aggressive presentation of prostate cancer (the raven). This latter presentation is most commonly associated with rapidly progressive disease and fatality. However, the more typical presentations of prostate cancer (the hare) would be diagnosed years earlier if attention was directed to PSA kinetics, along with confirmatory tests such as free PSA, uPM3 and other new diagnostic advances. Such earlier diagnosis of prostate cancer, and for that matter any type of cancer, is associated with a lesser volume of cancer, a decrease in the risk of spread of the disease and thus a greater likelihood of cure with local therapy.

These opposite extremes in the clinicopathological nature of prostate cancer, i.e., the very slow growing variants versus the aggressive ones, are important to differentiate due to the highly different evaluation and management recommendations advised for each circumstance.

 

Slow-Growing versus Aggressive Prostate Cancer
Slow-growing variants in general, have low PSA values (under 10) and long doubling times (greater than 24 months and often 48 months or longer), as well as low PSA velocities (<0.75 ng/ml/yr ± 10%). If a biopsy is done on a patient with a PSA that is under 10, the Gleason score often turns out to be (3,3). Depending on the calculated tumor volume, clinical stage, PSA doubling time, and other factors, these objectified biologic parameters may allow many such patients to be candidates for active objectified surveillance (also called watchful waiting).10 Patients who choose to monitor their illness rather than seek immediate local therapy must be cognizant of the significance of change in biology over time, or biologic trend. They need to be aware that if manifestations of disease progression become evident, their situation should be reevaluated. In such circumstances, consideration must be made for some form of local treatment – before the window of opportunity for successful local therapy is lost.

Aggressive variants, in general, have high PSAs (over 10) OR very low PSAs associated with very aggressive, high Gleason score [(4,3), (4,4), (4,5), (5,4), (5,5)] cancers. These variants are very dangerous, often escaping investigation for long periods of time because the PSAs appear to be in the so-called normal range. Investigating all PSAs of 2.0 and over will help to catch these aggressive prostate cancers while they are still organ-confined and treatable with local therapies such as surgery and radiation. The probability of detecting these low PSA/high Gleason score cancers is enhanced if patients and doctors monitor even very low PSA levels over time to note any persistent increases.

High Gleason score cancers often have reverted to an embryonic state in which PSA secretion into the blood is markedly reduced.
Checking the serum for abnormal elevations in markers such as CGA (Chromogranin A), NSE (Neuron Specific Enolase), CEA (Carcino- Embryonic Antigen) and PAP (Prostatic Acid Phosphatase) is important to discern PC activity secondary to these de-differentiated tumor cell populations. Therefore, in cases such as this, the normal guidelines for PSA velocity and doubling time may not be applicable. HOWEVER, the concept of slope or trend in a biomarker of disease activity remains valid, and any biomarker elevation should be tracked at regular intervals to determine the presence of abnormal growth of primitive (embryonic) tumor cell clones.

 

Conclusion
If we scientifically observe the biological manifestations of prostate health or disease, we can detect PC at a time when currently available therapies are most likely to cure the most common malignancy facing man. If we ignore the biological communications that can alert us to the presence of a life-threatening condition, we will miss a vital opportunity to change the course of the illness.

The loss of life, productivity, and the extreme costs to the health care system—all of which result from a late-stage diagnosis of this disease—should provide impetus for all of us to be proactive when it comes to an early diagnosis of a malignant condition. This fundamental concept has been heralded for many malignances, such as cancer of the cervix, lung cancer, colorectal malignancy and breast cancer. When will we make the same connection when it comes to men with PC?11 Aren’t the 300,000 American lives lost each decade too great a price to pay?

Working together and listening attentively to the biology of cancer, we will achieve vast inroads into the diagnosis, evaluation and treatment of this illness and alter the course of human lives.

References

1. Cerhan JR, Parker AS, Putnam SD, et al: Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8:53-60, 1999.

2. Hayes RB, Liff JM, Pottern LM, et al: Prostate cancer risk in U.S. blacks and whites with a family history of cancer. Int J Cancer 60:361-4, 1995.

3. Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, et al: Risk of cancer in relatives of prostate cancer probands. J Natl Cancer Inst 87:991-6,1995.

4. Bennett KE, Howell A, Evans DG, et al: A follow-up study of breast and other cancers in families of an unselected series of breast cancer patients. Br J Cancer 86:718-22, 2002.

5. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343:692-5, 1994.

6. Goldgar DE, Easton DF, Cannon-Albright LA, et al: Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86:1600-8, 1994.

7. Ito K, Yamamoto T, Ohi M, et al: Free/total PSA ratio is a powerful predictor of future prostate cancer morbidity in men with initial PSA levels of 4.1 to 10.0 ng/mL. Urology 61:760-4, 2003.

8. Ito K,Yamamoto T, Ohi M, et al: Usefulness of prostate-specific antigen velocity in screening for prostate cancer. Int J Urol 9:316-21, 2002.

9. Labrie F, Candas B, Cusan L, et al: Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-specific antigen. Urology 47:212-7, 1996.

10. Hardie C, Parker C, Norman A, et al: Early outcomes of active surveillance for localized prostate cancer. BJU Int 95:956-60, 2005.

11. Labrie F, Candas B, Dupont A, et al: Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 38:83-91, 1999