Prostate cancer screening controversy
According to the American Cancer Society (ACS), men aged 50 and older who receive an annual medical examination should be offered a digital rectal examination and a PSA test.¹ The ACS also recommends that men aged 40 and over be informed about the risk of prostate cancer² and that screening be considered at an earlier age, such as 40 or 45, in high-risk individuals, e.g., African-Americans and first-degree relatives of prostate cancer patients. In contrast, a number of physician organizations do not advocate routine screening.^3,4 This position is based on their claims that there is no conclusive evidence that early detection and treatment influence the overall death rate from this disease,⁵ and that the standard treatment (radical prostatectomy) is associated with a high incidence of side effects.⁶ Despite the conflicting recommendations, PSA testing has increased rapidly among asymptomatic men in the US,⁷ and ACS statistics show a remarkable decline in the death rate from prostate cancer over the past 5 years (Figure 1).⁸

Other technologies may also be contributing to earlier detection of prostate cancer. These include the availability of free PSA and use of the free-to-total PSA ratio; improved ultrasonography and prostate biopsy methods; and the wider application of risk assessment algorithms involving, for example, age-adjusted PSA, prostate gland volume, transition zone volume and PSA density. The decline in prostate cancer mortality may also be explained, in part, by improved treatments for early-stage disease and better follow-up care, as reviewed below.

Current PSA studies indicate that cancer cases exhibit a slow linear PSA phase initially, followed by a rapid exponential phase, and that PSA levels begin to increase exponentially approximately 7 to 9 years before diagnosis.⁹ Experts agree on the benefits of calculating PSA doubling times (PSADT), which are derived from a baseline measurement and subsequent PSA values obtained at appropriate intervals. Published data indicate that the median PSADT for localized prostate cancer is 4 years, but it is shorter in higher clinical stages and worse histologic grades.^10,11 In contrast, PSADT in age-matched controls is much longer.¹²

Because the IMMULITE^® and IMMULITE^® 2000 Third Generation PSA assays possess outstanding low-end precision, they are ideal tools for following PSA trends over time and obtaining accurate PSADT calculations.

Figure 1. Five-year trends in prostate cancer. Based on collated 1995-2000 mortality statistics from the American Cancer Society. ⁸

Monitoring treatment
The most generally useful clinical application of PSA determinations is in the monitoring of treated prostate cancer patients. Treatments include (radical) prostatectomy, radiation therapy, and hormonal therapies involving medical or surgical castration. Circulating PSA levels can provide invaluable information about the effectiveness of the therapy used and the existence of residual cancer, as well as early detection of cancer recurrence. Rising PSA levels can signal cancer activity well before any clinical signs of recurrence appear. This lead time can be further increased by months or even years when using ultrasensitive PSA immunoassays such as the IMMULITE and IMMULITE 2000 Third Generation PSA assays. The expected PSA results associated with good outcomes following various prostate cancer treatments are listed in Table 1.

Studies using DPC’s Third Generation PSA assays have established the value of highly sensitive PSA assays to detect early prostate cancer relapse following radical prostatectomy.^13-15 Witherspoon et al. demonstrated an average 18-month lead time in detecting disease progression using DPC’s IMMULITE Third Generation PSA compared to a conventional PSA assay (Figure 2).¹³ Vassilikos et al. confirmed this lead time and was able, over a 4-year follow-up period, to define a group of patients having rapid PSA relapse.¹⁴ Doherty et al. showed that a single baseline PSA level < 0.01 µg/L measured 4 to 6 weeks postsurgery indicates a lower probability of disease progression.¹⁵ On multivariate analysis, failing to achieve a PSA nadir of
< 0.01 µg/L was found to be an independent predictor of relapse, and a stronger factor than even the Gleason sum or pathological margin status.

Figure 2. Postoperative PSA levels over time in a 73-year-old man who underwent radical prostatectomy. No tumor was present at the surgical margins, seminal vesicles or regional lymph nodes; and the postoperative baseline PSA was 0.004 µg/L. PSA at 4.2 years after prostatectomy became detectable at 0.10 µg/L using a conventional PSA assay. Using the IMMULITE Third Generation PSA assay, a PSA rise was observed 2 years earlier.¹³

Definitive radiation therapy in which the gland remains in situ rarely results in an undetectable PSA, even when cure is achieved.¹⁹ However, there is a general consensus that PSA levels reaching a nadir < 1.0 µg/L are associated with improved biochemical disease-free survival.^16,17 Disease progression is strongly suspected if the PSA rises on consecutive determinations. The use of a highly sensitive PSA assay, such as the IMMULITE or IMMULITE 2000 Third Generation PSA, can help detect early disease progression in radiation-treated patients.

For patients suffering PSA progression following primary surgery, viable treatment options include salvage radiation or androgen deprivation therapy (ADT). Salvage radiation treatment will benefit only those patients with proven residual cancer in the prostatic fossa, whereas ADT can benefit those with residual cancer and/or metastatic disease. Serial PSA measurements in the months following surgery can be used to determine whether a patient is more or less likely to benefit from salvage radiation therapy.^18-20

Undetectable baseline PSA levels defined (by conventional assays) as < 0.2 µg/L following surgery, which later become detectable and progressively rise, suggest locally recurring cancer in the prostatic fossa.¹⁸ (See Figure 2 for an example.) On the other hand, detectable PSA levels at baseline which show progressive increases may represent microscopic metastatic disease that was present prior to radical prostatectomy. In the former scenario, salvage radiation treatment may be indicated, whereas systemic salvage treatment using ADT would appear to be indicated in the latter. Early PSA relapse, unfavorable Gleason sum and rapid PSADT are also associated with prostate cancer metastases following both surgery and radiation treatment.^26,27 The lead time afforded by ultrasensitive PSA assays and their superior low-end precision identifies patients with early disease relapse and can help guide medical decision-making regarding salvage therapy options.

Figure 3. Time course of PSA and testosterone levels in a 65-year-old patient with stage T2a prostate cancer (Gleason sum 3 + 2 = 5 disease) treated with intermittent androgen deprivation (IAD). Because therapy induced a rapid decline in circulating PSA to persistently undetectable levels (<=0.01), androgen deprivation was suspended in late 1997 and the subsequent rise in PSA was monitored. When therapy was reinstated three years later, PSA levels again dropped rapidly to undetectable levels. (Testosterone was measured periodically to check the impact of therapy on circulating androgen levels.)

For primary or salvage ADT, PSA is the most sensitive surrogate marker of disease activity with which to judge treatment efficacy. Even in advanced metastatic disease, achieving an undetectable PSA < 0.2 or < 0.3 µg/L within 6 months of starting ADT, distinguishes patients with a favorable and persisting response to ADT from those in whom only a limited response can be expected.^21,28 For patients with less extensive disease, response to ADT is likely to be extremely favorable.²² Attainment and maintenance of a PSA < 0.05 µg/L for a year or more while on ADT can be used to identify patients with androgen-dependent prostate cancer, in whom intermittent ADT is feasible.^23-25

Patients with low-volume disease, such as those having PSA relapse, can often enjoy prolonged time-off treatment with improved quality of life.²⁵ When retreatment is indicated in such patients, due to a rising PSA or other clinical findings, an excellent response to ADT can be anticipated.

Conclusion
It has become essential for all-purpose PSA assays to have third-generation capability. DPC’s Third Generation PSA assays effectively address the requirements of modern prostate cancer treatment modalities by providing extraordinary analytical sensitivity and a working range with excellent precision at very low concentrations. At the same time, they accommodate PSA values for general prostate cancer screening purposes.

Table 1. Relevant PSA values in various treatment modalities.

References
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2. American Foundation for Urologic Disease. Prostate cancer resource guide. Baltimore, MD: The Foundation, 1999. .

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4. American Cancer Society: Prostate cancer and cancer detection guidelines, 1999. Atlanta, GA: The Society, 1999.

5. Centers for Disease Control and Prevention. Screening with the prostate-specific antigen test-Texas 1997. Morbid Mortal Weekly Rep 2000 Sept 15;49(36).

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10. el-Galley RE, Petros JA, Sanders WH, Keane TE, Galloway NT, Cooner WH, et al. Normal range prostate-specific antigen versus age-specific prostate-specific antigen in screening prostate adenocarcinoma. Urology 1995 Aug;46(2):200-4.

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19. Forman JD, Meetze K, Pontes E, Wood DP Jr, Shamsa F, Rana T, et al. Therapeutic irradiation for patients with an elevated post-prostatectomy prostate specific antigen level. J Urol 1997 Oct;158(4):1436-9; discussion 1439-40.

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21. Zagars GK, Sands ME, Pollack A, von Eschenbach AC. Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: prognostic variables and outcome. J Urol 1994 May;151(5):1330-3.

22. Fowler JE Jr, Pandey P, Seaver LE, Feliz TP, Braswell NT. Prostate specific antigen regression and progression after androgen deprivation for localized and metastatic prostate cancer. J Urol 1995 Jun;153(6):1860-5.

23. Higano CS, Ellis W, Russell K, Lange PH. Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 1996 Nov;48(5):800-4.

24. Grossfeld GD, Small EJ, Carroll PR. Intermittent androgen deprivation for clinically localized prostate cancer: initial experience. Urology 1998 Jan;51(1):137-44.

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26. Fowler JE Jr, Pandey P, Braswell NT, Seaver L. Prostate specific antigen progression rates after radical prostatectomy or radiation therapy for localized prostate cancer. Surgery 1994 Aug;116(2):302-5; discussion 305-6.

27. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999 May 5;281(17):1591-7.

28. Stamey TA, Kabalin JN, Ferrari M, Yang N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. IV. Anti-androgen treated patients. J Urol 1989 May;141(5):1088-90.