Prostate cancer topics, links and more. Now at 200+ posts!

News: Health Day, Medical News Today, ScienceDaily, Urol Times, Urotoday, Zero Cancer Papers: Pubmed (all), Pubmed (Free only), Amedeo
Journals: Eur Urol, J Urol, JCO, The Prostate Others Pubmed Central Journals (Free): Adv Urol, BMC Urol, J Endourol, Kor J Urol, Rev Urol, Ther Adv Urol, Urol Ann
Reviews: Cochrane Summaries, PC Infolink Newsletters: PCRI, US Too General Medical Reviews: f1000, Health News Review

Monday, May 14, 2007

PSA Screening and Early Detection - Part 2. Key Points on PSA

[Updated July 31, 2014]

PSA Screening and Early Detection. Part 1 - Guides [previous]
PSA Screening and Early Detection. Part 2 - Key Points on PSA [current]
PSA Screening and Early Detection. Part 3. Current Environment [next]
PSA Screening and Early Detection - Part 4. Diagnostic Testing Concepts
PSA Screening and Early Detection - Part 5. More Diagnostic Testing Concepts

Establishing Baseline. Because variation in PSA can be substantial it is desirable to build up a baseline history of how your PSA fluctuates at an age that is sufficiently young that its unlikely that there is prostate cancer. Then
  1. later rises can be judged against this baseline to decide whether they represent meaningful rises or just natural variation.
  2. a series of tests will allow one to calculate not only the PSA level but also the PSA velocity (PSAV) and PSA doubling time (PSADT).
Building up such a baseline is why this PCRI pamphlet (also PCRI article) and some others recommend PSA testing starting at 40 or earlier even though its unlikely that one would have prostate cancer at such an age.

Testing Frequency By performing tests at least annually sufficiently many samples can be collected to establish a baseline.

Another viewpoint comes from the large scale PCLO trial, also here, which so far concludes that there is only a 0.24% and 1.5% chance of developing a PSA > 4.0 within one year and five years if your PSA < 1.0 now. This suggests that it may be possible for such individuals to have a PSA test only every 5 years rather than every year. See slide 12 in this article by Roehrborn which requires signup but such signup is free. Similarly, Loeb et al (2007) [PMID: 17437803] concludes that "men 40 to 49 years old with a prostate specific antigen less than the age specific median (PSA = 0.7) have a low risk of prostate cancer so performing a baseline prostate specific antigen measurement in the fifth decade led to few additional biopsies, and was extremely useful for risk stratification since men with levels greater or less than the age specific median had strikingly different risk profiles."

Cutoff Levels Traditionally a cutoff level above 4.0 has been used to indicate biospy is required; however, Dr. Catalona and a number of other sources (see PCRI pamphlet and also PCRI article) recommend 2.5 since the 4.0 level misses a significant number of prostate cancer cases. Loeb (papers) and Catalona (papers) discuss this in the March 2008 issue of the Oncologist [PMID: 18378540] where they point out that "Among men with serum PSA levels 0.5, 0.6–1.0, 1.1–2.0, 2.1–3.0, and 3.1–4.0 ng/ml, prostate cancer was detected in 6.6%, 10.1%, 17.0%, 23.9%, and 26.9%, respectively.". PSA Cutoff Levels

In the above cited paper, which is highly recommended to all readers, Loeb and Catalona summarize their discussion into a very helpful flow chart showing the clinical actions to take based on PSA testing.

Rather than a fixed cutoff level, age-specific and race-specific levels have been proposed. Age-specific cutoff levels are discussed in the Part 1 post of this series, the Australian brochure and the above mentioned Loeb and Catalona paper. Also race-specific cutoff levels have been proposed to take into account the higher risk faced by blacks and the lower risk faced by Asians. On the other hand they are more complicated and a 2006 analysis by Grunkemeier and Vollmer [PMID: 16753606] [Full Text] found no advantage in incorporating race or age. Also see references to that article.

Loeb and Catalona recommend that rather than modifying cutoff levels based on age that age specific levels be used for risk assessment in order to determine which men need to be followed more closely in the future. Loeb and Catalona cite results from Fang et al's 796 person Baltimore study as well as their own studies showing that men with PSA values above the age-specific median are at significantly heightened risk for prostate cancer many years later. Thus the way they suggest that age-specific levels be used is that for men in their 40's, 50's, 60's and 70's that closer future monitoring be done if their PSA is found to be 0.7, 0.9, 1.3, 1.7 or higher, respectively. Use of median age-specific PSA levels to determine who needs to be followed more closely is also mentioned in the Australian brochure even if the PSA level is below the cutoff, if it is above the median PSA then the individual is still at heightened risk for prostate cancer and should be monitored more closely. Median PSA vs. Age

In the same March 2008 issue of The Oncologist, Michael Berry (papers) of Harvard Medical School presents an alternative view that the increased PSA testing recommended above will lead to greater number of healthy men being unnecessarily having to undergo biopsy. See [PMID: 18378541].

Not only the level but the PSA kinetics (PSA velocity and doubling time) have been advocated as other measures to look at. This PCRI pamphlet (also PCRI article) recommend biopsy even for low PSA values if the PSA doubling time (PSADT) is less than 10 years.

Factors Affecting PSA. Becasuse PSA can be affected by a number of factors, not just prostate cancer, it is important to closely read the following list of factors that affect PSA:

  • increased by prostate cancer as tumour cells leak more PSA than benign cells (but some aggressive tumours are not associated with high PSA levels, e.g. JoeC comment regarding his experience with low PSA and aggressive PC).
  • increases with age. It is well known that PSA increases as one gets older and it has even been recommended that PSA cutoff levels be age-dependent. [PMID: 18522630]
  • increased by larger prostate volume and by patient age (as older patients tend to have higher prostate volume). Thus for a given level of PSA a smaller prostate is associated with a higher likelihood of prostate cancer than a larger prostate. In particular a rule of thumb is that for each cubic centimeter (cc) of benign prostate tissue that 0.067 ng/ml of PSA will be produced. Thus for a prostate of 40cc one would expect a PSA of 40 x 0.067 = 2.68 ng/ml so if the PSA were 4.0 ng/ml then there is 4.0 - 2.68 = 1.32 ng/ml that is unexplained and might be due to cancer cells or other factor listed here. See [link].
  • increased by activities which include ejaculation, prolonged exercise and possibly bicycle riding. The effect of these activities is somewhat inconsistent across studies. See, for example, [PMID:8653893] [full text] and [PMID:9267335] [full text]. Special bicycle seats referred to as split bicycle seats or a variety of other names are available to address this problem of pressure on the perineal area. Also see this June 27/11 NY Times article on bicycle seats.
  • increased by other prostatic diseases (BPH, prostatitis ([treatment]], inflammation, prostate ischemia) and non-prostatic diseases (urinary infection, acute renal failure, bypass surgery). Wait 6 weeks for PSA testing after resolution of inflammation.
  • increased by clinical manipulation (DRE, TURP, TRUS). Effect of DRE has been disputed; however, Dr. William J. Catalona" says patients should wait 48 hours after a DRE before getting a PSA test. [Quest Fall 2009]. The time needed to wait for PSA testing after biopsy is said to be one month by each of these two papers (on PSA and fPSA) [PMID: 12479122], [PMID: 10197848] while this article says 8-12 weeks. Dr. William J. Catalona" says patients should wait 6-7 weeks after a biopsy before getting a PSA test. [Quest Fall 2009] The half life of PSA is 3 days [PMID: 1376933] [full text] so it would halve 10 times in 30 days reducing the excess PSA to (1/2) ^ 10 = 0.1% of its original value.
  • increased by certain genetic variations even in the absence of prostate disease. Genetic variations can affect the normal level of PSA even in the absence of prostate cancer. See [PMID: 12865450], [Full Text], [PMID: 12865440], [Full Text], [JNCI press release].
  • decreased by androgen deprivation therapy (ADT) -- nafarelin (Synarel), buserelin (Suprefact), goserelin (Zoladex), leuprolide (Lupron, Lucrin), flutamide (Drogenil, Eulexin), finasteride (Proscar).
  • decreased by statins which are cholesterol lowering drugs. "For every 10% decrease in LDL after starting a statin, PSA levels declined by 1.64." See [PMID: 18957682] and [PMID: 18957671] [Full Text].
  • decreased by urinary retention.
  • decreased by weight loss. [PMID: 16342294].
  • decreased by metabolic syndrome [link]
  • variation from lab to lab (10%), inherent analytical variation of the same lab (small) and biological variation (20% provided repeats are done > 1 month apart). See this post on PSA Variation.
  • assay Standard PSA tests are usually standardized to the WHO 90:10 standard or standardized to the original Hybritech(R) standard. [PMID: 18801532]. If ones switches among tests using different standards then a significant difference may appear even if there is no real difference in the underlying PSA. The situation with ultrasensitive tests is even worse since there is no real harmonization at all among such tests.
  • decreased by obesity thought to be due to the larger amount of blood in obese men diluting the PSA. Thus for a given PSA the greater the Body Mass Index (BMI) the higher the likelihood of prostate cancer. [PMID: 18267334] has even suggested that it may be necessary to lower the cutpoints used to assess the presence of prostate cancer in the obese. Also see [PMID: 18029831] [Full Text] [Journal Watch comment].
  • season. PSA is lower in summer when there are more hours of sunlight. [PMID: 17174467].
  • liver and lipid profile tests. PSA varies inversely with alanine aminotransferase (ALT), high-density lipoprotein (HDL) and with fasting blood sugar. It has also been observed to vary inversely with certain other liver and lipid profile tests; however, those associations ceased to be significant when all variables were taken into account at the same time. See [PMID: 18522630].

For more information see (1) page 3 of The Australian National Seniors Foundation guide, (2) Table 2 on page 3 of Mayo Clinic article and (3) the table from [PMID: 7554241] which can be found on the QA page of the Ontario intro and at this Prostate Help page.

Regarding the discussion of bicycling above, an observational study of 5282 male cyclists over 50 years old found an association between cycling and prostate cancer. Those cycling more than 3.75 hours per week were 3 to 6 times more likely to develop prostate cancer than those who cycled for less than 3.75 with the risk increasing the more they cycled. No relationship was found between cycling and ED or fertility. [full text]

Free PSA. If the PSA (called Total PSA or tPSA to distinguish it from the Free PSA or fPSA component) is in the 4-10 range and the DRE is negative a fPSA test can be given to determine if the level is due to inflammation or other causes rather than cancer. The fPSA is divided by the tPSA to give a ratio, fPSA/tPSA, that is used in diagnosis as discussed on page 3 of decision card. Note that the fPSA assay that is used must be compatible with the tPSA assay that was used as mentioned by the FDA on Immulite fPSA test. See the PSA Rising Decision Chart and the Australian decision card for more info.

Prognoses. A variety of and other online calculators are available to get prognoses based on lab results.

Home Testing. PSA Testing is normally performed at a lab or doctor's office but according to this site a test, the Biosafe Prostate Screen exists that can be done at home and then sent to a lab for processing.

Assay. The first PSA assay was Hybritech. This 2003 presentation by Petra Stauber lists several dozen different assays and indicates that over 70 exist. A comparison of four assays are discussed in the linked article. The assays are sometimes categorized into generations according to their sensitivity, i.e. how small a difference in PSA they can detect. In this presentation by Lynn Witherspoon three generations of PSA assays are identified with their sensitivities:
  • First generation. Sensitivity 0.3 ng/mL (Yang, Hybritech-R)
  • Second generation. Sensitivity 0.03 ng/mL (IMx, Tosoh)
  • Third generation. Sensitivity 0.003 ng/mL (Immulite, Elecsys)

Ultrasensitive Tests. The more sensitive assays are referred to as ultrasensitive tests. They are widely used in the US after surgery or radiation for earlier recognizition of rising PSA and earlier salvage therapy. (Such salvage therapy would typically be radiation after surgery if the disease were localized to the prostate bed or hormonal therapy if it were metastatic.) Even in the recurrence application some countries such as Canada primarily use the less sensitive tests based on the idea that low levels of PSA are also consistent with indolent disease and one presumably wants confirmation that the disease is, in fact, presenting a danger to avoid unnecessary treatment for recurrence. Furthermore, if the cancer is metastatic then conventional thought has been that it is best to delay hormone treatment since such delay also delays the time that it becomes androgen independent and therefore presumably prolongs survival; however, there is accumulating data that suggests that the actual situation is just the opposite -- early use of hormone therapy prolongs survival. See [PMID: 12667882], [PMID:] [Full Text] and [Full Text]. Also Urotoday, May 2007 based on [PMID: 17513807] indicates that outcomes of salvage RT were better if the PSA was below 0.6 when RT was performed. Of course if early use prolongs survival then there is an advantage to early detection and therefore to ultrasensitive PSA testing.)

Even though there is some question on whether ultrasensitive testing has utility for detecting recurrence, there seems to be broad agreement over multiple studies that if PSA levels below 0.01 are reached after surgery (a level which can only be detected using ultrasensitive assays) then there is overwhelming likelihood of freedom from disease progression for a number of years following surgery:

  • In a 2000 study of 200 patients over 2 years, Doherty et al [PMID: 11076649] concluded that patients who achieved a PSA of less than 0.01 after surgery had only a 3% chance of subsequent recurrence vs. 76% for those who did not achieve this level. The 0.01 level was achieved at a median of 10.4 weeks after surgery. Biochemical relapse was defined as three successive PSA rises.
  • In a study of 225 patients Taylor et al (2006) [PMID: 16925750] followed 225 patients for 5-65 months and concluded that, like the Doherty study, low levels of PSA were also associated with favorable outcomes although they did not quantify the result. Biochemical relapse was defined as two succesive rising after PSA reached 0.20
  • In a 2006 study Sakai et al, [PMID: 16601384] followed 127 patients for 6-75 months, and got consistent results with recurrence rates of 6.3%, 25% and 91.7% for patients achieving a PSA of < 0.01, 0.01-0.05 and >=0.05. Biochemical relapse was defined as PSA persistently above 0.20.

As already mentioned above, the particular test as well as the lab performing the test can influence the result too so tests should be done at the same lab to make them comparable. The ultra sensitive tests may include retesting prior saved blood samples to eliminate equipment drift errors from one reading to the next several weeks or months later.

Despite attempts at harmonization among PSA assays, becauase the particular assay that is used for the PSA test can affect the results, use the same assay and same lab for all your PSA tests. See [PMID: 17355366].

Keeping Track of Results. If your hospital has a hospital-wide information system that distributes test results to the doctors it may be preferable to get tested at the hospital rather than an external lab so that your results are entered directly into the system and do not get lost. Always get copies of your PSA and other test results and keep them filed since the history will be important in future assessment.

New Tests. Bostwick Labs is offering a uPM3 urine test for the PCA3 gene for prostate cancer. uPM3 is expressed in the urine after prostatic massasge. Also see Diagnocure press release and this 2003 PCA3 article from the PCRI site.

Future. Additional new urinary and serum diagnostic tests (including genetic tests) are under investigation. Tables 1 and 2 of this 2004 review summarize the various biomarkers and their sensitivity and specificity. A 2006 review of biomarkers can be found here.

Miraculins is working on a new urine-based test for prostate cancer. See this press release. The company claims that their test has a higher sensitivity and specificity than the PSA test.

PSA Screening and Early Detection. Part 1 - Guides [previous]
PSA Screening and Early Detection. Part 2 - Key Points on PSA [current]
PSA Screening and Early Detection. Part 3. Current Environment [next]
PSA Screening and Early Detection - Part 4. Diagnostic Testing Concepts
PSA Screening and Early Detection - Part 5. More Diagnostic Testing Concepts

No comments: