The role of PSA in detection and management of prostate cancer

Abstract

The prostate specific antigen (PSA) test clearly provides the opportunity for clinically relevant prostate cancer to be detected at a stage when treatment options are greater and outcomes may be improved. However, in some patients the PSA test may lead to investigations which can identify clinically insignificant cancers which would not have become evident in a man's lifetime. In addition, a raised PSA may often indicate benign prostatic enlargement, and this may provide an opportunity for treatment of this condition before complications develop.

The lack of sensitivity and specificity that characterises PSA testing in the initial diagnosis of prostate cancer largely disappears after treatment of localised prostate cancer, especially after surgery. Three monthly PSA measurement is usually recommended for the first year after primary treatment. Subsequently less frequent testing is required. A PSA rise after primary treatment usually indicates biochemical recurrence and often the need for further therapy.

There are two promising urinary RNA biomarkers, prostate cancer antigen 3 (PCA3) and fusion gene TMPRSS2:ERG, both of which aim to distinguish between men with low-risk (indolent) and those with aggressive (clinically significant) cancers.


Practitioner. 2016 Apr;260(1792):17-21, 3.

Prostate Specific Antigen

1. What is the PSA test?

   Prostate-specific antigen, or PSA, is a protein produced by cells of the prostate gland. The PSA test measures the level of PSA in a man’s blood. For this test, a blood sample is sent to a laboratory for analysis. The results are usually reported as nanograms of PSA per milliliter (ng/mL) of blood.
   The blood level of PSA is often elevated in men with prostate cancer, and the PSA test was originally approved by the FDA in 1986 to monitor the progression of prostate cancer in men who had already been diagnosed with the disease. In 1994, the FDA approved the use of the PSA test in conjunction with a digital rectal exam (DRE) to test asymptomatic men for prostate cancer. Men who report prostate symptoms often undergo PSA testing (along with a DRE) to help doctors determine the nature of the problem.
   In addition to prostate cancer, a number of benign (not cancerous) conditions can cause a man’s PSA level to rise. The most frequent benign prostate conditions that cause an elevation in PSA level are prostatitis (inflammation of the prostate) and benign prostatic hyperplasia (BPH) (enlargement of the prostate). There is no evidence that prostatitis or BPH leads to prostate cancer, but it is possible for a man to have one or both of these conditions and to develop prostate cancer as well.
   
   

2. Is the PSA test recommended for prostate cancer screening?

   Until recently, many doctors and professional organizations encouraged yearly PSA screening for men beginning at age 50. Some organizations recommended that men who are at higher risk of prostate cancer, including African American men and men whose father or brother had prostate cancer, begin screening at age 40 or 45. However, as more has been learned about both the benefits and harms of prostate cancer screening (see Questions 5 and 6), a number of organizations have begun to caution against routine population screening. Although some organizations continue to recommend PSA screening, there is widespread agreement that any man who is considering getting tested should first be informed in detail about the potential harms and benefits.
   Currently, Medicare provides coverage for an annual PSA test for all Medicare-eligible men age 50 and older. Many private insurers cover PSA screening as well.
   
   

3. What is a normal PSA test result?

   There is no specific normal or abnormal level of PSA in the blood. In the past, most doctors considered PSA levels of 4.0 ng/mL and lower as normal. Therefore, if a man had a PSA level above 4.0 ng/mL, doctors would often recommend a prostate biopsy to determine whether prostate cancer was present.
   However, more recent studies have shown that some men with PSA levels below 4.0 ng/mL have prostate cancer and that many men with higher levels do not have prostate cancer (1). In addition, various factors can cause a man’s PSA level to fluctuate. For example, a man’s PSA level often rises if he has prostatitis or a urinary tract infection. Prostate biopsies and prostate surgery also increase PSA level. Conversely, some drugs—including finasteride and dutasteride, which are used to treat BPH—lower a man’s PSA level. PSA level may also vary somewhat across testing laboratories.
   Another complicating factor is that studies to establish the normal range of PSA levels have been conducted primarily in populations of white men. Although expert opinions vary, there is no clear consensus regarding the optimal PSA threshold for recommending a prostate biopsy for men of any racial or ethnic group.
   In general, however, the higher a man’s PSA level, the more likely it is that he has prostate cancer. Moreover, continuous rise in a man’s PSA level over time may also be a sign of prostate cancer.
   
   

4. What if a screening test shows an elevated PSA level?

   If a man who has no symptoms of prostate cancer chooses to undergo prostate cancer screening and is found to have an elevated PSA level, the doctor may recommend another PSA test to confirm the original finding. If the PSA level is still high, the doctor may recommend that the man continue with PSA tests and DREs at regular intervals to watch for any changes over time.
   If a man’s PSA level continues to rise or if a suspicious lump is detected during a DRE, the doctor may recommend additional tests to determine the nature of the problem. A urine test may be recommended to check for a urinary tract infection. The doctor may also recommend imaging tests, such as a transrectal ultrasound, x-rays, or cystoscopy.
   If prostate cancer is suspected, the doctor will recommend a prostate biopsy. During this procedure, multiple samples of prostate tissue are collected by inserting hollow needles into the prostate and then withdrawing them. Most often, the needles are inserted through the wall of the rectum (transrectal biopsy); however, the needles may also be inserted through the skin between the scrotum and the anus (transperineal biopsy). A pathologist then examines the collected tissue under a microscope. The doctor may use ultrasound to view the prostate during the biopsy, but ultrasound cannot be used alone to diagnose prostate cancer.
   
   

5. What are some of the limitations and potential harms of the PSA test for prostate cancer screening?

   Detecting prostate cancer early may not reduce the chance of dying from prostate cancer. When used in screening, the PSA test can help detect small tumors that do not cause symptoms. Finding a small tumor, however, may not necessarily reduce a man’s chance of dying from prostate cancer. Some tumors found through PSA testing grow so slowly that they are unlikely to threaten a man’s life. Detecting tumors that are not life threatening is called “overdiagnosis,” and treating these tumors is called “overtreatment.”
   Overtreatment exposes men unnecessarily to the potential complications and harmful side effects of treatments for early prostate cancer, including surgery and radiation therapy. The side effects of these treatments include urinary incontinence (inability to control urine flow), problems with bowel function, erectile dysfunction (loss of erections, or having erections that are inadequate for sexual intercourse), and infection.
   In addition, finding cancer early may not help a man who has a fast-growing or aggressive tumor that may have spread to other parts of the body before being detected.
   The PSA test may give false-positive or false-negative results. A false-positive test result occurs when a man’s PSA level is elevated but no cancer is actually present. A false-positive test result may create anxiety for a man and his family and lead to additional medical procedures, such as a prostate biopsy, that can be harmful. Possible side effects of biopsies include serious infections, pain, and bleeding.
   Most men with an elevated PSA level turn out not to have prostate cancer; only about 25 percent of men who have a prostate biopsy due to an elevated PSA level actually have prostate cancer (2).
   A false-negative test result occurs when a man’s PSA level is low even though he actually has prostate cancer. False-negative test results may give a man, his family, and his doctor false assurance that he does not have cancer, when he may in fact have a cancer that requires treatment.
   
   

6. What research has been done to study prostate cancer screening?

   Several randomized trials of prostate cancer screening have been carried out. One of the largest is the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which NCI conducted to determine whether certain screening tests can help reduce the numbers of deaths from several common cancers. In the prostate portion of the trial, the PSA test and DRE were evaluated for their ability to decrease a man’s chances of dying from prostate cancer.
   The PLCO investigators found that men who underwent annual prostate cancer screening had a higher incidence of prostate cancer than men in the control group but the same rate of deaths from the disease (3). Overall, the results suggest that many men were treated for prostate cancers that would not have been detected in their lifetime without screening. Consequently, these men were exposed unnecessarily to the potential harms of treatment.
   A second large trial, the European Randomized Study of Screening for Prostate Cancer (ERSPC), compared prostate cancer deaths in men randomly assigned to PSA-based screening or no screening. As in the PLCO, men in ERSPC who were screened for prostate cancer had a higher incidence of the disease than control men. In contrast to the PLCO, however, men who were screened had a lower rate of death from prostate cancer (4).
   The United States Preventive Services Task Force has analyzed the data from the PLCO, ERSPC, and other trials and estimated that, for every 1,000 men ages 55 to 69 years who are screened every 1 to 4 years for a decade (5):
   
   Enlarge

   

   An infographic illustrating the benefit and harms of PSA screening for prostate cancer.

   • 0 to 1 death from prostate cancer would be avoided.
   • 100 to 120 men would have a false-positive test result that leads to a biopsy, and about one-third of the men who get a biopsy would experience at least moderately bothersome symptoms from the biopsy.
   • 110 men would be diagnosed with prostate cancer. About 50 of these men would have a complication from treatment, including erectile dysfunction in 29 men, urinary incontinence in 18 men, serious cardiovascular events in 2 men, deep vein thrombosis or pulmonary embolism in 1 man, and death due to the treatment in less than 1 man.
   
   

7. How is the PSA test used in men who have been treated for prostate cancer?

   The PSA test is used to monitor patients who have a history of prostate cancer to see if their cancer has recurred (come back). If a man’s PSA level begins to rise after prostate cancer treatment, it may be the first sign of a recurrence. Such a “biochemical relapse” typically appears months or years before other clinical signs and symptoms of prostate cancer recurrence.
   However, a single elevated PSA measurement in a patient who has a history of prostate cancer does not always mean that the cancer has come back. A man who has been treated for prostate cancer should discuss an elevated PSA level with his doctor. The doctor may recommend repeating the PSA test or performing other tests to check for evidence of a recurrence. The doctor may look for a trend of rising PSA level over time rather than a single elevated PSA level.
   
   

8. What does an increase in PSA level mean for a man who has been treated for prostate cancer?

   If a man’s PSA level rises after prostate cancer treatment, his doctor will consider a number of factors before recommending further treatment. Additional treatment based on a single PSA test is not recommended. Instead, a rising trend in PSA level over time in combination with other findings, such as an abnormal result on imaging tests, may lead a man’s doctor to recommend further treatment.

9. How are researchers trying to improve the PSA test?

   Scientists are investigating ways to improve the PSA test to give doctors the ability to better distinguish cancerous from benign conditions and slow-growing cancers from fast-growing, potentially lethal cancers. Some of the methods being studied include:
   
   • Free versus total PSA. The amount of PSA in the blood that is “free” (not bound to other proteins) divided by the total amount of PSA (free plus bound). Some evidence suggests that a lower proportion of free PSA may be associated with more aggressive cancer.
   • PSA density of the transition zone. The blood level of PSA divided by the volume of the transition zone of the prostate. The transition zone is the interior part of the prostate that surrounds the urethra. Some evidence suggests that this measure may be more accurate at detecting prostate cancer than the standard PSA test.
   • Age-specific PSA reference ranges. Because a man’s PSA level tends to increase with age, it has been suggested that the use of age-specific PSA reference ranges may increase the accuracy of PSA tests. However, age-specific reference ranges have not been generally favored because their use may delay the detection of prostate cancer in many men.
   • PSA velocity and PSA doubling time. PSA velocity is the rate of change in a man’s PSA level over time, expressed as ng/mL per year. PSA doubling time is the period of time over which a man’s PSA level doubles. Some evidence suggests that the rate of increase in a man’s PSA level may be helpful in predicting whether he has prostate cancer.  
   • Pro-PSA. Pro-PSA refers to several different inactive precursors of PSA. There is some evidence that pro-PSA is more strongly associated with prostate cancer than with BPH. One recently approved test combines measurement of a form of pro-PSA called [-2]proPSA with measurements of PSA and free PSA. The resulting “prostate health index” can be used to help a man with a PSA level of between 4 and 10 ng/mL decide whether he should have a biopsy.
   
   

Selected References

1. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. New England Journal of Medicine 2004;350(22):2239-2246.
   [PubMed Abstract]
2. Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. New England Journal of Medicine 2001;344(18):1373-1377.
   [PubMed Abstract]
3. Andriole GL, Crawford ED, Grubb RL, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. Journal of the National Cancer Institute 2012;104(2):125-132.
   [PubMed Abstract]
4. Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. New England Journal of Medicine 2012;366(11):981-990.
   [PubMed Abstract]
5. Moyer VA on behalf of the U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 2012; 157(2):120–134.
   [PubMed Abstract]

Prostate Cancer-Fighting Compound Found in Jamaican Allspice

Essential to jerk seasoning, allspice is known for flavoring Jamaican and other cuisines around the world with a blend of cinnamon, cloves, nutmeg and pepper but, according to a new study by Miller School researchers, the aromatic spice could be known one day for impeding the growth of, or maybe even preventing, prostate cancer, the No. 2 cancer-killer of men in the U.S. In the study published online May 8 in the Oxford Journals’ Carcinogenesis and led by Bal L. Lokeshwar, Ph.D., professor of urology and radiation oncology and Co-Director of Research in the Department of Urology, researchers demonstrated that Ericifolin, a complex compound in the allspice berry, significantly slows the growth of prostate cancer tumors by suppressing the androgen receptor (AR).

A molecule central to the growth and metastasis of prostate cancer, AR enables prostate cancer cells to survive even after hormone therapy, which along with surgery and radiation is the standard treatment for prostate cancer. “Androgen receptor, or AR for short, is the principal drug target for the treatment of prostate cancer, but there is no drug that completely eliminates AR. This complex compound in allspice seems to do that,” Lokeshwar said. “The most interesting data shows that it actually kills tumor cells which express the very specific prostate cancer marker, the androgen receptor. That is not to say that people should start eating allspice with every meal, but there exists the potential that the slow and steady consumption of this chemo-dietary agent may slow or even prevent prostate cancer.” For now, Lokeshwar and his study team, including first author Shamaladevi Nagarajarao, Ph.D., a post-doctoral research associate, and Lei Zhang, a graduate student, have demonstrated that Ericifolin kills prostate cancer cells and reduces tumor growth by more than 50 percent in animal models, specifically mice that were injected with prostate cancer cells, then, either fed or injected daily doses of an aqueous allspice extract. “To our surprise, it worked very well,” Lokeshwar said. “It was surprising because lots and lots of products kill cells in the test tube, but they are not effective when consumed or injected in animal models. In this case, the tumors did not disappear, but they grew about 50 percent more slowly with both methods. Further, these mice did not exhibit any obvious toxicity associated with other anticancer drugs.”

Next the researchers hope to determine whether Ericifolin, a member of the family of polyphenols, the richest source of antioxidants in our diet, can actually prevent prostate cancer from developing altogether. With a $1.5 million NIH grant, they are currently exploring Ericifolin’s anticancer activities — and its translational potential as a cancer chemopreventive agent for humans — in mice that have been genetically programmed to naturally develop prostate cancer at a certain age. They also hope to begin a clinical trial in the near future with UHealth patients who are under active surveillance for early-stage or slow-growing prostate cancer, which does not yet warrant treatment. Since allspice is not toxic, Lokeshwar reasons those patients would be ideal candidates to take Ericifolin as a daily dietary supplement. A biologist who began exploring the feasibility of natural anticancer agents about seven years ago, Lokeshwar turned his sights on allspice at the suggestion of a former research associate, Dominic A. Lyn. A co-author on the study, Lyn happened to be from Jamaica, the world’s No. 1 exporter of allspice, which is the dried, unripe berry of Pimenta dioica, an evergreen tree native to Jamaica. “He said, ‘Let’s try allspice. It’s from Jamaica, and it’s unique,’” Lokeshwar recalled. At the time, there were — and still are — few scientific studies on allspice, but the researchers were intrigued by what they learned: Not only is allspice a popular folk medicine remedy for a number of maladies, but “pound for pound,” Lokeshwar said, “it has the highest amount of antioxidants of any food we know.” Their interest would escalate when they performed some rudimentary experiments with a jar of allspice powder Lyn borrowed from his wife’s kitchen. Turning the powder into a water extract, they applied it to cancer cells and found it inhibited their growth. More elaborate and sophisticated experiments with allspice purified and liquefied in the Lokeshwar lab would produce the same results, first in cells, then in mice. The next step, which would prove harder, was pinpointing which of the hundreds of compounds in allspice blocked the antigen receptor. Fortunately, Nagarajarao mistakenly knocked on Lokeshwar’s door inquiring about a job in a different lab. When Lokeshwar learned she was a chemist and biophysicist, he enlisted her in the hunt. With analysis provided by collaborators in the University of Kentucky’s College of Pharmacy, the team eventually isolated Ericifolin as the anticancer agent.

Prostate Cancer Fighting Compound Found in Jamaican Allspice In an intriguing footnote, Zhang, a student in the Sheila and David Fuente Graduate Program in Cancer Biology, has since demonstrated that their aqueous allspice extract also impedes the growth of breast cancer cells, but with a different polyphenol, not Ericifolin. They are not sure yet which one but, in Lokeshwar’s mind, that discovery raises the possibility that allspice may have many anticancer properties worth exploring. In addition to Lokeshwar, Nagarajarao, Lyn and Zhang, other co-authors of the study, “Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer,” are Khaled A. Shaaban, Ph.D., and Jurgen Rohr, Ph.D., of the University of Kentucky, and Susana Villate, a former research associate in the Department 

This article taken from Science Blog http://scienceblog.com/63595/prostate-cancer-fighting-compound-found-in-jamaican-allspice/

Relationship Between Prostate-specific Antigen, Age, and Body Mass Index in a Prostate Cancer Screening Population

Background: Recent studies questioning the benefit of prostate-specific antigen (PSA) screening have increased the need for evaluating factors contributing to variance in levels and their clinical relevance. An inverse relationship between body mass index (BMI) and PSA has been illustrated, however the clinical implications have not been specified. We performed a retrospective review of patients screened through our free screening clinic to delineate any relationship between PSA and BMI in an attempt to understand its possible clinical significance.

Methods: The authors retrospectively reviewed data collected in relation to PSA values and patient characteristics from a community outreach program supplying information and screening for prostate cancer between June of 2003 and August of 2009.

Results: Mean BMI of our patient population was 28.7 m/kg2 (SD 5.4) and our mean PSA value was 1.28 (SD 1.77). Our data indicate a small, but statistically significant decrease in PSA for an increasing BMI with a 0.026 decrease in PSA for every unit increase in BMI.

Conclusions: Our study confirms the previously reported inverse relationship between PSA value and BMI. The significance of this finding and its impact on the value do not seem to indicate a rationale to change the accepted abnormal value in obese patients and should be used in the context of the clinical scenario and other PSA altering factors.

Pater, Luke E. MD; Hart, Kimberly W. MA; Blonigen, Brian J. MD; Lindsell, Christopher J. PhD; Barrett, William L. MD
American Journal of Clinical Oncology

Seasonal variation in prostate-specific antigen levels: a large cross-sectional study of men in the UK

School of Social and Community Medicine, University of Bristol, Bristol, Oncology Centre, Addenbrooke's Hospital, Cambridge, andNuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Abstract
Study Type - Aetiology (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Evidence for seasonal or climatic effects on PSA levels is mixed and inconclusive. In this large, long-term study, no seasonal or climatic patterns in PSA levels were identified.

OBJECTIVE: To assess whether a seasonal change in prostate specific antigen (PSA) levels can be detected in men recruited to a large clinical trial.

PATIENTS AND METHODS: A total of 66 969 men aged 50-69 years were drawn from a large study conducted at general practices across the UK between 2002 and 2007. Trigonometric algorithms and regression methods were used to assess the relationship between the time of year and serum PSA and blood pressure measurements. We obtained local daily mean temperatures and hours of sunlight per day to assess whether these factors were potential mechanisms for seasonal variation in PSA levels or blood pressure. The proportion of participants who would be considered clinically at risk according to their PSA or blood pressure measurement, by month, was also assessed. The strength of associations between time of year and blood pressure were used to reinforce conclusions from the PSA models.

RESULTS: There was no relationship between time of year and PSA levels (P= 0.11) or between climate and PSA levels (P= 0.42). No difference was found in the prevalence of clinically raised PSA content by month (P= 0.50). This lack of an association with PSA content was despite our data being sufficient to provide clear evidence of an association between blood pressure and time of year (systolic P < 0.001; diastolic P < 0.001), and to show that this association was largely explained by climatic factors (temperature and sunlight).

CONCLUSIONS: There was no pattern in PSA levels by time of year, air temperature or levels of sunlight in this cohort, so there is no need to take these factors into account when reviewing PSA results