Elevated PSA Dr.Nesaretnam Barr Kumarakulasinghe Associate Consultant Medical Oncology National University Cancer Institute, Singapore 9 th July 2017
Issues we will cover today.. The measurement of PSA, causes of abnormal values, and advances in PSA testing, and recommendations for biopsy based on abnormal PSA will be reviewed here. Recommendations for the clinical use of PSA testing in screening for prostate cancer is complicated and will only be covered briefly
Case A 59-year-old white man in good health, with no family history of prostate cancer, visited his primary care physician. His digital rectal examination (DRE) revealed an enlarged prostate without nodules. He previously made an informed decision to undergo prostatespecific antigen (PSA) screening for prostate cancer. His PSA history is displayed in the table.
A 59-year-old white man in good health, with no family history of prostate cancer, visited his primary care physician. His digital rectal examination (DRE) revealed an enlarged prostate without nodules. He previously made an informed decision to undergo prostate-specific antigen (PSA) screening for prostate cancer. His PSA history is displayed in the table.
Indications for serum PSA test What are we trying to diagnose or monitor Prostate cancer of course! To diagnose prostate cancer before it progresses to a stage beyond curability
When do we do it? Screening of asymptomatic individuals for prostate cancer Still controversial General population vs High risk, e.g those with strong family history Part of work up for patients suspected to have prostate cancer E.g Nodular prostate on DRE Part of risk stratification & follow up for patients with known prostate cancer Patients with PSA>20ng/ml high risk of having distant metastasis at diagnosis PSA levels help risk stratify patients to decide on management for early prostate cancer, E.g for observation vs definitive treatment Post radical prostatectomy or radical radiotherapy, patients followed up for recurrence with serial serum PSA Patients with metastatic prostate cancer followed up with serum PSA to assess for response to Androgen Deprivation Therapy
Our focus today is on.. An elevated PSA when used for screening of asymptomatic individuals for prostate cancer Essentially what to do if you find an elevated PSA on screening Total PSA is 4 to 10.0 ng/ml is the range in which decisions regarding further diagnostic testing are most difficult.
Why its complicated? What is normal? What are we trying to diagnose Prostate cancer What is the sensitivity and specificity of serum PSA for diagnosing prostate cancer? What are the non malignant causes of raised PSA How can we improve the sensitivity and specificity of PSA testing to diagnose prostate cancer? Is there a PSA threshold for a prostate biopsy?
Prostate Specific Antigen Glycoprotein produced by prostate epithelial cells Half-life 2.2 days with variable recovery Less PSA is produced in cancerous cells compared to non-cancerous cells However, the disruption in tissue borders / glandular lumen / capillaries increase leakage into the bloodstream Rise in PSA precedes cancer diagnosis by 5-10 years propsa Secreted into prostatic lumen Active PSA Proteolysis Inactive PSA (free) Enters bloodstream PSA secreted by CA cells escape proteolysis
In normal circumstances Secreted into prostatic lumen Proteolysis & enter bloodstream PSA Test Inactive PSA (free) propsa Active PSA Enters bloodstream Active PSA (Bound by ACT & α-2 macroglobulin PSA secreted by CA cells escape proteolysis Free prostate-specific antigen in serum is becoming more complex. Mikolajczyk SD et al, Urology. 2002;59(6):797.
More about PSA 28.4 kda single chain chymotrypsin-like serine protease. Physiological function: liquefaction of semen to promote the release and motility of spermatozoa Prostate cancer is the only malignancy giving rise to elevated PSA in serum However, PSA has been found in cells from various cancer types and different normal tissues Free prostate-specific antigen in serum is becoming more complex. Mikolajczyk SD et al, Urology. 2002;59(6):797.
More about PSA In men without prostate cancer, serum PSA reflects the amount of glandular epithelium, which in turn reflects prostate size. Thus as prostate size increases with increasing age, the PSA concentration also rises; it increases at a faster rate in elderly men Free prostate-specific antigen in serum is becoming more complex. Mikolajczyk SD et al, Urology. 2002;59(6):797.
Serum PSA testing Measures both free and bound PSA in serum Many commercially available sources of PSA antibodies for serum tests Serum PSA measures obtained using different commercial assays are not directly comparable or interchangeable, since the values are calibrated against different standards
What is normal? The operating characteristics of the PSA test for prostate cancer screening depend on the definition of disease. What is the disease we are trying to identify? Prostate adenocarcinoma What is prostate cancer? How do we diagnose it? Not by PSA Based on histology Do all prostate cancers need to be diagnosed or treated? So then what is normal PSA?
What is the sensitivity and specificity of serum PSA in diagnosing Prostate cancer? Ans: Depends on Cut off of normal value e.g 4ng/ml vs 3ng/ml Depends on definition of disease e.g all cancer vs Gleason 7
Total PSA-cutoffs Most commonly used modality Traditional cutoff for abnormal level is 4ng/ml Higher threshold lower sensitivity, chance of missing cancer, but more specific Negative predictive value The Prostate Cancer Prevention Trial, which biopsied men with normal PSA levels, estimated a negative predictive value of 85% for a PSA value 4.0 ng/ml 75% of cancers detected are organ-confined Lower threshold increase sensitivity, but reduce specificity and more unnecessary biopsies Increasing the threshold to >10ng/ml Positive Predictive Value 64% But <50% of cancers detected are confined to the prostate J Urol. 2000;163(3):806. J Urol. 1994;151(5):1283.
Digital Rectal Examination Easily performed Only detects tumours which Are clinically palpable (ct2) Occur in the posterior and lateral aspects of the gland (85% of cases) However, significant inter-operator variability Urology. 1995;45(1):70 Sensitivity 59% Specificity 94% Fam Pract. 1999;16(6):621. Easy to do BUT UNCOMFORTABLE!
PSA<4ng/ml? Patients in the control arm had an end of study biopsy Increasing PSA threshold to >3ng/ml Increases sensitivity of Detecting CA Prostate: 32% Detecting High Grade CA Prostate: 68% Reduces specificity 85% **NO CLEAR CUT-OFF FOR ABNORMAL LEVEL**
But That Means Many Many Biopsies Reducing threshold to >2.5ng/ml would double the number of abnormal PSA levels in US to 6milllion cases a year
What is the sensitivity and specificity of serum PSA for diagnosing prostate cancer? Ans: Depends on the cut PSA cut off and definition of prostate cancer At a PSA threshold greater than 4.0 ng/ml, PSA was 20.5% sensitive and 93.8% specific when any histologic prostate cancer was considered disease. If only cancers with a Gleason score of at least 7 are considered disease, then sensitivity increases to 40.4%, and specificity would be 90.0%.
What is Prostate Adenocarcinoma-Histology Prostatic adenocarcinoma can be diagnosed by the presence of small infiltrating glands with prominent nucleoli. Architecturally, malignant cells form glands that are typically smaller and in an infiltrative and haphazard manner compared to normal.
Prognosis of prostate cancer by gleason 5year RFS 95% 83% 65% 63% 35% If Gleason 7 and above considered cancer serum PSA sensitivity increases to 40.4%, and specificity would be 90.0% Gleason score 6 adenocarcinoma: should it be labeled as cancer? Carter HB, et al, Clin Oncol. 2012
Do all prostate cancers need to be diagnosed Patients with indolent cancer may die with it rather than from it
Diagnose more cancers, but no difference in cancer mortality
PIVOT Trial This finding implies the PSA level at which prostate cancers progress beyond curability may be higher than the commonly used threshold of Compared radical prostatectomy vs observation in 13 022 men 43% low risk, 36% medium risk, 20% high risk No difference in All-Cause or CA Prostaterelated Mortality Reduced All-Cause Mortality in subgroup with PSA>10ng/ml greater than 4 ng/ml
Why its complicated- Changes with age &race Age Group (years) Age-specific Reference Range (ng/ml) 40-49 0-2.5 50-59 0-3.5 60-69 0-4.5 70-79 0-6.5 Age Group (years) Reference Range for Whites (ng/ml) 40-49 0-2.5 0-2 50-59 0-3.5 0-4 60-69 0-4.5 0-4.5 70-79 0-6.5 0-5.5 Reference Range for Blacks (ng/ml) Applying age-specific reference ranges would Miss 47% of clinically localised cancers in >70 years Increase number of unnecessary biopsies for men 50-60 years J Urol. 1994;152(6 Pt 1):2037 Blacks were also found to have similar or worse disease stage and grade compared to white men with similar PSA ranges J Urol. 2000;163(1):146.
Effect of weight on PSA Increasing body mass index (BMI) is associated with a mean PSA concentration which is up to 20% lower. Possibly due to increased plasma volume in men with higher BMI leading to hemodilution of the PSA. One study looked at total mass of PSA in the blood (PSA concentration multiplied by plasma volume) Despite having lower PSA concentrations, men with higher BMI had a similar amount of circulating PSA mass as men with lower BMI Bañez LL et al, Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA. 2007;298(19):2275.
Effect of medications- Falsely low PSA Source: UTD
Why its complicated- Random Variation In men with serial PSA concentration below 2.0 ng/ml average analytic variation in PSA was approximately 6% average biologic variation was less than 14%. 25% of men with initial PSA levels between 4 and 10 ng/ml had normal PSA values on repeat testing A change in PSA of more than 30% in men with a PSA initially below 2.0 ng/ml likely to indicate a true change Assessment of intra-individual variation in prostate-specific antigen levels in a biennial randomized prostate cancer screening program in Sweden. Bruun L, Becker C, Hugosson J, Lilja H, Christensson A Prostate. 2005;65(3):216.
Benign conditions with elevated PSA Condition Rise in PSA Recovery Period DRE 0.26-0.4ng/ml 48H Digital rectal examination (DRE) has Ejaculation 0.8ng/ml 48H minimal effect on PSA levels Bacterial prostatitis Variable 6-8 weeks Prostate biopsy 7.9ng/ml 2-4 weeks TURP 5.9ng/ml 3 weeks Acute Urinary Retention Variable 2 weeks UTD
Alternatives to Improve on PSA? Serial PSA Measurements Reduces the Detection Rate- reduces overdiagnosis PLCO: 14.2/1000 to 9.3/1000 men ESRPC: 5.1% to 4.4% Reduces the PPV PLCO: 44.5% to 34.9% ESRPC: 29.2 to 19.9% Increases the likelihood that detected tumours will be organ-confined and moderate or well-differentiated PLCO 94.2% to 98.5% ESRPC: 81.5% to 96.3% BJU Int. 2008;102(11):1524. PLCO NEJM 2009 ERSPC NEJM 2009
Alternatives to Improve on PSA? PSA Velocity Baltimore Longitudinal Study of Aging Specificity of PSA Velocity >0.75ng/ml/year increased to 90% compared to 60% for conventional PSA testing J Urol. 1997;157(6):2183.
Alternatives to Improve on PSA? PSA velocity PSA was <4 ng/ml, a PSA velocity >0.35 ng/ml per year measured over several years was associated with a high risk of death from prostate cancer 15 years later Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. Carter HBt al, J Natl Cancer Inst. 2006;98(21):1521.
Alternatives to Improve on PSA? Free PSA Ratio of Free / Total PSA is lower in CA Prostate Increases the detection rate of men with PSA 4-10 from 25% to 56% with a ratio <10% Single cut-off point: <25%, 95% detection rate but reduced unnecessary needle biopsy by 20% Urology. 2006;67(4):762
Free PSA % free PSA % cancer probability 0-10 56 10-15 28 15-20 20 20-25 16 >25 8 Hayes JH, Barry MJ. Screening for prostate cancer with the prostate-specific antigen test: a review of current evidence. JAMA. 2014;311(11): 1143-1149.
Alternatives to Improve on PSA? PSA Density Prostate CA associated with 10x more PSA per volume of prostatic tissue compared to benign condition Logistical problem TRUS / MRI Operator dependent Commonly recommended threshold of 0.15ng/ml/cm3 misses 50% of CA in men with PSA 4-10ng/ml Improves with adjustment of the cutoff value for different ranges of total PSA: 0.1 ng/ml/cc for total PSA 4 to 10 ng/ml 0.19 ng/ml/cc for total PSA 10 to 20 ng/ml J Urol. 1994;152(6 Pt 1):2031.
Prostate Cancer prevention Trial Risk calculator 2.0 Risk of negative biopsy vs low grade/high grade prostate cancer based on Race Ethnicity Age PSA level family history DRE
Risks of PSA screening Risk of biopsy unnecessary prostate biopsies, cost and morbidity Overdiagnosis Patients who are diagnosed with slow-growing disease whom will not derive any benefit from therapy Estimates of overdiagnosis in US annually Whites: 23-29% African-Americans: 34-44% Overtreatment Treatment of CA that, if undetected, would not cause harm Estimated 20-40% annually in the US Etxioni 2002; Telasca 2008
Problems with Screening There s no consensus on optimal treatment of organ confined disease Watchful waiting Active surveillance Radical prostatectomy EBRT Between 1986-2005 1 million more US men had surgery / RT / both compared to before J Natl Cancer Inst. 2009;101:1325-9.
Fight of the 2 Continents
MOH Guidelines 2010
Summary Discuss pros and cons of doing serum PSA testing in the first place before ordering Elevated PSA can be from many causes, can be non malignant. Exclude them
Summary Can improve test performance with Serial PSA Free PSA PSA velocity and density Online risk calculator
Summary No specific cut off to decide on referring for biopsy Lower threshold increase sensitivity, but reduce specificity and more unnecessary biopsies Higher threshold lower sensitivity, chance of missing cancer Generally traditional threshold of 4ng/ml is a good balance between risks and benefits in the average patient Elevated PSA should be repeated within short weeks, and referred for biopsy if still elevated Risk of screening can be limited with current recommendations favoring close monitoring of very low risk disease
A 59-year-old white man in good health, with no family history of prostate cancer, visited his primary care physician. His digital rectal examination (DRE) revealed an enlarged prostate without nodules. He previously made an informed decision to undergo prostate-specific antigen (PSA) screening for prostate cancer. His PSA history is displayed in the table.