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  • 1. Subject seminarTopic: Screening of CarcinomaProstateChair person: Prof. C. S. RatkalCo chair person: Dr. M. ShivalingaiahPresenter: Dr. Prakash. H. S.
  • 2. Screening Definition - the search for unrecognizeddisease or defect by means of rapidly appliedtests, examinations or other procedures inapparently healthy individuals Three types of screening have been describeda. Mass screening ( population screening)b. High risk or selective screeningc. Multiphasic screening
  • 3. Population screening Is where a test is offered to all individuals in atarget group, usually defined by age, as part ofan organized programme Have to be high standard. Services are checked and monitored bypeople from outside the programme. Everyone who takes part is offered the sameservices, information and support. Large numbers of people are invited to takepart
  • 4. Requirements for a populationscreening program The screening program should provide morebenefit than harm to the people beingscreened. The condition should– be an important health problem.– have a recognisable latent or early asymptomaticstage.
  • 5. The screening test should - Find the early stages of the disease (be highlysensitive) Very accurate in finding the early stages ofdisease (be highly specific) Provide consistent results from the test (bevalidated) Safe. Find most disease present at the time of thescreening test (have a relatively high positivepredictive value) Normal when there is no disease present (havea relatively high negative predictive value )
  • 6. Gold standard test
  • 7. True positive & True negative True positives = number of individuals withdisease and a positive screening test (a) False positives = number of individualswithout disease but have a positivescreening test (b) False negatives = number of individualswith disease but have a negativescreening test (c) True negatives = number of individualswithout disease and a negative screening
  • 8. Sensitivity & Specificity Sensitivity is defined as the ability of the test todetect all those with disease in the screenedpopulation Specificity is defined as the ability of thetest to identify correctly those free ofdisease in the screened population
  • 9. PPV and NPV
  • 10. PPV AND NPV… The positive predictive value (PPV) describesthe probability of having the disease given apositive screening test result in the screenedpopulation (The proportion of patients who testpositive who actually have the disease) The negative predictive value (NPV) describesthe probability of not having the disease givena negative screening test result in thescreened population (The proportion ofpatients who test negative who are actuallyfree of the disease)
  • 11. The screening test should be Minimally invasive, Easily available and performed, Acceptable to the general population, Cost effective Significantly affect the outcome of thedisease, such as quality of life and mortality.
  • 12. Population screening is associatedwith 3 biases Detection bias – (Overdiagnosis ) refers toidentification of disease in patients in whom itwould have never become symptomatic duringtheir lifetime Lead-time bias - refers to earlier diagnosis but noeffect on mortality. It gives the appearance oflonger survival because of earlier detection withno overall improvement in life expectancy Length bias - Detects less aggressive diseasedue to the longer interval before it becomessymptomatic
  • 13. Epidemiology of Carcinomaprostate Prostate cancer is the fifth most commonmalignancy worldwide and the second mostcommon in men Makes up 11.7% of new cancer cases overall(19% in developed countries & 5.3% indeveloping countries) Incidence varies widely between countries andethnic populations (more than 100-fold) Lowest yearly incidence rates in Asia (1.9) &highest in North America ( 249 per 100,000)
  • 14. Epidemiology of Carcinomaprostate… Mortality also varies widely among countrieshighest in the Caribbean (28 per 100,000 peryear) & lowest in Southeast Asia, China, andNorth Africa (<5 per 100,000 per year) Prostate cancer is rarely diagnosed in menyounger than 50 years old, accounting for only2% of all cases The median age at diagnosis is 68 years, with63% diagnosed after age 65
  • 15. Epidemiology of Carcinomaprostate… Incidence of prostate cancer in men 50 to 59years of age has increased by 50% between1989 &1992 due to PSA testing (agemigration) Also incidence of loco-regional disease hasincreased, whereas the incidence ofmetastatic disease has decreased (stagemigration)
  • 16. Carcinoma prostate in UnitedStates Is the most common visceral malignancy inmen. Is the second leading cause of cancer-relateddeaths. The estimated lifetime risk of disease is16.72%, with a lifetime risk of death at 2.57%. Incidence peaked in 1992 approximately 5years after the introduction of PSA as ascreening test, declined until1995, subsequently increased at a rate similarto that observed in the pre-PSA era, and isdeclining again in recent years
  • 17. Carcinoma prostate in UnitedStates… Mortality has declined since 1991 and forwhites is now lower than before PSA wasintroducedData from American Cancer Society. Cancer facts and figures 2008
  • 18. India versus United StatesAge adjusted incidences (per 100,000 personyears) of prostate cancerCountries1973-1977 1988-1992% change1977-19922002TotalIncidenceTotal Incidence IncidenceUS black 2664 79.9 7129 137 71.5US total124.8US white 24192 47.9 66,227 100.8 110.4India 193 6.8 764 7.9 16.2 4.6
  • 19. Screening for Carcinomaprostate Two types- Population screening- Early detection or opportunistic screening Early detection or opportunistic screeningcomprises individual case findings, which areinitiated by the person being screened(patient) and/or his physician.- Screening may not be checked ormonitored
  • 20. Primary endpoint of both types ofscreening Has two aspects:o Reduction in mortalityo Improvement in the quality of life asexpressed by quality-of-life adjustedgain in life years (QUALYs).
  • 21. The goals of population screeningfor carcinoma prostateFall into three categories Reduction of prostate cancer mortality Reduction of morbidity associated withprostate cancer Reduction of financial costs associated withsymptomatic prostate cancer
  • 22. Modalities of Screening DRE PSA Prostate Biopsy Transrectal Ultrasound Magnetic Resonance Imaging
  • 23. Modalities of Screening… The combination of DRE and serum PSA isthe most useful first-line screening test Prostate Biopsy is not recommended as a first-line screening test because of low predictivevalue for early prostate cancer and high cost ofexamination TRUS has poor sensitivity (71%) & specificity(50%) MRI also has poor sensitivity ( 57%) asscreening modality in Ca prostate
  • 24. Digital Rectal Examination Before the availability of PSA, physiciansrelied solely on DRE for early detection ofprostate cancer Has fair reproducibility Misses a substantial proportion of earlycancers PSA improves the positive predictive value ofDRE for cancer (tests are complementary andare recommended in combination) DRE and PSA do not always detect the samecancers
  • 25. Digital Rectal Examination… The optimal role of the DRE for the earlydetection of prostate cancer is unclear DRE performed poorest at the PSA levels atwhich it was needed the most. the sensitivityand PPV of the DRE were only 20% and 8.8%,respectively, in men who had PSA values 3.0ng/mL. With PSA values below 4.0ng/mL - only 17%of prostate cancers were diagnosed by DREalone.
  • 26. DRE Limitations are First, the sensitivity and specificity of the DRE dependon the examiner. Second, although some cases are detectable in menwith low PSA levels, the lethal potential of these cancersis uncertain Third, DRE may be a barrier to screening for some men. Finally, the capacity to detect clinically importantprostate cancers by DRE depends on the PSAthreshold used to perform a prostate biopsy.• The lower the biopsy threshold, the less likely that DREwill detect important prostate cancers that would bemissed by PSA.• Conversely, as the threshold is raised, the potentialvalue of the DRE goes up.
  • 27. Trans rectal Ultrasound Limitations of TRUS in prostate cancer detectionare• Most hypoechoic lesions found on TRUS arenot cancer• 50% of nonpalpable cancers more than 1 cm ingreatest dimension are not visualized byultrasonography Therefore, any patient with a DRE suspicious forcancer or a PSA elevation should undergoprostate biopsy regardless of TRUS findings ifan early diagnosis of cancer would result in arecommendation for treatment
  • 28. Trans rectal Ultrasound… The performance characteristics of TRUS inpopulations with low prevalence of prostatecancer are not conducive to its use forscreening. TRUS is an invasive test that also suffers fromoperator dependent variability. Various modifications such as power DopplerTRUS have not attained significantimprovement in sensitivity to justify its use as ascreening tool
  • 29. Screening by PSA Most widely used modality for populationscreening of Prostate cancer Approved as serum tumor marker in 1986 byFDA American Cancer Society from early 1990sadvocated screening by PSA testing PSA is prostate specific and not cancerspecific Specificity improves at higher PSA thresholdswhile sensitivity declines significantly
  • 30. Prostate-Specific Antigen (PSA) PSA is a 33-kD glycoprotein, produced by theprostatic luminal epithelial cells. PSA is secreted in high concentrations (0.5-5.0 mg/mL) into seminal fluid, where it isinvolved in liquefaction of the seminalcoagulum Found in low concentration in serum (1.0-4.0ng/mL). Circulates in bound (complexed) and unbound(free) forms - measured by assays
  • 31. Arguments for screening byPSA Men who had PSA testing had a 20 percentlower chance of dying from prostate cancerafter nine years, compared to men who did nothave prostate cancer screening Substantial number of men die from prostatecancer every year and many more suffer fromthe complications of advanced disease For men with an aggressive prostatecancer, the best chance for curing it is byfinding it at an early stage and then treating itwith surgery or radiation
  • 32. Arguments for screening…. The five-year survival for men who haveprostate cancer confined to the prostate gland(early stage) is nearly 100 percent; this dropsto 30 percent for men whose cancer hasspread to other areas of the body. The available screening tests are notperfect, but they are easy to perform and arefairly accurate.
  • 33. Arguments for screening…. Screening decreases the burden of distant-stage disease (Stage migration) US Surveillance, Epidemiology and Endresults (SEER) data shows incidence rates forstage T3–4 prostate cancer were 55.5 per100,000 in 1988–1989, 44.6 per 100,000 in1996–1997, and decreased to 8.4 per 100,000in 2004–2005 PSA screening seemed to account for 80% ofthe observed drop in distant-stage disease.
  • 34. Arguments for screening…. Grade migration in the PSA era has generatedconsiderable controversy Incidence of Gleason score 8–10 prostatecancer on biopsy has decreased from 47.5 per100,000 in 1988–1989 to 38.3 per 100,000 in2004–2005 Screening finds lower grade cancers thanwould be found in the absence ofscreening, but when cancers are found theyare assigned a higher Gleason score than theywould have received in the pre-PSA era
  • 35. Arguments against screening Only one man in every 1400 benefited fromPSA testing 75 percent of men with an abnormal PSA whohad a prostate biopsy did not have prostatecancer A large American study did not find thatprostate cancer screening reduced the chanceof dying from prostate cancer Many prostate cancers detected withscreening are unlikely to cause death ordisability
  • 36. Arguments against screening… Population screening initiatives carry asignificant risk of overdiagnosis Overdiagnosis refers to identification of latentdisease that would not have otherwise causedsymptoms or been identified during thepatient‘s lifetime (In US it is upto 23% to 42%) Overtreatment leads to unnecessary costs tothe health care system, and significantmorbidity and possible mortality to somepatients exposed to curative treatment
  • 37. Arguments against screening… Earlier detection of prostate cancer introducesthe problem of detection and treatment ofindolent tumors Indolent tumors are generally defined as smalltumors (<0.5 cm3), that are well differentiated(Gleason grade 1 or 2) or noninvasive, andlack the propensity to penetrate beyond theprostatic capsule Up to 30% of all cases of PSA-detected (stageT1c) prostate cancer are indolent tumors
  • 38. Arguments against screening… Most patients experience some deterioration inthe QOL as measured by sexual function,urinary incontinence, urinary irritation orobstruction, bowel or rectal function, andvitality Considering the morbidity of treatment asevidenced by deterioration of QOL for patientsand their spouses and the significantovertreatment associated with prostate cancer,the overall benefit of PSA screening isuncertain
  • 39. Pros and Cons of PSAscreeningPros ConsStage migration: morelocalized disease, and lessadvanced/metastaticdiseaseIncidence of indolent tumorsEarlier at diagnosis Problems associated withoverdiagnosis and treatmentLower PSA at diagnosis Lead-time and length-timebiases in survival rates inPSA eraImproved survival in thePSA eraIdeal PSA cut off forscreening unknown
  • 40. Effect on mortality From 1993 to 2003 after the onset ofwidespread PSA testing, the mortality ratefrom prostate cancer declined by 32.5%(Surveillance, Epidemiology, and End Results[SEER] Program), along with a 75% reductionin the proportion of advanced-stage disease atdiagnosis PSA screening is accounted for 45% to 70% ofthis reduction in prostate cancer mortality inthe United States
  • 41. Factors Influencing PSA PSA levels vary with age, race & prostatevolume Blacks without prostate cancer have higherPSA values than whites PSA increases 4% per milliliter of prostatevolume 30% and 5% of the variance in PSA can beaccounted for by prostate volume andage, respectively PSA expression is strongly influenced byandrogens
  • 42. Factors Influencing PSA… The presence of prostate disease (prostatecancer, benign prostatic hyperplasia[BPH], and prostatitis) is the most importantfactor affecting serum PSA levels Not all men with prostate disease haveelevated PSA levels, and PSA elevations arenot specific for cancer PSA elevations occur from disruption of thenormal prostatic architecture, allowing PSA togain access to the circulation
  • 43. Factors Influencing PSA… PSA is elevated in the setting of prostatedisease (BPH, prostatitis, prostate cancer) andwith prostate manipulation (e.g., prostatemassage, prostate biopsy, transurethralresection) DRE can lead to slight increases in serumPSA, the resultant change in PSA falls withinthe error of the assay and rarely causes false-positive tests
  • 44. Factors Influencing PSA… Prostate-directed treatments (for BPH orprostate cancer) can lower serum PSA bydecreasing the volume of prostatic epitheliumavailable for PSA production and bydecreasing the amount of PSA produced percell 5α-Reductase inhibitors that are used for BPHtreatment have been shown to lower PSAlevels, including both type 2 isoenzymeinhibitors (finasteride) and dual type 1 and 2isoenzyme inhibitors (dutasteride)
  • 45. Factors Influencing PSA… Prostate cancer treatments (medical orsurgical), such as manipulation of thehormonal axis (e.g., luteinizing hormonereleasing hormone (LHRH) agonists,orchiectomy), radiation therapy, and radicalprostatectomy lead to reductions in PSA The interpretation of PSA values shouldalways take into account age, the presence ofurinary tract infection or prostate disease,recent diagnostic procedures, and prostate-directed treatments
  • 46. Clinical use of PSADistribution(%) of PSA levels in men age 50years and older in an invitational screeningstudy
  • 47. Clinical use of PSA… Measurement of free and complexed PSA byassays is referred to as the serum PSA level Use of PSA increases the detection of prostatecancers that are more likely to be organ-confined when compared with detectionwithout PSA Observational studies and randomized trialshave shown that both the future risk ofprostate cancer and the chance of findingcancer on a prostate biopsy increaseincrementally with the serum PSA level
  • 48. Relative Risk of Subsequent Prostate CancerDiagnosis after an Initial Baseline PSA
  • 49. Clinical use of PSA… PSA is directly associated with the present riskof prostate cancer Predicts the future risk The probability of detecting prostate cancer onbiopsy increases directly with PSA across thefull spectrum of PSA levels When a PSA cutoff of 4 ng/mL and anabnormal DRE were used together asscreening criteria for prostatecancer, pathologically organ-confined diseasewas found in 71% of men who underwentsurgery for prostate cancer
  • 50. Clinical use of PSA… When DRE and PSA are used as screeningtests for prostate cancer detection, detectionrates are higher with PSA than with DRE andhighest with a combination of the two tests This is becauseo They do not always detect the same cancerso The tests are complementaryo And are therefore recommended incombination
  • 51. PSA increases lead time With the widespread use of PSA, a stage shiftfavouring localized disease occurred becausePSA increases the lead time for prostatecancer detection Lead time is the time by which the diagnosis ofprostate cancer is advanced by screening Estimates of lead time based on screenedpopulations, are in the range of 10 years
  • 52. PSA limitations It is organ specific and not disease specific There is an overlap in the serum PSA levelsamong men with cancer and those with benigndisease Because PSA elevations are associated withboth false-negative and false-positive results,a great deal of effort has been devoted toimproving the performance characteristics ofthe test
  • 53. Approaches for Improving PSATest Performance The use of PSA thresholds depending on ageand ethnicity The PSA density and PSA transition zonevolume index PSA velocity
  • 54. PSA threshold for prostatebiopsy Data from the PCPT clearly show that the riskof prostate cancer is continuous as PSAincreases The use of higher PSA thresholds risksmissing important cancers during the windowfor cure, whereas the use of lower thresholdsincreases the proportion of unnecessarybiopsies & overdiagnosis Many clinicians now use lower thresholds (2.5to 3 ng/mL) to do a biopsy
  • 55. PSA threshold… PSA cutoff -o 4.0 ng/mL for men age 50 to 70 years (thetarget population for screening at present) &o 2.5 ng/mL for men age 40 to 50 years hassensitivity of 95% The use of a PSA threshold of 4.0 ng/mL formen older than 50 years has been acceptedby most clinicians as striking a reasonablebalance
  • 56. PSA threshold… Regardless of the threshold chosen, anisolated PSA elevation should beremeasured before performing a prostatebiopsy because of fluctuations in PSA thatcould represent a false-positive elevationin the test
  • 57. Volume Based PSA parameters Distinguishing between men who have PSAelevations driven by BPH or cancer is difficultbecause PSA is not specific for cancer and theprevalence of BPH in the population is highcompared with prostate cancer
  • 58. Volume Based PSAparameters… Volume-based PSA parameters (with prostatevolume determined by ultra-sonography)includeso PSA density (PSA divided by prostate volume),o complexed PSA density (complexed PSAdivided by prostate volume), ando PSA transition zone index (PSA divided bytransition zone volume)- have been evaluatedas methods for excluding men with PSAelevations related to BPH
  • 59. Volume Based PSAparameters… PSA density of 0.15 or greater was proposedas a threshold for recommending prostatebiopsy in men with PSA levels between 4 and10 ng/mL and no suspicion of cancer on DREor TRUS The major determinant of serum PSA in menwithout prostate cancer is the transition zoneepithelium
  • 60. Volume Based PSAparameters… Because BPH represents an enlargement ofthe transition zone, adjusting PSA for transitionzone volume has been evaluated as a methodto help distinguish between BPH and prostatecancer Recommended cutoffs of 0.23 ng/mL/cm3when transition zone volume was above 20cm3 and 0.38 ng/mL/cm3 when transition zonevolume was below 20 cm3 as a thresholdabove which prostate cancer was more likely
  • 61. PSA velocity Substantial changes or variability in serumPSA can occur between measurements in thepresence or absence of prostate cancer The changes in serum PSA can be adjusted(corrected) for the elapsed time between themeasurements, a concept known as PSAvelocity or rate of change in PSA
  • 62. PSA velocity - Baltimore LongitudinalStudy of Aging (BLSA) -1992 by Carter There was a gradual and slow increase in PSAover time in most men. PSA increased more rapidly among men withprostate cancer The rate of increase was the greatest, in menwith the most aggressive tumors A rate of increase in PSA 0.75 ng/mL per yearwas associated with a higher risk of prostatecancer
  • 63. PSA velocity… The minimal length of follow-up—time overwhich changes in PSA should be adjusted—forPSA velocity to be useful in cancer detectionhas been calculated in separate studies to be18 months Evaluation of three repeated PSAmeasurements, to determine an average rateof change in PSA, would appear to optimizethe accuracy of PSA velocity for cancerdetection
  • 64. Free PSA Men with prostate cancer have a -o Greater fraction of serum PSA that iscomplexed to protease inhibitorso Lower percentage of total PSA that is free A free/total PSA cutoff of 0.18 (18% free/totalPSA) significantly improved the ability todistinguish between cancer and noncancersubjects as compared with use of total PSAalone
  • 65. Complexed PSA There is general agreement that at highsensitivity, complex PSA provides• Higher specificity compared with total PSA and• Comparable specificity to the percentage offree PSA in prostate cancer detection. The potential advantage of complex PSA as ascreening modality is the requirement for oneassay
  • 66. pPSA & truncated pPSA PSA is secreted from the prostatic luminalepithelium in a precursor or zymogen form(pPSA or proPSA) with a 7-amino-acid leadersequence and then either -o Cleaved by hK2 to active free PSA oro Partially cleaved into isoforms of free PSAwith 2- or 4-amino-acid leader sequences
  • 67. pPSA & truncated pPSA… The native form of pPSA and the truncated orclipped forms of pPSA are elevated in thetissue and blood of patients with prostatecancer compared with those without thedisease. These novel markers have the potential toimprove the accurate identification of men withcancer and the identification of those withmore aggressive disease
  • 68. Summary - Improving PSA testperformance PSA-D > 0.15 ng/mL/cc3 consideredsuspicious for Carcinoma prostate Cutoff of 0.23ng/ml/cm3 when transition zoneabove 20cm3 & 0.38ng/ml/cm3 when below20cm3 PSA-V >0.75ng/mL per year – seen inCarcinoma Proportion of ―complexed‖ PSA (PSA-ACT) to―free‖ PSA (F-PSA) is higher in CarcinomaProstate patients ( free/total PSA cutoff of0.18)
  • 69. hK2. hK2 is a closely related serine protease in thePSA/kallikrein gene family that has also beenevaluated for prostate cancer detection Expression of hK2 is higher in more poorlydifferentiated cancer tissues than in normaland benign tissues hK2 does appear to correlate directly withgrade and cancer volume and could be usefulin patient assessment after diagnosis
  • 70. Prostate cancer gene 3 (PCA-3) PCA-3 is a noncoding prostate-specific mRNAoverexpressed in prostate cancer tissuecompared with benign tissue Urine assays have been developed tomeasure PCA-3 mRNA, which is associatedwith the likelihood of a positive initial or repeatprostate biopsy
  • 71. Future of biomarkers In the future, it is likely that panels ofbiomarkers will be used in combination withstandard measures of risk (age, familyhistory, race) to selectively identify men whoshould undergo further evaluation for thepresence of prostate cancer
  • 72. Randomized trailsTwo large-scale randomized trials are - The Prostate, Lung, Colorectal, and Ovary(PLCO) cancer trial of the National CancerInstitute (NCI) The European Randomized Screening forProstate Cancer (ERSPC) trial
  • 73. Other RCT‘s are Prostate cancer prevention trail (PCPT) Norrkoping trial (with 20 years follow up) Quebec trial (with 11 years follow up) Stockholm trial (with 15 years follow up)
  • 74. Randomized trails… Designed to evaluate the effectiveness ofscreening for prostate cancer by comparingindividuals assigned to a screened arm withthose in a control arm who are not screened Both the PLCO and ERSPC have a commonendpoint - ‗prostate cancer specific mortality‘for assessing effectiveness of screening
  • 75. PLCO• Inclusion criteria– Age 55–74 (76,693)– Multi-institutional trial (across 10 study centres inUSA)• Exclusion criteria– History of prostate, lung, colon or ovarian cancer– More than 1 PSA test in the previous 3 year
  • 76. PLCO – Study design Enrollment 1993–2001 Annual PSA for 6 years; DRE for 4 years -intervention arm Community standard of care or no screening forcontrol group PSA >4 ng/mL- cutoff value Primary care physicians notified of the screeningtest (PSA and DRE) results Management based on community standard ofcare. No protocol for biopsy or treatment ofprostate cancer -community standard of care
  • 77. PLCO - Results The incidence of prostate cancer per 10,000person-years was 116 (2,820 cancers) in thescreening group & 95 (2,322 cancers) in thecontrol group No reduction in incidence of advanced cancer The incidence of death attributed to prostatecancer per 10,000 person-years was 2.0 (50deaths) in the screening group and 1.7 (44deaths) in the control group No difference in survival between screenedand non-screened arms at 7–10 years
  • 78. PLCO - Limitations Rate of compliance in the screening arm was85% for PSA testing and 86% for DRE. Rate of contamination in the control arm wasas high as 40% in the first year and increasedto 52% in the sixth year for PSA testing &ranged from 41% to 46% for DRE Biopsy compliance was only 40-52% versus86% in the ERSPC. Thus, the PLCO trial will probably never beable to answer whether or not screening caninfluence prostate cancer mortality
  • 79. ERSPC Inclusion criteria– Age 55–69 yrs (162243)– Collection of 7 European trials with differentscreening protocols, different ages of entry,controls (Across 9 countries - Netherlands, Belgium,Sweden, Finland, Italy, Spain, Switzerland, Portugal &France) Exclusion criteria– History of prostate cancer
  • 80. ERSPC - Study design Enrollment 1991–2003 PSA screening once every 4 years -intervention arm Control - no screening PSA >3 ng/mL cutoff value No protocol for treatment of prostate cancer -community standard of care
  • 81. ERSPC - Results 20% reduction in prostate cancer specific death inthe screened group at 9 years of follow-up. Nooverall survival difference between the screened& control Reduction in incidence of advanced cancer byscreening 1410 men screened and 48 men treated toprevent 1 mortality from prostate cancer False-positive PSA accounted for 75.9% ofbiopsies. PPV of biopsy was 24.1% 8.2% in the screening group and 4.8% in control
  • 82. ERSPC - Limitations Suboptimal treatment with low dose RT Screened men were 2.77 times more likely toundergo RP vs controls No information on possible control groupcontamination. Possible differences in management protocolsbetween groups make it difficult to separatebenefit from screening vs subsequentmanagement
  • 83. ERSPC - Benefit Real benefit will only be evident after 10-15years of follow-up, especially because the41% reduction of metastasis in the screeningarm will have an impact With longer follow-up, the Goteborgrandomized population-based screening trialreported a greater mortality benefit withscreening
  • 84. PLCO versus ERSPC PLCO compares PSA screening in acommunity practice setting versus anorganized screening program ERSPC investigates the use of PSA screeningin a best practice model (no screening versusscreening) PLCO study shows that more versus lessscreening makes little difference tomortality, whereas the ERSPC shows thatscreening versus not screening reducesprostate cancer mortality, albeit with a potentialrisk of overdiagnosis
  • 85. Prostate Cancer Prevention Trial (PCPT) Only trial that conducted a prostate biopsy forall participants at the end of the trial period andallows the reporting of true sensitivity of PSAat different cutoff values 114 Men who had PSA levels 3.0 ng/mL andnormal DRE results were included at baseline The men underwent annual PSA and DRE andwere recommended for a prostate biopsy if thePSA level was above 4.0 ng/mL or if their DREwas abnormal
  • 86. Prostate Cancer Prevention Trial (PCPT) At the end of the 7-year follow-up period, allmen without a diagnosis of prostate cancerunderwent a prostate biopsy Relatively low prostate cancer detectionsensitivities of 20.5% and 32.2% werereported for PSA cutoff values of 4.0 ng/mLand 3.0 ng/mL, respectively However, the sensitivity of PSA for aggressiveprostate cancer (Gleason grade8 or higher)was greater (51% and 68% for PSA values 4.0ng/mL and 3.0 ng/mL, respectively)
  • 87. Prostate Cancer Prevention Trial (PCPT)
  • 88. PCPT… Lowering the PSA test cutoff to 3.0 ng/mL -results in higher estimates for test positivityand prostate cancer detection rates but at acost of lower specificity and PPV Resulting in increases in false-positive screenresults, prostate biopsies, and diagnosis ofcancers that would never have becomeimportant clinically if they were left undetected
  • 89. GUIDELINES FOR EARLY DETECTIONOF PROSTATE CANCER Detection guidelines determine the burden ofscreening of the population in terms of• Unnecessary tests,• False-positive tests• Downstream effects of false-positive testing
  • 90. GUIDELINES FOR EARLY DETECTIONOF PROSTATE CANCER… The age at which screening should begin Rescreening intervals The age at which screening should bediscontinued are important in designing a cost-effective screening strategy
  • 91. U.S. Preventive Services TaskForce Routine screening for prostate cancer usingPSA testing or digital rectal examination (DRE)was not recommended for men over 75 andthat the evidence was insufficient torecommend for or against screening for menunder 75 years old
  • 92. National Comprehensive Cancer Network(NCCN) Baseline PSA test and DRE at ages 40 and 45 Annual PSA testing and DRE beginning at age50 through age 80, along with information onthe risks and benefits of screening At age 40 for African-American men, men witha family history of prostate cancer & men witha PSA ≥ 0.6 ng/mL (at age 45 if PSA <0.6 ng/mL)
  • 93. NCCN… Biopsy is recommended- if DRE is positive or PSA ≥ 4 ng/mL Biopsy considered- if PSA > 2.5 ng/mL- or PSA velocity ≥ 0.35 ng/mL/year whenPSA ≤ 2.5 ng/mL
  • 94. AUA PSA test should be offered to well-informedmen aged 40 yrs or older who have a lifeexpectancy of at least 10 yrs AUA does not recommend a single PSAthreshold at which a biopsy should beobtained. The decision to biopsy should take intoaccount additional factors, including free andtotal PSA, PSA velocity and density, patientage, family history, race/ethnicity, previousbiopsy history and co-morbidities
  • 95. EUA A baseline PSA determination at age 40 yearshas been suggested upon which thesubsequent screening interval may then bebased A screening interval of 8 years might beenough in men with initial PSA levels ≤ 1ng/mL PSA testing is not necessary in men olderthan 75 years and a baseline PSA ≤ 3 ng/mLbecause of their very low risk of dying fromprostatic carcinoma
  • 96. American Cancer Society(ACS) Asymptomatic men who have at least a 10-year life expectancy have an opportunity tomake an informed decision , after receivinginformation about• The uncertainties• Risks &• Potential benefits associated with prostatecancer screening Prostate cancer screening should not occurwithout an informed decision-making process
  • 97. ACS… Men at average risk should receive thisinformation beginning at age 50 years Men at higher risk, including African Americanmen and men who have a first-degree relative(father or brother) diagnosed with prostatecancer before age 65 years, should receivethis information beginning at age 45 years Men at appreciably higher risk (multiple familymembers diagnosed with prostate cancerbefore age 65 years) should receive thisinformation beginning at age 40 years
  • 98. ACS…For men who choose to be screened- Screening is recommended with PSA with orwithout DRE Screening should be conducted yearly formen whose PSA level is 2.5 ng/mL or greater For men whose PSA is less than 2.5 ng/mL,screening intervals can be extended to every 2years.
  • 99. ACS… A PSA level of 4.0 ng/mL or greater - used torecommend referral for further evaluation orbiopsy, which remains a reasonable approachfor men at average risk for prostate cancer For PSA levels between 2.5 ng/mL and 4.0ng/mL, health care providers should consideran individualized risk assessment thatincorporates other risk factors for prostatecancer, particularly for high-grade cancer, thatmay be used to recommend a biopsy
  • 100. ACS… Factors that increase the risk of prostatecancer include African American race, familyhistory of prostate cancer, increasing age, andabnormal DRE A previous negative biopsy lowers the risk
  • 101. Rescreening intervals Rescreening intervals can influence theeffectiveness of a screening program Long rescreening intervals could missdetecting curable disease for those with fast-growing cancers Short intervals could lead to unnecessarytesting, overdiagnosis, and overtreatment withno impact on disease mortality for those withslowly growing cancers
  • 102. Rescreening intervals… Annual screening is recommended for all menolder than 50 years regardless of risk by -• American Cancer Society• American Urological Association• NCCN ( National Comprehensive CancerNetwork) Extending the screening interval in men withinitially low PSA levels would delay diagnosisfor only a very few cases and would beunlikely to have a significant impact onprostate cancer mortality
  • 103. Rescreening intervals… Men with PSA levels below 2.5 ng/mL form asignificant portion of the screened population;thus, extending the screening interval for thesemen could lead to considerable reductions inPSA tests, biopsies, overdiagnosis, and costs Therefore, the ACS recommends that menwhose initial PSA level is below 2.5 ng/mL canreduce their screening frequency to every 2years. Men with higher PSA values should betested annually
  • 104. Summary of ‗CurrentGuidelines‘ AUA recommends routine PSA screening EAU & JUA (Japanese) – No routine screening ACS - No routine screening but offers to makean informed decision American College of Preventive Medicine alsooffers no recommendation for screening NHS (UK) – No organised screeningprogramme US Preventative services task Force – Norecommendation for screening
  • 105. Future Advances PSA based screening - Finasteride improvedthe ability of PSA to diagnose aggressivecancers (PCPT) Another means to improve PSA -basedscreening is through the use of urinarymarkers. In this regard, DNA, RNA and proteinmarkers are all under investigation Of these potential tests, only the PCA3 test iscommercially available now
  • 106. Future Advances… Because of controversy regarding the benefitof current screening strategies, better methodsfor the detection and treatment of early stageprostate cancer are needed urgently Innovations and new understanding in the fieldof molecular oncology have provided a host ofpotential prostate cancer tumor markers
  • 107. Future Advances… Identification of hyper methylated regions suchas GSTP1 and overexpressed proteins suchas DD3 and NMP48 provides greaterdiagnostic and prognostic potential to improvedetection of prostate cancer Novel urinary diagnostic tests are potentiallyinteresting screening tools for this disease. Forexample, uPM3 is a recently developed urine-based test for detecting prostate cancer. Itdetects DD3 - cancer gene & is effective fordiagnosing prostate cancer of all stages
  • 108. Future Advances… Development of these markers from researchinto clinically applicable tools will improvedetection and management of prostate cancer. Hopeful that future advances in the earlydetection of prostate cancer will lead to theability to distinguish accurately betweenindolent and aggressive cancers and that theadverse effects of prostate cancer treatmentwill be reduced sufficiently to tip the balanceclearly in favor of screening
  • 109. Future Advances… The ideal screening test would be verysensitive and specific for prostate cancer, andnot only specific, but specific for the tumor witha poor prognosis Serum protein profiling using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry(SELDI-TOF-MF) inthe detection of prostate cancer is on secondphase of validation now. It has incorporatedprognosis also by analyzing high & low riskdisease
  • 110. Conclusion Two decades into the PSA era of prostatecancer screening, the overall value of earlydetection in reducing the morbidity andmortality remains unclear Emerging evidence that early detection mayreduce the likelihood of dying from prostatecancer must be weighed against the seriousrisks incurred by early detection andsubsequent treatment
  • 111. Conclusion … PSA testing cannot distinguish nonaggressivefrom aggressive cancers and cannot resolve,on its own, issues of overdiagnosis andovertreatment By using strategies such as activesurveillance, we can separate detection ofprostate cancer from treatment among patientswith low-risk and very low-risk disease, andthereby achieve a reduction in overtreatment
  • 112. Conclusion … Important to involve men in the screeningdecision Men have to understand– The importance of prostate cancer– The potential benefits of early detection– The strengths and limitations of PSAtesting
  • 113. Conclusion … Life expectancy ≤ 10 years- No need forscreening Men at risk for developing cancer at early ageshould be provided the opportunity forinformed decision making at a youngerage, like in– African Americans– Men with a family history of prostate cancer
  • 114. Conclusion … There is no true PSA cut-off point thatdistinguishes cancer from non-cancer Lowering the PSA threshold for biopsy willincrease the rate of over-diagnosis PSA level of 4.0 ng/ml - reasonable thresholdfor further evaluation. PSA levels between 2.5-4.0 ng/ml -Individualized decision making ( particularly inmen who are at increased risk)
  • 115. Conclusion … Future advances in the early detection ofprostate cancer will lead to the ability todistinguish accurately between indolent andaggressive cancers and that the adverseeffects of prostate cancer treatment will bereduced sufficiently to tip the balance clearly infavour of screening
  • 116. References1. Campbell-Walsh Urology, 10th ed.2. AUA guidelines 20103. EUA guidelines 20114. ACS guidelines Update 20105. UCNA volume 37, No. 1 February 20106. T. B. of Prostate biopsy by J StephenJones, 20117. Prostate-specific Antigen Testing and ProstateCancer Screening, Primary Care: Clinics inOffice Practice - Volume 37, Issue 3 (September2010)8. Randomised prostate cancer screening trial: 20years follow up BMJ 2011: 342, March 2011
  • 117. Prostate Cancer Detection as aFunctionof Serum PSA and DRE
  • 118. PSA Derivatives and MolecularForms Numerous variations on PSA-based screeninghave been proposed to improve testperformance -• PSA level for total prostate volume (PSAdensity)• PSA Transition zone density• Evaluation of rate of change in PSA (PSAvelocity)• Complexed and free PSA assays
  • 119. PSA molecular derivatives
  • 120. Volume-Based PSA Parameters Volume-based PSA parameters have beenevaluated to reduce confounding from BPH These include - PSA density(PSAD), complexed PSA density and PSAtransition zone density PSAD of 0.15 or greater was proposed forrecommending prostate biopsy in men withPSA levels between 4 and 10 ng/mL andnormal DRE
  • 121. Prostate Specific AntigenVelocity Rate of change in PSA (PSA velocity, orPSAV) - PSA corrected for the elapsed timebetween measurements is associated with therisk of prostate cancer PSAV more than 0.75 ng/mL per year is aspecific marker for the presence of prostatecancer in men with PSA levels between 4 and10 ng/mL PSAV may play a role in the prediction of life-threatening prostate cancer
  • 122. Free Prostate Specific Antigen Men with prostate cancer generally have agreater fraction of serum PSA that iscomplexed and therefore a lower percentageof total PSA circulating in the free (unbound)form than men without prostate cancer This difference is thought to be due todifferential expression of PSA isoforms bytransition zone (zone of origin of BPH) tissuecompared with peripheral zone tissue(wheremost prostate cancers arise)
  • 123. Free PSA ( fPSA)… %fPSA appears to be most useful indistinguishing between those with and withoutprostate cancer at intermediate total PSAlevels In men with PSA levels of 4 to 10 ng/mL andpalpably benign prostate glands, a %fPSAcutoff of 25% detected 95% of cancers whileavoiding 20% of unnecessary biopsies The percentage of free PSA (%fPSA) does notappear to be significantly altered by race or5α-reductase inhibitors
  • 124. Complexed Prostate SpecificAntigen Because men with prostate cancer have agreater fraction of total PSA that is complexedto protease inhibitors than men withoutprostate cancer, measurement of complexedPSA (cPSA) has been studied as a marker fordetection At a high sensitivity, cPSA provides higherspecificity compared with total PSA andcomparable specificity to %fPSA in prostatecancer detection
  • 125. PSA Isoforms PSA is secreted from the prostatic luminalepithelium in a precursor form (pPSA orproPSA) Active free PSA can be further cleaved toBPSA or intact PSA (iPSA) that is inactive andnot complexed BPSA is found preferentially in nodular BPHtissue from the transition zone and can beconsidered a marker for BPH Larger relative proportion of proPSA has beenassociated with prostate cancer
  • 126. Differential cleavage and activation of proprostate-specific antigen (PSA)
  • 127. PSA Isoforms… PSA is secreted from the prostatic luminalepithelium in a precursor or zymogen form(pPSA or proPSA) with a 7-amino-acid leadersequence and then either -• Cleaved by hK2 to active free PSA or• Partially cleaved into isoforms of free PSAwith 2- or 4-amino-acid leader sequences
  • 128. PSA Isoforms… The native form of pPSA and the truncated orclipped forms of pPSA are elevated in thetissue and blood of patients with prostatecancer compared with those without thedisease. These novel markers have the potential toimprove the accurate identification of men withcancer and the identification of those withmore aggressive disease
  • 129. Prostate-specific antigen (PSA) synthesis innormalversus cancer tissue
  • 130. Active surveillance Active surveillance refers to the process ofregularly monitoring disease activity throughclinical parameters (PSA, DRE) and possiblyperiodic re-biopsy, with active treatment(surgery, radiation, brachytherapy) offered to menwhose disease appears to be progressing Benefit of active surveillance is its capacity toreduce overtreatment, that is, the treatment ofdisease that would not have become apparentclinically during the patient‘s lifetime, which isparticularly problematic for less aggressive tumors
  • 131. Watchful waiting Generally implies less aggressive surveillanceand no treatment until progressive symptomsor evidence of metastatic disease develop. Active surveillance generally is offered to menwhose cancers are Gleason grade 6 or less. Itusually includes regular clinical re-evaluationwith PSA and DRE as well as biopsy every 1to 4 years, depending on the protocol