Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Prostate Cancer screening Mahmoud Abdelsalam MD/PHD Medical Oncologist, Moncton Hospital Professor in IM dept. Dalhousie University, Canada Director of Clinical Trial Moncton, Canada Disclosure • Consultancy: Merck, Novartis, Astellas, BMS, Roche, • Ad. Board: Amgen, Pfizer, Johnson, Merck, Novartis • Grants: Roche, Amgen, Johnson, Astellas Objectives • List risk factors for prostate cancer, and discuss relative strength • Discuss potential prevention strategies • Discuss benefits and risks of prostate cancer screening, including expected survival rates • Counsel patients about primary treatment options for local disease • Recommend systemic therapy for advanced cancer. Canadian Cancer Statistics 2015 Canadian Cancer Statistics 2015 Canadian Cancer Statistics Risk Factors for Prostate Cancer • Age – Rare before 40; 65% over the age of 65 • Race - More common in African-American men; more likely diagnosed at advanced stage; 2x more likely to die of the disease; less common in Asian-American and Hispanic-American men than non-Hispanic whites. • Family History - 1st degree relatives, father, brother • Nationality - North America and NW Europe vs Asia, Africa, Central and South America • Genetics – BRCA1 and BRCA2 increase risk, but account for very small percentage of prostate cancer. Lynch syndrome?? • Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy – not much effect, BUT……. Life time dying from cancer prostate • Risk of dying from cancer prostate is around 3 % • Once metastatic disease developed, there is no cure. • Prior to PSA screening only 25% of prostate cancer presented confined to prostate vs. 91% since Screening • Should you screen at all? • What age should you start and stop screening? • Does PSA-based screening lead to decrease in risk of death from prostate cancer? • What are the advantages and disadvantages of screening? • Canadian guidelines? Screening • Two large trials done recently looking at survival benefit from screening: • PLCO screening trial (U.S.) and ERSPC screening trial (European) • These two RCT were largely basis for Canadian Task Force on Preventive Health Care (CTFPHC) recommendations. European Randomized Study of Screening for Prostate Cancer (ERSPC) • Main endpoint: prostate cancer (PC) mortality • Ages: 50-74, core age group 55-69 yrs (n=162,387) • Screen interval 4 years (87%) or 2 years (13%) • Sextant (lateral) biopsy recommended for PSA ≥3.0 ng/ml or ≥4.0 ng/ml • With ancillary tests: DRE, F/T ratio for PSA 3-4 ng/ml Schröder. ECCO 2009; Teaching Lecture: http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23 ERSPC screening trial (European) • European Randomized Study of Screening for Prostate Cancer • 182,000 men randomized • Ages 50-74 included • Median f/up of 9 years there was 20% reduction in CaP deaths in screened group • 41 % reduction in metastases at presentation Prostate cancer mortality – Intention to screen analysis • Relative risk (RR) of PC death 0.80 • (95% CI: 0.65-0.98, P=0.04), 20% relative reduction • Absolute risk reduction: 7 per 10,000 men screened • NNS: 1.410 (95% CI: 1.14-1.72) • NNT: 48 (in excess of control group) Schröder. ECCO 2009; Teaching Lecture: http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23 Göteborg Screening Trial • Göteborg randomized population-based prostate screening trial • 20,000 men randomized • Ages 50-64 included (median 56) • Median follow-up 14 years • Found 44% risk reduction in CaP specific death in screened group • NNT analysis revealed that 293 men needed to be screened and 12 men need to be diagnosed in order to prevent 1 death Hugosson et al. Mortality results from the Göteborg randomised Population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725-32. Lancet Oncology, published online July 1, 2010 Over 14 years PSA testing increased the number of cancers detected by 50% but reduced the risk of dying of prostate cancer by 44% in all men and 56% in screened men. The number needed to screen to prevent one death was 293, and number needed to diagnose or treat was 12. • 5 treated tp prevent one death Caveats – ERSPC • The 20% reduction in rate of death due to prostate cancer underestimates true effect since some controls were also screened (“contamination”) and some assigned to screening did not get screened (“noncompliance”), but … • Model-based adjustment to correct for contamination only indicates that screening reduces mortality by 27%, and … • Model-based adjustment to correct for both contamination and noncompliance indicates that screening reduces mortality by 31% Roobol MJ, et al., Eur Urol 2009:56(4);584-591 More Caveats – ERSPC • Initial data analysis indicates need to screen 1410 men and treat 48 with cancer to save 1 life, but … • Further modeling* indicates numbers needed to screen (NNS) & treat (NNT) to prevent 1 prostate cancer death decrease over time: Definition: The number needed to screen (NNS) is the number of people who would need to be screened to prevent one person from dying. (Similarly for the number needed to treat, abbreviated NNT.) NNS is computed by taking the reciprocal of the difference between the fraction of people who die in the screening arm and the fraction of people who die in the control arm. * Loeb S et al., J Clin Oncol 29(4):464-467, 2011 The prostate, lung, colon, ovary cancer screening trial (PLCO) (Andriole et al, NEJM 2009) RCT of screening versus “general care” control group, to show 20% mortality reduction n=76,693 men aged 55-74 PSA testing yearly for 6 years, DRE year 1-4 Biopsy for PSA >4.0 ng/ml or abnormal DRE Andriole et al. New Engl J Med 2009;360:1310-1319 Schröder. ECCO 2009; Teaching Lecture: http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23 PLCO – results • Follow-up 7 years • Compliance with PSA testing 85%, compliance with biopsy indication ± 40% • In the screen and control arm 85% and 52% of men were PSA tested • Cancer detection: S arm 2.86 (7.4%), C arm 2.32 (6.1%), rate ratio 1.22 • Deaths from PC: S arm 2.0/10.000, (50 deaths), C arm 1.7/10,000 (44 deaths) • Rate ratio 1.13, 95%CI 0.75-1.70, NS Andriole et al. New Engl J Med 2009;360:1310-1319 Schröder. ECCO 2009; Teaching Lecture: http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23 PLCO trial flaws • Significant rates of screening in “control” arm • 52% contamination (men were screened prior to study) • Relatively low rate of biopsy in men who had “abnormal” screening results in screen arm • Less than 50% of men in screened arm with indication had biopsy done • Short follow-up (less than 10 yrs) Does PSA Screening Reduce Prostate Cancer Mortality? PLCO: No ERSPC: Yes, but at high cost Over 9 years, PSA screening reduced deaths from prostate cancer by 20% but was associated with a high risk of over diagnosis: 1410 men would need to be screened and 48 additional cases would need to be diagnosed or treated to prevent one death from prostate cancer. Findings: Benefits of Screening with PSA Study (country) PLCO† U.S. population ERSPC‡ (Finland, Sweden, Italy, Netherlands, Belgium, Switzerland and Spain) Study Characteristics PSA Threshold Contaminatio n (rate of screening in control group) Prostate cancer mortality Relative Risk (95% C.I.) All-Cause Mortality Relative Risk (95% C.I.) Absolute Effect (per 1000 men screened) GRADE Quality of Evidence* RCT 76,693 men age 55-74, annual PSA screening for six years and DRE annually for four years 14 year follow-up 4 ng/ml 52% 1.09 (0.87-1.36) 0.96 (0.93 - 1.00) No effect moderate RCT 162,243 men Age 50-74 (core group 5569) PSA every 4 years 13 year follow-up Most sites 3.0 ng/ml 20% Core gp: 0.79 (0.69-0.91) All ages: 0.83 (0.73-0.94) Core gp: 1.00 (0.98 - 1.02) All ages: 1.00 (0.98 – 1.02) 1.28 fewer deaths per 1,000 men screened moderate *Grading of Recommendations, Assessment, Development and Evaluation (GRADE) rates the continuum of quality of evidence in four categories of high, moderate, low or very low – see evidence review for complete assessment of study quality †Prostate, Lung, Colorectal and Ovarian Screening Study ‡European Randomized Study for Screening for Prostate Cancer (published online August 7, 2014) 24 Screening Problems with both studies • Short follow-up <10 years (mortality from CaP is very low in first 10 years) • Subset analysis not done for high risk men (i.e. those with +FH, AA) • Contamination level is high specially in PLCO trial • Compliance was low Findings: Harms of Screening with PSA The main harms of screening identified were: • Harms of biopsy • Harms of over-diagnosis • False positives • Cost Complications Following Prostate Biopsy Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011;186:1830-1834. Nam RK, Saskin R, Lee Y, Liu Y, Law C, Klotz LH, Loblaw DA, Trachtenberg J, Stanimirovic A, Simor AE, Seth A, Urbach DR, Narod SA. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010;183:963-968. Pinkhasov GI, Lin YK, Palmerola R, Smith P, Mahon F, Kaag MG, Dagen JE, Harpster LE, Reese CT, Raman JD. Complications following prostate needle biopsy requiring hospital admission or emergency department visits - experience from 1000 consecutive cases. BJU Int 2012;110:369-374. OVER DETECTION Of all screen-detected cancers, an estimated 10-56% would not have become apparent or caused symptoms in the patients’ lifetimes, and the lead time for diagnosis is estimated at 5-12 years. Risks of Screening • Screening detects cancers that do not threaten the patient’s life. • Finding such cases cannot be avoided at present. • When screening the general population for PCa by PSA, over 50% of the PCa’s detected will be minimal cancers (Draisma 2003). • As immediate treatment of these has not been shown to be beneficial, detection and diagnosis of some tumors may be unnecessary and counter-productive, as in some patients there will be treatment-associated morbidity (and, rarely, even mortality). PIVOT (Prostate cancer Intervention Versus Observation Trial) • Randomized men ≤75yrs old to radical prostatectomy vs. expectant management with all-cause mortality as primary end-point • 731 men studied • Median f/up 10 years • Different than Scandinavian trial • looked at same thing, but now in PSA screening era Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012 Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011 PIVOT (Prostate cancer Intervention Versus Observation Trial) • Found 47% (171/364) men died who had surgery vs. 49.9% (183/367) in observation arm • 5.8% (21) men who had surgery died from CaP or treatment vs. 8.4% (31) in observation arm • Essentially NO Difference between groups • Surgery associated with ↓ all-cause mortality in men with PSA>10 and possibly in intermediate or high-risk tumors Wilt et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med, 367, 2012 Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011 ProtecT (Prostate testing for cancer and Treatment) • RCT of treatment effectiveness in UK • Opened 2001 and closed 2008 • 111,000 men randomly assigned to surveillance, radiation, or surgery • Primary end-point will be CSS at 10yrs • With numerous secondary end-points including QOL analyses Donovan et al. Prostate testing for cancer and treatment (ProtecT) feasibility study. Health Technol Assess 2003; 7:14 Use of Watchful Waiting among U.S. Patients with Localized Prostate Cancer by Risk Category (1990-2006) Low Intermediate High Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate c J Clin Oncol 2010; 28: 11117-1123. Findings: Additional Harms of Screening Not all men who screened above threshold had a biopsy Some men who screen positive on the first round could be diagnosed with prostate cancer on a subsequent round Some men will have multiple biopsies ‡ ‡ Kilpelainen TP, Tammela TL, Roobol M, et al. False-positive screening results in the European Randomized Study of Screening for Prostate Cancer. Eur J Cancer 2011;47:2698-705. Causes of false positive PSA Why Has Diagnostic Progress Not Resulted In Greater Long-Term Survival Rates? Death rate is comparatively low considering prevalence • Lifetime risk of diagnosis: 1 in 6 • Lifetime risk of death: 1 in 33 • 5-year survival rate: 98% Diagnostic and therapeutic advances have improved quality of life, but not necessarily the years of life • Risk is tied to age - All ages: 17.7 cases per 100,000 - Age 75 to 84: 248 cases per 100,000 - Over 85: 591 cases per 100,000 Prostate cancer cells are generally less aggressive with increasing age, suggesting “many prostate cancers detected in routine practice may be clinically unimportant” Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. NEJM. 2004;350:2239-2245. Screening for Prostate Cancer with the Prostate Specific Antigen (PSA) Test: Recommendations 2014 • Canadian Task Force on Preventive Health Care Summary of the Recommendations Clinicians and Policy Makers For men aged less than 55 years of age, we recommend not screening for prostate cancer with the prostate-specific antigen test. (Strong recommendation; low quality evidence) Basis of the recommendation • The CTFPHC based this recommendation on the low incidence of prostate cancer and prostate cancer mortality, and the lack of evidence for benefit of screening in this age group, as well as the evidence of harms. • The strong recommendation implies that the CTFPHC is confident the harms of screening and subsequent testing/treatment outweigh the benefits. Summary of the Recommendations Clinicians and Policy Makers For men aged 55-69 years, we recommend not screening for prostate cancer with the prostate specific antigen test. (Weak recommendation; moderate quality evidence) Basis of the recommendation •The CTFPHC placed a relatively low value on a small and uncertain potential reduction in the risk of prostate cancer mortality and a relatively higher value on the risk of harms associated with diagnosis and treatment due to false positive results and overdiagnosis. •The weak recommendation against screening implies that the harms of screening and subsequent testing/treatment probably outweigh benefits, but uncertainty exists. Summary of the Recommendations Clinicians and Policy Makers For men aged 70 years and older, we recommend not screening for prostate cancer with the prostatespecific antigen test. (Strong recommendation; low quality evidence) Basis of the recommendation • The CTFPHC based this recommendation on the lower life expectancy and the lack of evidence for benefits of screening in this age group, as well as the evidence of harms. • The strong recommendation implies that the CTFPHC is confident the harms of screening and subsequent testing/treatment outweigh the benefits. USPSTF To Downgrade PSA Screening From "I" to "D" — As In "Don't Do It" • U.S. Preventative Service Task Force recommended NOT to use PSA to screen for prostate cancer • Based on meta-analysis of available literature ABSTRACT Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages, when treatments might be more effective. Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer. Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists. Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of perioperative harms. Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed quality using predefined criteria. Conclusions: After about 10 years, PSA-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary. The Cancer Letter, Oct. 7, 2011 Current Screening Guidelines from Major U.S. Organizations • American Urological Assoc Best Practice Statement – Individual decision for those with 10yr life expectancy – Baseline PSA at 40 – PSA at subsequent intervals based on PSA level and risk factors • American Cancer Society – Advises against routine screening – PSA should be offered as option • Age 45 in those with risk factors (FH, AA) • Age 40 in those at highest risk (multiple family members or a family member diagnosed at a young age) • US Preventive Services Task Force – Do not screen routinely over age 75 – Inadequate evidence regarding younger ages – Current (October 2011) recommendation against PSA-based screening of any asymptomatic men © Stanley H. Weiss, 2011 Slide 44 Presented By Mark Stein at 2014 ASCO Annual Meeting Prostate Cancer—Indolent vs. Aggressive? • Low Risk – PSA < 10 – Gleason score ≤6 • Intermediate Risk – PSA 10-20, Gleason 7 or Gleason 6 with PSA >10 • High Risk – PSA > 20, Gleason 8-10 TREATMENT OPTIONS FOR PROSTATE CANCER Watch +/hormones Curable At Diagnosis NonCurable Watch +/treat for cure later TREAT NOW for cure Active Surveillance • Watch, and if need be treat for cure later • Means watching PSA and re-biopsy of prostate every 12 years • Go on to curative Rx if PSA jumps quickly, urinary symptoms, or biopsy shows worsening cancer • Best for men with very slow growing cancers whose life expectancy is less than 15 years. Low-risk prostate cancer • Cancer is VERY LIKELY restricted to the prostate gland • Must have T2 (or less) and PSA <10 and Gleason Score 6 (or less) • Expect 80-95% chance of cure with treatment • Active surveillance is good option for many Low-risk prostate cancer T1/T2 and PSA<10 and GS<7 Surgery Therapy Low risk Surveillance Seed implant External Radiotherapy Treatments of Localized Prostate Cancer • • • • • The primary treatments reviewed: Radical Prostatectomy Radiation Therapy Androgen Deprivation Therapy (ADT) Combination Therapy Treatment for cure: operation • Radical prostatectomy – removes the prostate and seminal vesicles • Has a specific side effects – – – – Related to major operation Urinary incontinence 5-10% Erectile dysfunction 30-70% Bladder neck stricture 10% • Is an excellent option in a situation where prostate cancer cells are likely restricted to the prostate gland • Removing the prostate gland provides much more information about the aggressiveness and extent of cancer • Radiotherapy can be used after surgery if it looks like cancer is likely left behind in the surgical bed or if PSA begins to rise in follow up Treatment of cure: Radioactive seeds in prostate • Also called Low Dose Rate or Seed Brachytherapy • Best for men with early disease when cancer cells likely in prostate gland of just beyond capsule • Very high cure rates similar to operation when done by an experienced specialist • “Simple” outpatient procedure – General anaesthetic – Rapid return to normal activity – Men appear happy with this treatment Findings: Benefits of Treatment • Some treatments were found to reduce the risk of prostate cancer-specific mortality, although the quality of evidence was variable. • Prostatectomy was the only treatment with high QoE • Hormone therapy alone was found to produce an increased risk of prostate cancer-specific mortality. • Very limited and low QoE to support a reduction in the risk of all-cause mortality for the following treatments: • Prostatectomy • Radiation Therapy • Combination Therapy (Radiation and Hormone Therapy) Management of CRPC How to Improve screening benefits • • • • • • High Risk Family History Age PSA velocity PSA Density PCA 3 (non-coding mRNA molecule that is believed to be prostate specific) • Risk Score Considerations for High Risk Populations High risk populations include men of black ethnicity or men with a family history of prostate cancer. • Men of black ethnicity were included in the USA studies, however, the results are not broken down by risk level or risk factor. Instead, the studies provide results for the male population as a whole. • Therefore, there is currently no trial data to suggest that men at high risk should be screened differently from men in the general population. • Clinicians may wish to discuss the benefits and harms of screening in men at high risk, with explicit consideration of their values and preferences. Screening Smarter: How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer • Risk-adjust screening by age and PSA (reduce false positives) • Reduce false positive PSA results by repeating (verifing) positives and by adding additional markers (4 kallikrein panel or -2(pro)PSA) (reduce indications for biopsy) • Active surveillance for low-risk cancers (reduce harms of unnecessary therapy) • Refer patients who need treatment to high-volume physicians or centers (reduce harm of necessary therapy) Memorial Sloan-Kettering Cancer Center 2010 Guidelines Risk-adjusted Screening for Prostate Cancer • Begin PSA testing at age 45 • For men age 45 - 59 • PSA ≥ 3 ng/ml : consider biopsy • PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years • PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60, whichever comes first • For men age 60 – 70 • PSA ≥ 3 ng/ml : consider biopsy • PSA > 1 but < 3 ng/ml : return for PSA every two years • PSA < 1 ng/ml : no further screening • For men age 71 or higher • No further screening © Stanley H. Weiss, 2011 Example: 2011-Oct-29 © Stanley H. Weiss, 2011 A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy • we compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) levels of 2 to20 ng/mL. • the urine exosome gene expression assay plus SOC was associated with improved discrimination between GS7 or greater and GS6 and benign disease: AUC 0.77 (95% CI, 0.71-0.83) vs SOC AUC 0.66 (95% CI, 0.580.72) (P < .001). • Independent validation in 519 patients Urine exosome gene expression assay plus SOC AUC 0.73 (95% CI, 0.68-0.77) was superior to SOC AUC 0.63 (95% CI, 0.58-0.68), (P < .001). JAMA Oncol March 31st, 2016 online Conclusions Prostate Cancer screening using PSA is controversial with evidence of ?? Reduced mortality. Long term follow-up is needed to prove mortality reduction. Harms related to screening, biopsy, treatment and cost should be considered. Guidelines do not encourage routine screening. Conclusions (continued) High Risk Group Screening????? Smarter screening?????? Other screening tests?????? Risk adjusted models??????