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To Screen or Not to Screen: That is the Question……… New Guidelines for Prostate Cancer Diagnosis: The Global perspective Gabriel P. Haas, MD. FACS Medical Director, Astellas Scientific and Medical Affairs This is not an Astellas sponsored presentation and the opinions expressed are my own New Guidelines for Prostate Cancer Diagnosis: The Global perspective Preguntas: Usan PSA por detecion temprano de Pca? Familiares con recommendaciones de USA para NO USAR PSA? Acceptan estos recommendaciones en Portugal? BREAKING NEWS !!! USPSTF PANEL RECOMMENDS AGINST PROSTATE CANCER SCREEING WITH PSA (MAY 2012) PIVOT TRIAL PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE (367:203, 2012) JULY 2012: “RADICAL PROSTATECTOMY HAS NO SURVIVAL BENEFIT OVER OBSERVATION” Estimated New Cancer Cases and Deaths By Sex, United States, 2011 From Siegel, R. et al. CA Cancer J Clin 2011;0:caac.20121v1 Copyright ©2011 American Cancer Society INTRODUCTION Generaliztions about prostate cancer__clinical issues PCA is very common PCA left untreated or treated late can be deadly Early detection with PSA leads to diagnosis of PCA at much earlier stage Early detection with PSA PROBABLY leads to decreased mortality EPIDEMIOLOGY PCA starts in 20’s and 30’s and may take decades to be clinically detectable Prevalence of PCA is MUCH HIGHER than clinical cases Early detection with PSA DOES lead to detection of some (many) clinically insignificant cancers Characterization of early prostate cancer is difficult because only diagnosed cancers can be studied – undiagnosed cancers are UNKNOWN Lifetime Risk of Developing or Dying From Prostate Cancer* Lifetime Risk of Risk Risk Ratio Developing Histologic Prostate Cancer (Autopsy) 42% 11.7 Developing Clinical Prostate Cancer 16.7% 4.4 Dying from Prostate Cancer 3.6% 1 * For a 50 year old American man. Modified from Scardino PT Urol Clin N Am 1989 and Human Path 1992 Incidence of Prostate Cancer by World Region North America 92.39 Australia/New Zealand 46.70 Caribbean 42.35 Western Europe 39.55 Northern Europe 34.70 Southern Africa 31.03 Middle Africa 29.58 Tropical S. America 28.05 Central America 24.77 Western Africa 23.85 Temperate S. America 22.86 Micronesia/Polynesia 21.22 Southern Europe 16.91 Eastern Africa 16.75 Eastern Europe14.06 Japan 8.51 Western Asia 7.11 Melanesia 6.04 S.E. Asia 5.85 Other Eastern Asia 5.37 Northern Africa 5.13 S. Central Asia 4.53 China 1.08 0 20 40 60 80 100 Prostate Cancer, USA Year 2010 Incidence Prevalence Mortality 217,730 ? 32,050 2003 220,900 ? 28,900 2001 198,100 ? 31,500 1999 179,300 ? 37,000 1996 317,000 ? 41,400 1994 200,000 ? 38,000 1990 106,000 ? 30,000 1985 86,000 ? 24,000 1976 64,000 ? 20,000 PSA Level(ng./ml) % Prostate Ca 0-0.5 6.6% 0.6-1.0 10.1% 1.1-2.0 17.0% 2.1-3.0 23.9% 3.1-4.0 26.9% Rise in Incidence After PSA, 1988 Dramatic rise in incidence as prevalent cases are culled (2.5X) Sustained rise in incidence as earlier cancers are detected (1.5X) Reduction in Prostate Cancer Mortality After PSA 40% decline in PCA mortality 45 to 70% of the observed decrease in mortality “attributable” to PSA screening Jemal A, et al. CA Cancer J Clin 2010; 60:277-300 Etzioni R, et al. Cancer Causes Control 2008;19:175-181 Screening for Prostate Cancer Does it save lives? Does it lead to OVERDETECTION? Does it lead to unnecessary treatment? AUA Guidelines 2009 (New Guidelines at AUA, May 2013) Well informed men aged 40 and over who have a life expectancy of at least 10 years should be offered PSA and DRE to establish a base line and follow-up should be individualized The decision as to whether to do a biopsy or not should not rely only on the PSA reading(s) but should take into account a range of other factors such as free and total PSA, PSA velocity and density, age of the patient, family history, ethnicity/race, other illnesses/diagnoses, general health and previous biopsy history American Cancer Society 2012 (2/27/12) The ACS recommends that men make an informed decision with their doctor about whether to be tested for prostate cancer. Starting at age 50 men with more than 10 years of life expectancy should talk to their doctor about the pros and cons of testing so they can decide if testing is right for them. If they are African American or have a father or brother who had prostate cancer before age 65, men should have this talk with a doctor starting at age 45. If men decide to be tested, they should have PSA with/without DRE How often they are tested should depend on their PSA level – If PSA < 2.5 ng/ml, may be tested every 2 years – If PSA > 2.5 ng/ml, recommend annual testing Screening: NCCN Guidelines For men with life expectancy of > 10 years – Life expectancy is comprised of age and comorbidity Have a risk/benefit discussion – “Shared decision-making” Offer baseline DRE and PSA at age 40 If PSA < 1, recheck in 5 years – Median PSA for a man in his 40s is about 0.75 If PSA > 1 or patient is African-American or +FH, offer annual screening Consider biopsy if PSA > 2.5 or rate of rise is > 0.35 ng/mL per year NY Times: Health Section 2012 U.S. Panel Says No to Prostate Screening for Healthy Men By GARDINER HARRIS Healthy men should no longer receive a PSA blood test to screen for prostate cancer because the test does not save lives over all and often leads to more tests and treatments that needlessly cause pain, impotence and incontinence in many US Preventive Services Task Force, May, 2012 US Preventive Services Task Force critiques Screening for Prostate Cancer For every 1000 men treated for PCa – 5 die of complications – 10-70 experience complications but survive – 200-300 develop long-term complications Impotence Incontinence Increased Morbidity – Complications of biopsy (68 events/10,000 biopsies) – Psychological consequences – Complications of overtreatment US Preventive Services Task Force critiques Screening for Prostate Cancer Main concern: Too many of the patients who are diagnosed have clinically insignificant cancers which do not need treatment and therefore should not be diagnosed GRADE ‘D’ Recommendation: Evidence is AGAINST screening Harms outweigh benefits Engl JJ Med 2009 NN Engl Med360:1310, 360:1310, 2009 NN Engl Med360:1320, 360: 1320, 2009 Engl JJ Med 2009 Comparison of ERSPC and PLCO studies Control Screening Age PSA screening interval PSA indication for biopsy Compliance for PSA test PCA detected Control Screening Follow-up PCA death rate ratio ERSPC (Europe) PLCO (USA) 89,353 72,890 55-69 4 yr (87% men) >3-4 ng/ml 82% 4,307 (4.8%) 5,990 (8.2%) 15 yr 0.8 (95% CI, 0.65-0.98) 38,350 38,343 55-74 1 yr (6 yr period) >4 ng/ml 85% 2,974 3,452 10 yr 1.1 (95% CI, 0.75-1.70) Randomized US Study GL Andriole et al. NEJM 360:1310, 2009 Randomized European Study FH Schroder et al. NEJM 360:13220, 2009 Limitations of the studies ERSPC (EU) PSA test prior to the study PLCO (USA) ? 43% PSA test compliance 82% 85% PSA test in controls ? 52% ERSPC: PROS AND CONS Absolute risk difference: 0.71 deaths/1000 For each cancer death prevented, 48 cancer cases need to be detected AND treated – 1410 men need to be screened OVERDETECTION -- 50% of cancers detected by screening would not be detected in the men’s lifetime ERSPC ERSPC 162,243 men randomized Screening q 2-4 years vs. usual care – PSA > 3 ng/ml – Sextant biopsies – Compliance in screening group 82% – Screening in the control group ?? (20%) 11 years of follow up (median) Detection was higher in screening group – 6963 cases vs. 5396, or cumulative incidence of 9.6% vs. 6.0% At 11 years, 299 prostate-cancer deaths in screening group and 462 in the control group. Rate ratio 0.79, 95% confidence interval 0.68-0.91, p=0.003. ERSPC Screening 21% reduction in prostatecancer death* To save 1 life: Number needed to screen: 1055 Number needed to detect: 37 * Up to 29% reduction if corrected for noncompliance in the screening arm and contamination of the control arm. How does prostate cancer screening efficacy compare with screening for other common cancers? Breast Cancer Screening (Mammogram) 9 randomized trials with 650,000 participants Relative risk reduction of 22% at 14 years Number needed to screen: 1792 S Fletcher. Screening for Breast Cancer. UpToDate.com; accessed January 14, 2010 LL Humphrey. Summary of the Evidence for Breast Cancer Screening. Ann Intern Med 2002;137:344-6 Colon Cancer Screening 5 randomized trials (at least) Relative risk reduction of 15-21% at 8-13 years Number needed to screen: 1173 BD Boggs. How does colonoscopy compare with fecal occult blood testing as a screening tool for colon cancer. JFP 2005; 54(11) Towler BP, Irwig L, Glasziou P, Weller D, Kewenter J. Screening for colorectal cancer using the faecal occult blood test, hemoccult. Cochrane Database Syst Rev 2000;(2):CD001216. Pignone M, Rich M, Teutsch S, Berg AO, Lohr KN. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137:132–141. Screening for Prostate Cancer: Comparison with Other Cancers Similar risk reduction Similar number needed to screen AND Two recent studies suggest that appropriately targeted screening may improve these figures substantially for prostate cancer… Goteborg Planned analysis of one site of the ERSPC Differs in that – Randomization occurred before invitation to participate – Younger at randomization (median 56 years) – Lower PSA threshold for biopsy (2.5) – High compliance with screening (76%) and follow-through (93%) – Negligible contamination in the control group (est. 3%) – Higher PCa mortality – Longer follow up (median 14 years) Hugosson et al, Lancet Oncol 2010 Goteborg Rate ratio for death from PCa among the screening group was 0.56 (0.39-0.82, p=0.002) Number needed to invite to screen 293 and number needed to treat 12 to prevent one PCa death. Hugosson et al, Lancet Oncol 2010 PLCO Sub-set Analysis of Healthy Men No Comorbidities Sub-set analysis of men with no comorbidities (that predict cardiovascular or cancer mortality) Adjusted hazard ratio for screening group vs. unscreened group was 0.56 (0.33-0.95), p=0.03. Number needed to treat to prevent one PCa death at 10 years was 5. Crawford et al, JCO 2011 One or more Comorbidities Summary of Randomized Trial Data PLCO – Flawed due to contamination of the control arm ERSPC – 21% relative risk reduction – 1055 needed to screen; 37 needed to treat Screening is more beneficial – In younger, healthier men – As follow up lengthens – Targeted screening reduces NNS to ~300 and NNT to 10 or 12. Efforts to Improve Test Characteristics of PSA Age-adjusted PSA PSA velocity : 0.75 ng/ml or 0.35 ng/ml PSA density : 0.15 PSA doubling time : less clear in pre-tx evaluation Free PSA : < 18% OTHER MARKERS? Improved biopsy regiments Improved Radiologic Guidance and Identification of Significant Cancers (MRI fusion, etc) Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment PSA +/DRE Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment PSA +/DRE Prostate Biopsy (type of biopsy) Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment PSA +/DRE Prostate Biopsy (type of biopsy) Re-Biopsy? Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment Treatment PSA +/DRE Prostate Biopsy Re-Biopsy? Active Surveillance (type of biopsy) Surgery Radiation Other • HIFU • Focal therapy • Hormones Screening Summary There are potential benefits – Reduction in morbidity due to progressive disease – 20-40% prostate-cancer specific survival benefit – More likely to benefit younger, healthier patients There are potential harms – False-positive test leading to other tests – Detection of indolent prostate cancer leading to unnecessary treatment Screening decisions must – Balance potential benefits and potential harms – Involve the patient – “shared decision-making” Leads us to… LATIN AMERICA…. AFRICA…. ASIA….. The issues are different: – – – – – PSA use very limited Prostate cancer presents in advanced form Mortality from prostate cancer is 50-80% Effective treatment is unavailable RESOURCES, RESOURCES ,RESOURCES Age-standardized rate (world) of PCA GLOBOCAN 2008 Incidence Mortality Ratio (per 100,000) (incid./mortality) World USA Canada Congo Kenya Senegal Tanzania Uganda Portugal 25.3 124.8 78.2 29.0 16.6 7.5 20.1 38.0 50.1 8.2 15.8 16.6 25.2 14.1 6.5 17.4 32.5 15.2 3.09 7.90 4.71 1.15 1.18 1.15 1.56 1.17 3.36 CONCLUSIONS Prostate Cancer Screening Prostate cancer mortality is dropping in Western Countries Trials to PROVE that screening saves lives are very expensive Methodologies and follow up different Very little difference may be detected in societies where PSA use has been pervasive However, in Portugal, recommendations from US may not be applicable