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

Generaliztions about prostate cancer__clinical issues 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* 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

Prostate Cancer, USA Year Incidence Prevalence Mortality 2010 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 Despite the fact that some primary care doctors argue that most prostate cancer is not clinically significant, this opinion is unfortunately wrong. Over a quarter of a million cases of prostate cancer are diagnosed every year. Deaths due to prostate cancer, account for 14% of all cancer deaths. This doesn’t count men that have prostate cancer and get hit by a car this is deaths specifically related to prostate cancer. This is not a trivial disease Putting this into numbers we all can relate to this means that 1 in 6 men will develop prostate cancer in their lifetime. Or, more pointedly 3 of you in this room are likely to develop prostate cancer in your lifetime and one of you, if left untreated has a 50% chance of dying from it. But if you can beat the odds you can give yourself up to an 80% chance of being cured

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

For every 1000 men treated for PCa 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

N Engl J Med 360:1310, 2009 N Engl J Med 360: 1320, 2009

Comparison of ERSPC and PLCO studies ERSPC (Europe) PLCO (USA) Control 89,353 38,350 Screening 72,890 38,343 Age 55-69 55-74 PSA screening interval 4 yr (87% men) 1 yr (6 yr period) PSA indication for biopsy >3-4 ng/ml >4 ng/ml Compliance for PSA test 82% 85% PCA detected Control 4,307 (4.8%) 2,974 Screening 5,990 (8.2%) 3,452 Follow-up 15 yr 10 yr PCA death rate ratio 0.8 1.1 (95% CI, 0.65-0.98) (95% CI, 0.75-1.70)

Limitations of the studies ERSPC (EU) PLCO (USA) PSA test prior to the study ? 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 prostate-cancer 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 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. No Comorbidities One or more Comorbidities Crawford et al, JCO 2011

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.

A good screening test? Sensitive Specific Non-invasive and safe Detects a common condition Detects a harmful condition Detects a condition that has effective treatment Treatment works better in early stages Cost-effective Benefits outweigh harms

PSA a good screening test? Sensitivity at 4.0 ng/ml = 75% Specificity at 4.0 ng/ml = 25% Non-invasive and safe yes/ but leads to biopsy/treatment? Detects a common condition yes Detects a harmful condition yes, but also indolent ca Detects a condition that has an effective treatment, yes, Treatment works better in early stages, yes, but only if needed to be treated Cost-effective debated Benefits outweigh harms debated

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 Re-Biopsy? Prostate Biopsy (type of biopsy) ? ? ?

Decision Tree of Prostate Cancer Screening, Diagnosis and Treatment Active Surveillance PSA +/- DRE Prostate Biopsy (type of biopsy) Re-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”

Benefits AND Harms Potential benefits 20%-40% relative risk reduction in prostate cancer mortality (i.e., from 3 or 4% to a little less) Potential harms: For every one life saved… Between 300 and 1000 men have to undergo screening Between 10 and 40 men have to undergo treatment Indiscriminate treatment of low-risk disease Estimates indicate over one million extra men have undergone treatment in the US due to PSA screening to save at most 56,000 lives Albersten JNCI 2009

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 25.3 8.2 3.09 USA 124.8 15.8 7.90 Canada 78.2 16.6 4.71 Congo 29.0 25.2 1.15 Kenya 16.6 14.1 1.18 Senegal 7.5 6.5 1.15 Tanzania 20.1 17.4 1.56 Uganda 38.0 32.5 1.17 Portugal 50.1 15.2 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