Prostate Cancer. Axiom. Overdetection Is A Small Issue. Reducing Morbidity and Mortality

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1 Overdetection Is A Small Issue (in the context of decreasing prostate cancer mortality rates and with appropriate, effective, and high-quality treatment) Prostate Cancer Arises silently Dwells in a curable state silently Passes into an incurable state silently William J Catalona, MD Northwestern University Feinberg School of Medicine Chicago Reducing Morbidity and Mortality Prevention Cure advanced disease Early detection and appropriate, effective treatment Axiom Some overdetection is necessary to reduce suffering and death from prostate cancer 1

2 Overdetection is necessary By the time prostate cancer causes symptoms, it is usually incurable To detect prostate cancer early, screening is required To be effective, screening must detect cancers at an earlier stage, i.e., create lead time Lead time virtually always results in overdetection Early Cancer Detection and Overdetection Any attempt to detect cancer early implies some degree of over diagnosis even an advanced cancer, associated with an average survival of 3-4 years, may actually be overdiagnosed.. Citto (Eur J Cancer 36:1347) Lead-Time PSA screening might detect cancers that otherwise never would become clinically evident during the patient s life time Estimation of lead-time have ranged from 5 to 13 years These estimates have been used in statistical models to suggest that approximately 25-80% or more screendetected cancers may be clinically insignificant 2 Methods of Estimating Overdetection 1. Epidemiologic (statistical models using assumptions) 2. Clinico-pathologic (examining grade, stage, and volume of cancer in the prostatectomy specimen) There is a discrepancy between estimates of overdetection by these methods 2

3 Definitions of Overdetection There is disagreement on the best definition of overdetection Many different definitions have been used Epidemiologic Definitions Early Studies: Zappa et al measured overdetection as the estimated percent increase in PCa incidence rate in Italy caused by biennial screening Etzioni et al calculated overdetection through PSA screening as the probability of dying of other causes during the lead time McGregor et al defined overdiagnosis as the detection of non-lethal cancers Example: Detection of Non-Fatal Cancer If the cancer does not kill you, it is overdetected (e.g., 16% of screen-detected cancers were lethal; therefore, the overdetection rate was considered to be 84%) 3

4 Other Criteria High incidence-to-mortality ratios Excess observed-to-expected incidence rates without subsequent decrease in mortality rate Detection of low-volume, low-grade tumors Overdetection in young men Overdetection rates calculated in older men should not be extrapolated to younger men In fact, overdetection is impossible to prove in very young men, as even focal, indolent tumors can acquire aggressive features over time Example of a Statistical Model Overdetection 27% at age 55 vs. 56% at age 75 4

5 Low Grade High Grade Our calculations show that the prostate overdiagnosis rate of 33% is associated with annual screening for men between the ages of assuming a mean preclinical sojourn time [time cancer remains in a preclinical state] of 10 years and exam sensitivity of 0.9. Example of a Computer Simulation Model JNCI 94:981,

6 Bias for overdetection Overdiagnosis 44% blacks vs. 29% whites Autopsy cancers detected: 15% in whites vs. 37% in blacks Excess Incidence Rates without Decrease in Mortality Rates Excess incidence rate does not necessarily mean excessive overdetection It is not excessive overdetection if increase in incidence is followed by a decrease in mortality, as in the US (37.5% decrease in mortality) Ciatto, S et al Eur J Cancer 41: 411, 2005 SEER. Accessed 10/27/08 Example of High Incidence-to-Mortality Rate Florence Pilot Screening Study Observed-to-expected incidence and mortality rates from registry: first screen was 12.5 and second screen was 4.1 Estimated a 66% excess incidence over 9-year period Observed no decrease in all-cause mortality Caveats: age 60-74; PSA > 10 ng/ml for biopsy; twice as many T3 cancers detected as T1c Assuming all patients would be screened and biopsied and including older patients intruduces a bias towards overdetection High PSA cutoff detecting advanced cancer and short follow-up introduces a bias against reducing mortality Ciatto, S et al Eur J Cancer 41: 411,

7 Other Reports of Overdetection Detection of cancer in 22% in the Prostate Cancer Prevention Trial when the incidence rate in the general population is 18% and death rate is is only 3% In PCPT, all men were actively screened and many were biopsied for no cause In clinical practice ~50% are screened and biopsies are performed only for cause Epstein JI et al Urology 66:356, 2005 Incidence-to-Mortality vs. Other Cancers The ratio of PCa incidence to mortality appears to be relatively high (8:1) compared to 1.3 for lung cancer and 2.1 for colon cancer Many state that the high incidence in the US suggests a potentially higher detection rate of clinically insignificant tumors Would it be desirable for 1 of every 2 men diagnosed with prostate cancer to die of it? One possible reason for the high ratio is that many men with potentially lethal cancers are diagnosed early and cured with effective treatment Autopsy Cancers Autopsy Studies Cancers that otherwise would not be detected during the patient s lifetime (e.g., autopsy cancers) 7

8 WSU Coroner s Autopsy Study: Prevalence of cancer by decade AA (N=617) C (N=420) Autopsy studies Autopsy studies have shown that approximately 1 in 3 men aged >50 years has histologic evidence of prostate cancer. Up to 80% of these cancers are less than 0.5 cm in side and low grade. Konety et al reported a significant decrease in the prevalence of (more extensive) autopsy cancer after the introduction and widespread use of PSA testing He proposed that PSA screening is identifying autopsy cancers before death from other causes Konety BR et al J Urol 174:1785, Core Biopsy Detects 50% of Autopsy Cancers Men > 60 years old at autopsy No clinical evidence of prostate cancer Median PSA 2.2 ng/ml Step sectioning detected cancer in 29% 12-core biopsy detected 50% of these cancers J Urol 179:892,2008 Haas GP et al, JNCI 99:1484,

9 Not All Autopsy Cancers Are Harmless Because a cancer was first detected at autopsy for traumatic or violent death, does not necessarily mean that it could not have caused suffering or death in the future, if an untimely cause of death had not intervened Overdetection in Surgical Series Example of using a nomogram to estimate overdetection in surgical patients Organ confined, < 0.5 cc volume, no poorly-differentiated elements Kattan, et al, using his nomogram estimated that 20% of tumors treated with radical prostatectomy their series were insignificant cancers Kattan et al J Urol 2003, 170: 1792 Example: Gleason Score to Estimate Overtreatment Overdetection & Overtreatment Miller et al used SEER data to estimate that from 2000 to 2002: 10% of low-risk patients were over-treated with radical prostatectomy vs. 45% with radiotherapy However, men were categorized into risk groups based only upon Gleason score without taking into consideration other tumor features that are used for treatment decisions in clinical practice Example: Estimating Overdetection in a Screening Study Using Ohori et al and Epstein et al Criteria in Surgical Patients J Urol 175:902,

10 Underdetection vs. Overdetection Underdetection more common than overdetection Graif et al: 2,126 men with stage T1c 1-7% overdiagnosed vs % underdiagnosed Pelzer et al: 680 men PSA % overdiagnosed vs % underdiagnosed Graif T et al, J Urol 2007;178:88-92 Pelzer AE et al, J Urol 2007;178:93-7 Are All Low-Volume, Low-Grade Cancers Harmless? It is argued that patients with low-grade cancer rarely suffer or die from prostate cancer Not true with long-term follow-up Albertsen PC et al JAMA 1995; 274:626 Johansson JE et al JAMA 2004;291:2713 Death Rates from Low-Grade Prostate Cancer The watchful waiting studies of Johansson et al and of Albertsen et al are frequently cited to show that cancer-specific mortality rates are low for men with low-grade tumors diagnosed in the pre-psa era In the Johansson studies, there was a 3-fold increase in cancer progression and mortality after 15 years of follow-up This was not observed in the Albertsen study, but in Albertsen s study many of the patients were old at the time of diagnosis and died of other causes before their prostate cancer could kill them; >30% of all deaths in patients with Gleason 6 were from prostate cancer Gleason 6 Patients with Cause of Death Determined Age at Dx PCa death (No.) Other death (No.) % PCa death 31% 34% 31% 28% 10

11 PCa Mortality and Screening by PSA and DRE: Population-Based Study Prostate Cancer Screening Saves Lives King County Seattle in men aged 50 to 64 years, PSA screening reduced prostate cancer specific mortality by 62% Did not see this effect in men > 65 years Agalliu I Cancer Causes Control 2007;18:931 PCa Mortality Relates to PSA Screening Evaluated PCa death rates and number of urologists per population More urologists per population resulted in higher percentage of PSA screening and correlated to lower prostate cancer death rates in white men but not black men Colli and Amling, Pros Ca and Pros Diseases :247 Quantifying PSA Screening s Effect on PCa Mortality Rate Does PSA screening explain >30% PCa mortality decline in the U.S. SEER Database? 2 independent groups used their respective mathematical models Both attribute most, but not all, (45% and 70%, respectively) of the PCa declines to PSA screening Etzioni, et al. Ca Causes and Control 19:175,

12 Example of National Mortality Rate Trends Interpreting Trends in PCa Incidence and Mortality in the 5 Nordic Countries Rapid increase in incidence during early 1990s (except Denmark, which occurred 5 years later) coincided with introduction of PSA Mortality rates have recently stabilized or declined in countries where PSA testing and curative treatment have been commonly practiced but have continued to increase in Denmark Trends are consistent with moderate effect of curative treatment of early diagnosed PCa and improved treatment of advanced disease Kvale R et al JNCI 2007;99: Example of WHO Global Mortality Rate Trends The trends in prostate cancer mortality rates in examined countries suggest that PSA screening may be effective in reducing mortality from prostate cancer. 12

13 Pattern A: Prostate Cancer Mortality Lower than before PSA Era Pattern B: Prostate Cancer Mortality Decreasing but Still Higher than Before PSA Era Pattern C: Prostate Cancer Rate Still Increasing Constantly (18 of 38 Countries Examined) Conclusion PCa overdetection rates based upon epidemiologic criteria are estimated to be 20-85% (exaggerated) Based upon surgical pathology data are 7-20% (still an overestimate) Prostate cancer mortality rates have decreased by 37.5% in the U.S. in the PSA era and also have decreased in 20 of 38 other countries examined in WHO database 13

14 Conclusion: Overdetection: A Relatively Small Issue When considered in the context of the larger issue of preventing suffering and death from prostate cancer Especially when good clinical judgment is used And patients receive appropriate, effective, high-quality treatment Practical Strategy Avoid under-detection by beginning regular screening early and by identifying the most aggressive cancers early by rapidly rising PSA, Gleason score, and biopsy findings Deal with the risks of possible overdetection by using good clinical judgment in selecting patients for treatment and ensuring their treatment is high-quality and effective 14