1. A Prostate Cancer Update: Screening, Over Diagnosis, and Treatment Matthew D. Katz, M.D. Assistant Professor Urologic Oncology Robotic and Laparoscopic Surgery University of Arkansas for Medical Sciences Winthrop P. Rockefeller Cancer Center

2. Anatomy Genitourinary System Campbell-Walsh UROLOGY, 9th edition

3. Prostate Cancer Most common non-skin cancer in men Second leading cause of cancer death in U.S. men About 25% of prostate cancers are thought to be clinically significant Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

4. New Cases and Death Estimates Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4.

5. Trends in Incidence Rates for Selected Cancers by Sex, United States, 1975 to 2010 Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4.

6. Trends in Death Rates Overall and for Selected Sites by Sex, United States, 1930 to 2010 Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4

7. Lifetime Risk of Developing CaP Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4. Probability of Developing Invasive Cancers Within Selected Age Intervals by Sex, United States, 2004–2006* BIRTH TO 39 (%)40 TO 59 (%)60 TO 69 (%) 70 AND OLDER (%) BIRTH TO DEATH (%) All sites†† Male1.43 (1 in 70)8.42 (1 in 12)15.61 (1 in 6)37.84 (1 in 3)44.05 (1 in 2) Female2.10 (1 in 48)8.97 (1 in 11)10.18 (1 in 10)26.47 (1 in 4)37.63 (1 in 3) Urinary bladder‡‡ Male0.02 (1 in 4,741)0.39 (1 in 257)0.95 (1 in 106)3.66 (1 in 27)3.81 (1 in 26) Female0.01 (1 in 10,613)0.12 (1 in 815)0.26 (1 in 385)1.01 (1 in 99)1.18 (1 in 84) BreastFemale0.49 (1 in 206)3.75 (1 in 27)3.40 (1 in 29)6.50 (1 in 15)12.08 (1 in 8) Colorectum Male0.08 (1 in 1,269)0.91 (1 in 110)1.48 (1 in 67)4.50 (1 in 22)5.39 (1 in 19) Female0.08 (1 in 1,300)0.72 (1 in 139)1.07 (1 in 94)4.09 (1 in 24)5.03 (1 in 20) Leukemia Male0.17 (1 in 603)0.21 (1 in 475)0.33 (1 in 299)1.19 (1 in 84) 1.51 (1 in 66) Female0.13 (1 in 798)0.15 (1 in 690)0.20 (1 in 504)0.78 (1 in 128)1.08 (1 in 92) Lung & bronchusMale0.03 (1 in 3,461)0.95 (1 in 105)2.35 (1 in 43)6.71 (1 in 15)7.73 (1 in 13) Female0.03 (1 in 3,066)0.79 (1 in 126)1.75 (1 in 57)4.83 (1 in 21)6.31 (1 in 16) Melanoma of the skin§§Male0.16 (1 in 638)0.64 (1 in 155)0.72 (1 in 138)1.77 (1 in 56)2.67 (1 in 37) Female0.28 (1 in 360)0.55 (1 in 183)0.36 (1 in 274)0.79 (1 in 126)1.79 (1 in 56) Non-Hodgkin lymphonaMale0.13 (1 in 782)0.44 (1 in 225)0.59 (1 in 171)1.71 (1 in 58)2.28 (1 in 44) Female0.09 (1 in 1,172)0.32 (1 in 315)0.44 (1 in 227)1.39 (1 in 72)1.92 (1 in 52) ProstateMale0.01 (1 in 9,422)2.44 (1 in 41)6.45 (1 in 16)12.48 (1 in 8)15.90 (1 in 6) Uterine cervixFemale0.15 (1 in 648)0.27 (1 in 374)0.13 (1 in 755)0.19 (1 in 552)0.69 (1 in 145) Uterine corpusFemale0.07 (1 in 1,453)0.73 (1 in 136)0.83 (1 in 121)1.23 (1 in 81)2.53 (1 in 40

8. Lifetime Risk of Dying from CaP Risk of dying from prostate cancer is ~3% Once metastatic disease develops there is no cure Prior to PSA screening only 25% of CaP presented confined to prostate vs. 91% since 5 year CSS rates increased from ~70% to 100% (from 1980s to early 2000s) Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4. Comprehensive Textbook of Genitourinary Oncology, 3rd edition Catalona et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270(8):948

9. Presentation Most patients are asymptomatic Diagnosed due to elevated PSA or abnormal DRE Advanced cancer may present with bone pain, unintentional weight loss, hematuria, worsening LUTS, urinary retention, hydronephrosis, LE weakness/leg numbness/difficulty with ambulation Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

10. Risk Factors Age + Family history African American Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

11. Prevention PCPT (Prostate Cancer Prevention Trial) – 18,000 men randomized to placebo vs. Proscar 5mg qDay – 7 year follow-up – Decreased risk of prostate cancer by 25% – Found small increase in high-grade cancer development – Further subset analysis did NOT show this to be true Thomson IM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med, 349, 2003 Kaplan SA et al. PCPT- Evidence that finasteride reduces the risk of most frequently detected intermediate and grade (Gleason score 6 and 7) cancer. Urology, 73, 2009

12. Prevention REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) – 8,000 men >50 yrs old were randomized to placebo vs. Dutasteride 0.5mg qDay – Follow-up 4 years – Decreased risk of developing Gleason score 5-6 cancer by 27% – Did not reduce risk of Gleason 7-10 cancer – Did not increase risk of developing high grade cancer – Enhanced ability of PSA to detect high grade cancers Andriole GL et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 362, 2010

13. Screening American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010 GuidelineAge to start CaP screeningSuggested Screening Tests AUA 200940PSA and DRE NCCN 201040PSA and DRE EAU45PSA and DRE ACS 201040-50 (depends on risk)PSA with or without DRE

14. Screening Should you screen at all? What age should you stop screening? Some advocate men >75 should not be screened* AUA and NCCN guidelines state that screening should be individualized based on overall health (life expectancy >10yrs, FH of longevity, minimal competing medical comorbidities) American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010 *U.S. Preventative Service Task Force Guidelines, 2008

15. Screening Controversial Does PSA-based screening lead to decrease in risk of death from prostate cancer? Advantages – May prolong survival and save lives – Save men from long painful death with little effective treatments available (costs?) Disadvantages – Overdiagnosis which leads to Overtreatment – Potential decrease in QOL from treatment (costs?) Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

16. 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 The Cancer Letter, Oct. 7, 2011

17. Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force 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

18. 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 USPSTF recommendations Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009 Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

19. PLCO (US trial) Prostate, lung, colorectal, ovarian Cancer screening trial (U.S.) – 76,693 men randomized – Ages 55-74 included – After 7 years risk of death same – Significant flaws in study makes conclusions questionable Found no survival benefit for PSA based screening Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

20. 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) Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

21. 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 Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

22. ERSPC screening trial (European) flaws Numerous sites of trial entry (7 countries) Mortality reduction of 20% came with large investment To prevent one cancer death, need over 1400 men to be screened over decade and 48 men would require treatment Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

23. 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) Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009 Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

24. 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.

25. Diagnosis PSA can be elevated secondary to BPH, prostatitis, recent ejaculation, prostate trauma (massage, biopsy, urethral instrumentation, cycling, etc…) Use of age and ethnicity adjusted PSA values Campbell-Walsh UROLOGY, 9th edition AgeCaucasianAfrican-AmericanAsian-American 40-490-2.50-2.0 50-590-3.50-4.00-3.0 60-690-4.5 0-4.0 70-790-6.50-5.50-5.0

26. Diagnosis PSA not perfect and can only be used to define risk of prostate cancer NOT diagnosis No universally accepted threshold value Decision to biopsy based on many different criteria (age, overall health, PSA velocity, PSADT, FH, race, etc…) Campbell-Walsh UROLOGY, 9th edition

27. Indications for Prostate Biopsy Suspicious DRE Age, ethnicity, +FH Abnormal total PSA Campbell-Walsh UROLOGY, 9th edition

28. When to Perform Imaging to Evaluate for Metastatic Disease Bone scan – Indicated: PSA>20, Gleason score ≥8, Bone pain Pelvic CT/MRI – Indicated: PSA>20, Gleason score ≥8 Newer data suggests fused PET/CT with 11 C- Acetate may be much better at detecting microscopic +LN Campbell-Walsh UROLOGY, 9th edition Oyama et al. 11 C-Acetate PET imaging of prostate Cancer: detection of recurrent disease at PSA relapse. 2003. J Nuc Med. 44; 549

29. When to Perform Imaging to Evaluate for Metastatic Disease (bone scan) Campbell-Walsh UROLOGY, 9th edition Total PSAProbability of +Bone Scan <102.3% 10-205.3% 20-5016% >50>35% Biopsy Gleason Score Probability of +Bone Scan ≤75.5% ≥828%

30. Pet Imaging in Prostate Cancer

31. Example of Positive LN

32. Prostate Cancer—Indolent vs. Aggressive? Risk based on individual results – PSA – DRE – Gleason Score: major score + minor score = sum score (1-5) + (1-5) = (2-10) – Number of + biopsies Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

33. 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 Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

34. Treatment options for Localized Prostate Cancer Active Surveillance Surgery Radiation Cryoablation Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

35. Active Surveillance Not discussed enough in this country Strict selection criteria Low risk: cT1-2a, PSA<10, life expectancy <10yrs, Gleason 6 or less Very low risk: cT1-2a, PSA<10, life expectancy up to 20yrs, Gleason 6 or less, <3 cores +, <50% of each core involved Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

36. Cryoablation (freezing of prostate) Cancer-specific outcomes not as mature as surgery or radiation – Almost all men will have significant ED after Tx – Not good option for locally advanced or high risk patients – Useful for men with previous pelvic radiation, rectal disorders, or inflammatory bowel disease Good salvage therapy option for men with recurrent disease after radiation, brachytherapy or cryoablation Campbell-Walsh UROLOGY, 9th edition

37. Radiation Various delivery methods – XRT (external beam radiotherapy) Whole pelvis, 3-D conformal, IMRT (intensity modulated radiation therapy) – Brachytherapy (radioactive seeds) Temporary high dose rate (usually combined with XRT boost) permanent low dose rate Campbell-Walsh UROLOGY, 9th edition

38. Radiation For low risk disease IMRT or Brachytherapy good treatment choices – No need to add ADT For intermediate risk disease should add ADT – 2 months before, during, and for 6 months after XRT For high risk disease should add longer course of ADT – Just before, during, and for 3 years after XRT No randomized prospective trials comparing surgery to radiation D’Amico et al. Androgen suppression and radiation vs. radiation alone for prostate cancer. JAMA, 299, 2008 Bolla et al. Three years of adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy. N Engl J Med, 337, 1997

39. Surgery Different approaches to remove prostate – Open – Laparoscopic (use straight instruments) – Robotic (use wristed instruments with 7 degrees of freedom) Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

40. Surgery Only form of treatment with randomized trial revealing CSS and OS advantage when compared to surveillance Survival benefit was seen for men <65 yrs of age Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group 4 randomized trial. J Natl Cancer Inst, 100, 2008

41. Surgery Authors of that study recently published updated 15 year follow-up data Again found CSS and OS benefit for men undergoing RP vs. surveillance in <65 yrs of age Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

42. Original Article Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D., Ph.D., Hans Garmo, Ph.D., Jennifer R. Rider, Sc.D., Kimmo Taari, M.D., Ph.D., Christer Busch, M.D., Ph.D., Stig Nordling, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D., Ph.D., Anders Spångberg, M.D., Ph.D., Ove Andrén, M.D., Ph.D., Juni Palmgren, Ph.D., Gunnar Steineck, M.D., Ph.D., Hans-Olov Adami, M.D., Ph.D., and Jan-Erik Johansson, M.D., Ph.D. Volume 370(10):932-942 March 6, 2014, N Engl J Med

43. Original Article Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer This randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. Follow-up of 18 years Volume 370(10):932-942 March 6, 2014, N Engl J Med

44. Prevalence of Metastases and Use of Palliative Treatment in Men Alive at Various Time Points since Randomization Bill-Axelson A et al. N Engl J Med 2014;370:932-942 Volume 370(10):932-942 March 6, 2014, N Engl J Med

45. 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

46. 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

47. 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

48. Conclusions Prostate cancer very common problem Need to know which men to offer screening, when to begin and end, and how often to offer screening Currently we overdiagnose, which leads to overtreatment of prostate cancer in U.S. Desperately need to find better ways to delineate aggressive forms of prostate cancer from indolent disease in order to offer treatment to men who will benefit and spare those who will not