Carcinoma of the Prostate

1. Carcinoma of the Prostate Prevention, Screening, Diagnosis, and Treatment Roland T. Skeel, M.D.

2. Conflict of Interest Disclosure • Neither I nor my immediate family members have any Financial Interests or Significant Relationships that might affect – or reasonably appear to affect – this presentation on “Prostate Cancer”

3. 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.

4. Carcinoma of Prostate • Most common cancer in United States with exception of skin cancer • Increases in new cases by 50% between 1980 and 1990 • New cases in 2009 – 192,280 (Est.), 80 % early disease • Deaths – 27,360 (Est.) • Increasing number of “non-lethal” tumors being diagnosed • 1 in 6 will be diagnosed, 1 in 35 will die from it. (10% of cancer related deaths in men.)

5. Survival Rates – Prostate Cancer • 5-year relative survival rate nearly 100% • 10-year relative survival rate is 91% • 15 year relative survival rate is 76%

9. 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 • Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy – not much effect, BUT…….

10. Risk Factors for Prostate Cancer Claimed by some studies • Diet Red meat, high fat dairy products Fruits, vegetables, grains • Exercise and maintaining healthy weight may decrease the risk

11. Finasteride Chemoprevention for Prostate Cancer • Finasteride = 5-alpha reductase inhibitor, blocks intracellular conversion of testosterone to dihydrotestosterone • Based on solid evidence, chemoprevention with finasteride reduces the incidence of prostate cancer (6% absolute; 25% relative risk reduction), but the evidence is inadequate to determine whether chemoprevention with finasteride reduces mortality from prostate cancer. • Harms: erectile dysfunction, loss of libido, gynecomastia, higher grade cancers. Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003

12. Chemoprevention - Other • The Selenium and Vitamin E cancer Prevention Trial was a large randomized placebo-controlled trial of Vitamin E and selenium, alone or in combination. It failed to demonstrate that these drugs reduce prostate cancer in relatively healthy men. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009

13. Early detection and screening • Digital rectal exam – Feel for nodules • PSA – How high? • Transrectal ultrasound – not for screening First two tests are convenient and inexpensive, but consequences may not be

14. ACS, AUA, ACR, NCI Screening Recommendations • No major scientific or medical organizations, including the American Cancer Society (ACS), American Urological Association (AUA), US Preventive Services Task Force (USPSTF), American College of Physicians (ACP), National Cancer Institute (NCI), American Academy of Family Physicians (AAFP), and American College of Preventive Medicine (ACPM) support routine testing for prostate cancer at this time. • In 2008 the USPSTF concluded that the risks of screening for prostate cancer outweigh the benefits for men age 75 years or older. • The ACS and AUA recommend that health care professionals offer the option of testing for early detection of prostate cancer to all men who are at least 50 years old (or younger if at higher risk).

15. PSA and Prostate Cancer Risk • When prostate cancer develops, the PSA level usually goes above 4. Still, a level below 4 does not mean that cancer isn't present -- about 15% of men with a PSA below 4 will have prostate cancer on biopsy. Men with a PSA level in the borderline range between 4 and 10, have about a 1 in 4 chance of having prostate cancer. If the PSA is more than 10, the chance of having prostate cancer is over 50%

16. Confounding Factors for PSA • Increase • BPH • Age • Prostatitis • Ejaculation • Decrease • Finasteride, dutasteride • Some herbal mixtures • Obesity

17. Under investigation: PSA Density, PSA Velocity, % free PSA • PSA Density - Normalized to prostate volume • PSA Velocity - Change in PSA over time (e.g., more than 15% per year) • Free PSA/Total PSA - lower ratio suggests cancer, since more free PSA from normal prostate is degradated (< 10% - biopsy)

18. Presenting Symptoms of Prostate Cancer • Decreased urinary stream • Urinary frequency • Hematuria • Bone pain • LE numbness or weakness • Badder/bowel incontinence

19. Understood:• Natural history• Prevalence • Patterns of spread Questions:• Universal use of screening tests• Choices of therapy• Contributing factors Prostate Cancer: Remarkably Common With Many Unanswered Questions ? ? ? Sources: Nelson WG, DeMarzo AM, Isaacs WB. Prostate cancer. NEJM. 2003;349:366-381.

20. Aging and Prostate Cancer • As men age, prostate cells are increasingly likely to turn cancerous • Autopsies reveal: - Age 30-40: 29% prevalence - Age 60-70: 64% prevalence Bad News: American male has a 16.7% risk of being diagnosed with prostate cancer Good News: In most cases, the cancer cells are slow growing and occur late in life – only 3.5% of U.S males die from prostate cancer Sources: Nelson WG, DeMarzo AM, Isaacs WB. Prostate cancer. NEJM. 2003;349:366-381. 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.

21. Why Has Diagnostic Progress Not ResultedIn 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.

22. Use of PSA Testing is a Double-Edged Sword Illustrates challenges of using imperfect markers/surrogates to indicate disease. “Although the use of PSA testing in the United States has led to earlier diagnosis and a marked shift in the stage at which prostate cancer is identified, it is unclear whether PSA testing reduces the rate of death from prostate cancer.” Unresolved dilemma: Over-treating clinically unimportant disease revealed by PSA testing vs. Under-treating clinically important disease that goes undetected without extensive use of PSA testing – Clinical experts Sources: 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.

23. PSA Levels and Their Predictive Value for Diagnosis Other conditions besides prostate cancer can increase PSA levels • infection • inflammation • benign growths 2004 Study of men: PSA never above 4ng/ml; no abnormal rectal exam Percent with prostate cancer PSA level (ng/ml) 26% 24% 17% 10% 7 % 3.1 to 4.0 2.1 to 3.0 1.1 to 2.0 .6 to 1.0 less than .5 In those with cancer and low PSA levels, 12.5% had aggressive, rapidly multiplying high-grade tumors likely to spread. Sources: Cooner WH, Mosley BR, Rutherford CL Dr. et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol. 1990;143:1146-52. Cited in Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Krumholtz JS, Carvalhal GF, Ramos CG, et al. Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features. Urology. 2002;60:469-473.

24. Economics of Treating and Screening For the Disease Cost of treating prostate cancer in California – $360 million per year Cost of universal screening (as previously recommended by ACS) – approximately $12.7 billion per year Savings from increased diagnosis at earlier stages, minus increased costs from pursuing false positives or occasional high-grade tumors with false negative PSAs remains to be explored. Against PSA Screening (all men 50+) American Urological Association American Cancer Society National Cancer Institute U.S. Preventive Services Taskforce Sources: Max W, et al. The economic burden of prostate cancer in California. Cancer. June 2002;94:2906-13.

25. What Can We Learn? Markers are imperfect predictors requiring a strong understanding of the upsides and downsides when used Prevention requires screening — screening often relies on markers Answer is not to throw away markers, but learn from and improve them

26. Effect of Early Diagnosis • Unknown: In areas where there is aggressive screening, the incidence in higher than where there is not; the death rate from prostate cancer is similar • Randomized trials to test screening underway • Conclusion: • Do not screen over age 70, or if life expectancy < 10 years • Do not screen under age 60, unless strong family history • Recognize limitations age 60-70

27. Prostate Cancer Survival • Related to • Stage • Grade • Extent of tumor at diagnosis • Local disease - Median Survival > 5 years • Metastatic disease Median Survival 1-3 years, but individuals may survive 10 or more years

28. Establishing a Diagnosis of Prostate Cancer • DRE • PSA/PSA velocity/percent-free PSA • Transrectal U/S • U/S- guided biopsy

29. Evaluation of Abnormal PSA or Prostate Mass • Ultrasound guided needle biopsies (6-12) • If positive, Gleeson score (2 predominant histologies). Range - 2 (1+1) to 10 (5+5) • 2-4 - Best • 5,6 - Intermediate • 7-10 - Worse • PSA < 10, rarely have detectable metastatic disease

30. What Does the Grade of the Tumor Mean? Grade of a tumor is predictive of its likelihood to spread beyond confines of the prostate, affecting curability. 12% of low-gradetumors (2-4)spread beyond prostate in 10 years 33% of medium-gradetumors (5,6) spread beyond prostate in10 years 61%of high-grade tumors (7-10) spread beyond prostate in 10 years Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999. Prostate Cancer in California. Ed. Mill PK. Public Health Institute. 2000.

31. Staging and Prognostic Factors • TNM staging system • Prognostic Factors • Gleason grading • DNA analysis by flow cytometry • PSA level • Predictive models for organ-confined versus non-organ confined disease

32. Staging Prostate Cancer • Abdominal and pelvic CT scans • Chest x-ray • Bone scan • LFT’s • Serum PSA and acid phosphatase

33. Staging Prostate Cancer • Stage I - T1a and grade 1 (Incidental, early) • Stage II - • T1a and Grade 2-4; T1b,c (By biopsy only) • T2 (Confined to Prostate) • Stage III - T3 (Through prostate capsule) • Stage IV - T4 (Invades adjacent structures), N1-3, M1

34. Recurrence Risk for Clinically Localized Prostate Cancer • Low Risk: • T1-T2a and Gleason score 2-6 and PSA < 10 ng/ml • Intermediate Risk: • T2b-T2c or Gleason score 7 or PSA 10-20 • High Risk: • T3a or Gleason score 8-10 or PSA > 20 • Very High Risk: • T3b-T4(locally advanced)

35. Treatment Decisions for Clinically Localized Prostate Cancer • Based on recurrence risk (Low, intermediate, or high) and • Life expectancy (<10 years vs > 10 years).

36. Prostate - Goals of Therapy • Primary Therapy • T1a - Except in very young (< 60), follow with no therapy • T1b, T1c, T2 - radical prostatectomy or high dose radiation therapy. (May also observe if low-grade) • T3 (Stage III) - Usually treated with radiation therapy • Metastatic - Treat when symptoms. • In high risk disease, may add hormonal therapy

37. Radical Retropubic Prostatectomy (RRP) • “Nerve Sparing” procedure developed by Walsh consisted of modified surgical technique to control blood and enhance visibility within surgical site. • Allowed for the identification and potential preservation of the nerves that control erectile function (potency). • Two neurovascular bundles on either side of the prostate that control erectile function.

38. The Da Vinci Robot • Surgeon operates from a console with a 3-D screen. • Grasp controls to manipulate surgical tools within the patient. • Robotic arms translate finger, hand, and wrist movements. • Very High-Precision ? http://www.intuitivesurgical.com

39. Radiation Therapy (RT) • High-Powered X-Rays that damage DNA and kill prostate cancer cells. • External Beam Radiation Therapy (EBRT): X-rays aimed at prostate. • Brachytherapy: Radioactive seed implants into prostate.

40. External Beam Radiation Goal: Maximize damage to the prostate and minimize damage to surrounding tissues (i.e. bladder and rectum) Seminal Vesicles Prostate

41. Urethra Ultrasound-guided bead placement for even distribution Uneven Distribution Brachytherapy: Distribution Cross-Section of Prostate

42. Image of Prostate With Radioactive Bead Implants

43. RT: Complications EBRT • Most symptoms occur during treatments and subside after completion. • Diarrhea, rectal irritation, fatigue, frequent and painful urination, blood in the urine. • Erectile dysfunction: less common than radical prostatectomy following treatment but slower recovery.

44. RT: Complications Brachytherapy • High initial dose of radiation that slowly fades over 1 year. • Prostate inflammation and swelling, sometimes with severe urinary symptoms. • Other, more rare symptoms include persistent urinary and bowel frequency and urgency. • Erectile dysfunction: similar to EBRT.

45. Watchful Waiting • A.K.A. observation, expectant therapy or deferred therapy. • Diagnosis of an early-stage (T1-T2), low-grade tumor. • No medical treatment is provided. • Patient receives regular follow-up to monitor tumor.

46. Why Wait? • PSA and DRE can detect prostate cancer at a very early stage. • Average doubling time of a prostate tumor is quite slow (2-4 years). • Immediate radical therapy may constitute over-treatment and an introduce unnecessary urinary and potency risks. • May be appropriate if the patient is elderly and/or in poor health, and will live out their life spans without the cancer causing problems. • May also be appropriate for a younger patient who is willing to be vigilant and accept the risk of the cancer spreading.

47. Treatment of Symptomatic Metastatic Disease 1. Hormonal Therapy - initial therapy for locally advanced or metastatic disease • Orchiectomy • Estrogens (No longer used) • LHRH analogs (+/- anti-androgens) • Antiandrogens + finasteride • Second line therapies consist of one of therapies not used before, e.g., anti-androgens if used only LHRH analogs

49. Adrenal Androgen Testosterone 5% 95% Prostate Growth and Function Testes Hormone Therapy • Prostate cells and prostate cancer cells are dependant upon androgens (male sex hormones) for survival and growth. • Removal of androgens kills a majority of prostate cancer cells.

50. Adjuvant Hormone Therapy • Hormone therapy (androgen ablation) is a standard method of treating advanced and metastatic prostate cancer. • However, for newly-diagnosed advanced cancers, androgen ablation may be performed prior to prostatectomy or radiation in order to shrink the tumor. • The effectiveness of this technique is still under debate.