1、Carcinoma of the Prostate,Prevention, Screening, Diagnosis, and TreatmentRoland T. Skeel, M.D.,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 “Pr
2、ostate Cancer”,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 Recomme
3、nd systemic therapy for advanced cancer.,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 bein
4、g diagnosed 1 in 6 will be diagnosed, 1 in 35 will die from it. (10% of cancer related deaths in men.),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%,Risk Factors for Prostate Cancer,Age Rare before
5、 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
6、- 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.,Risk Factors for Prostate Cancer Claimed by some studi
7、es,Diet Red meat, high fat dairy products Fruits, vegetables, grains Exercise and maintaining healthy weight may decrease the risk,Finasteride Chemoprevention for Prostate Cancer,Finasteride = 5-alpha reductase inhibitor, blocks intracellular conversion of testosterone to dihydrotestosterone Based o
8、n 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 li
9、bido, 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,Chemoprevention - Other,The Selenium and Vitamin E cancer Prevention Trial was a large randomized placebo-contro
10、lled 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
11、E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009,Early detection and screening,Digital rectal exam Feel for nodules PSA How high? Transrectal ultrasound not for screeningFirst two tests are convenient and inexpensive, but consequences may not be,ACS, AUA, ACR, NCI Screening Recommendati
12、ons,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 A
13、merican 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
14、 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).,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 isnt present - about 15%
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%,Confounding Factors for PSA,Increase BPH A
16、ge Prostatitis Ejaculation Decrease Finasteride, dutasteride Some herbal mixtures Obesity,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 sugg
17、ests cancer, since more free PSA from normal prostate is degradated ( 10% - biopsy),Presenting Symptoms of Prostate Cancer,Decreased urinary stream Urinary frequency HematuriaBone pain LE numbness or weakness Badder/bowel incontinence,?,Understood: Natural history Prevalence Patterns of spread Quest
18、ions: 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.,Aging and Prostate Cancer, As men age, prostate cells are increasin
19、gly likely to turn cancerous Autopsies reveal:- Age 30-40: 29% prevalence - Age 60-70: 64% prevalence,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 pro
20、state-specific antigen level 4.0 ng per milliliter. NEJM. 2004;350:2239-2245.,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,Why Has Di
21、agnostic Progress Not Resulted In 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 necessari
22、ly 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
23、unimportant”,Sources: Mayo C. Prostate Cancer Guide. Available at: http:/ 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.,Use of PSA Testing is a Double-Edg
24、ed 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
25、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,Sources: Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Pre
26、valence of prostate cancer among men with a prostate-specific antigen level 4.0 ng per milliliter. NEJM. 2004;350:2239-2245., Clinical experts,PSA Levels and Their Predictive Value for Diagnosis,Other conditions besides prostate cancer can increase PSA levels infection inflammation benign growths,So
27、urces: 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
28、 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.,26% 24% 17% 10% 7 %,Percent with prostate cancer,PSA level (ng/ml),3.1 to 4.0 2.1 to 3.0 1.1 to 2.0 .6 to
29、1.0 less than .5,2004 Study of men: PSA never above 4ng/ml; no abnormal rectal exam,In those with cancer and low PSA levels, 12.5% had aggressive, rapidly multiplying high-grade tumors likely to spread.,Economics of Treating and Screening For the Disease,Cost of treating prostate cancer in Californi
30、a $360 million per yearCost of universal screening (as previously recommended by ACS) approximately $12.7 billion per yearSavings 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 exp
31、lored.,Sources: Max W, et al. The economic burden of prostate cancer in California. Cancer. June 2002;94:2906-13.,Against PSA Screening (all men 50+),American Urological Association American Cancer Society,National Cancer Institute U.S. Preventive Services Taskforce,What Can We Learn?,Markers are im
32、perfect predictors requiring a strong understanding of the upsides and downsides when usedPrevention requires screening screening often relies on markersAnswer is not to throw away markers, but learn from and improve them,Effect of Early Diagnosis,Unknown: In areas where there is aggressive screenin
33、g, 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-
34、70,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,Establishing a Diagnosis of Prostate Cancer,DRE PSA/PSA velocity/percent-free PSA Transre
35、ctal U/S U/S- guided biopsy,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,What Does
36、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-grade tumors (2-4) spread beyond prostate in 10 years 33% of medium-grade tumors (5,6) spread beyond prostate in10 years 61% of high-grade tumors (
37、7-10) spread beyond prostate in 10 years,Sources: Mayo C. Prostate Cancer Guide. Available at: http:/ Prostate Cancer in California. Ed. Mill PK. Public Health Institute. 2000.,Staging and Prognostic Factors,TNM staging systemPrognostic Factors Gleason grading DNA analysis by flow cytometry PSA leve
38、l Predictive models for organ-confined versus non-organ confined disease,Staging Prostate Cancer,Abdominal and pelvic CT scans Chest x-ray Bone scan LFTs Serum PSA and acid phosphatase,Staging Prostate Cancer,Stage I - T1a and grade 1 (Incidental, early) Stage II - T1a and Grade 2-4; T1b,c (By biops
39、y only) T2 (Confined to Prostate) Stage III - T3 (Through prostate capsule) Stage IV - T4 (Invades adjacent structures), N1-3, M1,Recurrence Risk for Clinically Localized Prostate Cancer,Low Risk: T1-T2a and Gleason score 2-6 and PSA 20 Very High Risk: T3b-T4(locally advanced),Treatment Decisions fo
40、r Clinically Localized Prostate Cancer,Based on recurrence risk (Low, intermediate, or high) and Life expectancy ( 10 years).,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
41、 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,Radical Retropubic Prostatectomy (RRP),“Nerve Sparing” procedure developed by Walsh consisted of modified surgical technique to control
42、 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.,The Da Vinci Robot,Surgeon operates from a cons
43、ole 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:/,?,Radiation Therapy (RT),High-Powered X-Rays that damage DNA and kill prostate cancer cells.External Beam Radiation Therapy (EBRT):
44、 X-rays aimed at prostate.Brachytherapy: Radioactive seed implants into prostate.,External Beam Radiation,Goal: Maximize damage to the prostate and minimize damage to surrounding tissues (i.e. bladder and rectum),Prostate,Seminal Vesicles,Brachytherapy: Distribution,Cross-Section of Prostate,Image o
45、f Prostate With Radioactive Bead Implants,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 treatm
46、ent but slower recovery.,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 dysfunctio
47、n: similar to EBRT.,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.,Why Wait?,PSA and DRE can detect prostate cancer at a very earl
48、y 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
49、 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.,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,
