Carcinoma of the ProstatePrevention, Screening, Diagnosis, and Treatment

Roland T. Skeel, M.D.

Conflict of Interest DisclosureNeither 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

ObjectivesList risk factors for prostate cancer, and discuss relative strengthDiscuss potential prevention strategiesDiscuss benefits and risks of prostate cancer screening, including expected survival ratesCounsel patients about primary treatment options for local diseaseRecommend systemic therapy for advanced cancer.

Carcinoma of ProstateMost common cancer in United States with exception of skin cancerIncreases in new cases by 50% between 1980 and 1990New cases in 2009 192,280 (Est.), 80 % early diseaseDeaths 27,360 (Est.)Increasing number of non-lethal tumors being diagnosed1 in 6 will be diagnosed, 1 in 35 will die from it. (10% of cancer related deaths in men.)

Survival Rates Prostate Cancer5-year relative survival rate nearly 100%10-year relative survival rate is 91%15 year relative survival rate is 76%

Risk Factors for Prostate CancerAge Rare before 40; 65% over the age of 65Race - 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, brotherNationality - North America and NW Europe vs Asia, Africa, Central and South AmericaGenetics BRCA1 and BRCA2 increase risk, but account for very small percentage of prostate cancerObesity, Diet, Exercise, prostatitis, STDs, Vasectomy not much effect, BUT.

Risk Factors for Prostate Cancer Claimed by some studiesDiet Red meat, high fat dairy productsFruits, vegetables, grainsExercise and maintaining healthy weight may decrease the risk

Finasteride Chemoprevention for Prostate CancerFinasteride = 5-alpha reductase inhibitor, blocks intracellular conversion of testosterone to dihydrotestosteroneBased 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

Chemoprevention - OtherThe 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

Early detection and screeningDigital rectal exam Feel for nodulesPSA How high?Transrectal ultrasound not for screening

First two tests are convenient and inexpensive, but consequences may not be

ACS, AUA, ACR, NCI Screening RecommendationsNo 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).

PSA and Prostate Cancer RiskWhen 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%

Confounding Factors for PSAIncreaseBPHAgeProstatitisEjaculationDecreaseFinasteride, dutasterideSome herbal mixturesObesity

Under investigation: PSA Density, PSA Velocity, % free PSAPSA Density - Normalized to prostate volumePSA 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)

Presenting Symptoms of Prostate CancerDecreased urinary streamUrinary frequencyHematuria

Bone painLE numbness or weaknessBadder/bowel incontinence

?Understood:Natural historyPrevalence Patterns of spread

Questions: Universal use of screening testsChoices of therapyContributing 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 increasingly likely to turn cancerousAutopsies reveal: - Age 30-40: 29% prevalence - Age 60-70: 64% prevalenceSources: 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. Bad News: American male has a 16.7% risk of being diagnosed with prostate cancerGood 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 Diagnostic Progress Not Resulted In Greater Long-Term Survival Rates? Death rate is comparatively low considering prevalenceLifetime risk of diagnosis: 1 in 6Lifetime 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 lifeRisk 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 100,000Prostate cancer cells are generally less aggressive with increasing age, suggesting many prostate cancers detected in routine practice may be clinically unimportantSources: 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.

Use of PSA Testing is a Double-Edged SwordIllustrates 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

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. Clinical experts

PSA Levels and Their Predictive Value for DiagnosisOther conditions besides prostate cancer can increase PSA levels infection inflammation benign growthsSources: 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. 26%24%17%10%7 %Percent with prostate cancerPSA level (ng/ml)3.1 to 4.02.1 to 3.01.1 to 2.0.6 to 1.0less than .52004 Study of men: PSA never above 4ng/ml; no abnormal rectal examIn 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 DiseaseCost 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.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 AssociationAmerican Cancer SocietyNational Cancer InstituteU.S. Preventive Services Taskforce

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

Effect of Early DiagnosisUnknown: In areas where there is aggressive screening, the incidence in higher than where there is not; the death rate from prostate cancer is similarRandomized trials to test screening underwayConclusion: Do not screen over age 70, or if life expectancy < 10 yearsDo not screen under age 60, unless strong family historyRecognize limitations age 60-70

Prostate Cancer SurvivalRelated toStageGradeExtent of tumor at diagnosisLocal disease - Median Survival > 5 yearsMetastatic disease Median Survival 1-3 years, but individuals may survive 10 or more years

Establishing a Diagnosis of Prostate CancerDREPSA/PSA velocity/percent-free PSATransrectal U/SU/S- guided biopsy

Evaluation of Abnormal PSA or Prostate MassUltrasound guided needle biopsies (6-12)If positive, Gleeson score (2 predominant histologies). Range - 2 (1+1) to 10 (5+5)2-4 - Best5,6 - Intermediate7-10 - WorsePSA < 10, rarely have detectable metastatic disease

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-grade tumors (2-4) spread beyond prostate in 10 years 33% of medium-grade tumors (5,6) spread beyond prostate in10 years61% of high-grade tumors (7-10) spread beyond prostate in 10 yearsSources: 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.

Staging and Prognostic FactorsTNM staging system

Prognostic FactorsGleason gradingDNA analysis by flow cytometryPSA levelPredictive models for organ-confined versus non-organ confined disease

Staging Prostate CancerAbdominal and pelvic CT scansChest x-rayBone scanLFTsSerum PSA and acid phosphatase

Staging Prostate CancerStage 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

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

Treatment Decisions for Clinically Localized Prostate CancerBased on recurrence risk (Low, intermediate, or high) and Life expectancy ( 10 years).

Prostate - Goals of TherapyPrimary TherapyT1a - Except in very young (< 60), follow with no therapyT1b, T1c, T2 - radical prostatectomy or high dose radiation therapy. (May also observe if low-grade)T3 (Stage III) - Usually treated with radiation therapyMetastatic - 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 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 RobotSurgeon 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-Precisionhttp://www.intuitivesurgical.com?

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.

External Beam RadiationGoal: Maximize damage to the prostate and minimize damage to surrounding tissues (i.e. bladder and rectum) ProstateSeminalVesicles

Brachytherapy: DistributionCross-Section of Prostate

Image of Prostate With Radioactive Bead Implants

RT: ComplicationsEBRTMost 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.

RT: ComplicationsBrachytherapyHigh 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.

Watchful WaitingA.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 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.

Treatment of Symptomatic Metastatic Disease1. Hormonal Therapy - initial therapy for locally advanced or metastatic diseaseOrchiectomyEstrogens (No longer used)LHRH analogs (+/- anti-androgens)Antiandrogens + finasterideSecond line therapies consist of one of therapies not used before, e.g., anti-androgens if used only LHRH analogs

Hormone TherapyProstate 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.

Adjuvant Hormone TherapyHormone 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.

Removing AndrogensOrchiectomy (castration): surgical removal of the testicles.Oral drug which has the same effect as castration. Blocks testosterone production. Include LHRH agonists and (oral estrogens). Anti-androgens which block the effects of testosterone. (Blocks binding of DHT to androgen receptors.)5- reductase inhibitor (enhances intracellular androgen blockade)Combination therapies.

LHRH AnalogsGoserelin (Zolodex)Leuprolide (Lupron)

Available as every 1, 3, or 4 month injectionsCastrate levels of testosterone attainable in a few weeks

AntiandrogensFlutamideBicalutamideNilutamide

Combined androgen blockade not superior to LHRH therapy aloneHigher cost and more side effects than LHRH therapy alonePrimary value when starting LHRH to limit the flare reaction

Finasteride and bicalutamide as primary hormonal therapy in advanced adenocarcinoma of the prostateDuration of control comparable to castration, with preserved sexual function in some patientsWith recurrence, some patients may still respond to LHRH agonists

Tay, MH et al. Annals of Oncology 15:974, 2004

Results of Androgen RemovalImpotence Loss of sexual desire (libido) Hot flashes Weight gain Fatigue Reduced brain function Loss of muscle and bone massSome cardiovascular risks

Hormone-Refractory Prostate Cancer (HRPC)Despite initial response rates of 80-90%, nearly all men with advanced prostate cancer develop hormone-resistant prostate cancer after 18-36 months. These hormone-refractory (HR) prostate cancer cells can grow in the absence of androgens.The behavior of HR prostate cancers differ widely between patients.

Treatment of Symptomatic, Hormone Refractory Metastatic Disease1. Cytotoxic chemotherapyDocetaxel (every three weeks) and prednisone improves pain and reduces need for analgesic agents MitoxantroneOther agents have had limited effectivenessContinue hormone therapy to prevent flare with rising testosterone levels.2.Bisphosphonates - decreases skeletal complications

Treatment of Symptomatic Metastatic Disease3. Radiation therapyExternal beam radiotherapyRadioisotopes, such as Strontium 89

Evaluation of ResponsePSA and Acid Phosphatase are useful in selected circumstancesBone scans are difficult, because increase can be seen in healing as well as worsening

Complications of Systemic Prostate Cancer TherapyAll hormonal therapies can cause sexual dysfunction and decreased libido; less with finasteride and anti-androgenOrchiectomy - rarely local infection or hematomaAnti-androgen - diarrhea, hepatic dysfunctionEstrogen - thromboembolic disease, fluid retention, cardiac diseaseChemotherapy - nausea, vomiting, mucositis, marrow suppression, and alopecia

Management of Prostate Cancer Bone MetastasesGoal: prevent pain, improve mobility, prevent complications such as fractures or compression.Goal: Maintain acceptable quality of life.Methods: bis-phosphonates, radiation of detected metastatic lesions, surgery.?

ConclusionsRisk factors are age, family history, race, and possibly diet and exerciseOverall survival excellent (many years)Early detection can find localized cancer, but survival benefits still uncertainTreatment depends on grade, extent and location of diseaseSurgery and radiation are equivalent therapeutic tools for localized prostate cancerHormonal therapy is effective for metastatic prostate cancerHormone refractory prostate cancer responds to chemotherapy, with occasional long term improvement.

2007 Estimated US Cancer Deaths*ONS=Other nervous system.Source: American Cancer Society, 2007.Men 289,550Women 270,10026%Lung & bronchus15%Breast10%Colon & rectum 6%Pancreas 6%Ovary 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Brain/ONS 2% Liver & intrahepaticbile duct23% All other sitesLung & bronchus31%Prostate9%Colon & rectum 9%Pancreas6%Leukemia4%Liver & intrahepatic4% bile ductEsophagus4%Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney3%All other sites 24%

Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2004WomenMenNumber of Cancer DeathsMenWomenSource: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

2007 Estimated US Cancer Cases**Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.26%Breast15%Lung & bronchus11%Colon & rectum6%Uterine corpus 4%Non-Hodgkin lymphoma 4%Melanoma of skin 4% Thyroid 3%Ovary 3%Kidney3%Leukemia21%All Other SitesProstate29%Lung & bronchus15%Colon & rectum10%Urinary bladder7%Non-Hodgkin4% lymphomaMelanoma of skin4%Kidney4%Leukemia 3%Oral cavity3%Pancreas2%All Other Sites19%

Men 766,860Women 678,060

Cancer Incidence Rates*, All Sites Combined, All Races, 1975-2003*Age-adjusted to the 2000 US standard population and adjusted for delay in reporting.Source: Surveillance, Epidemiology, and End Results Program, 1973-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.Both SexesMenWomenRate Per 100,000

Cancer Death Rates*, for Men, US,1930-2003*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.Lung & bronchusColon & rectumStomachRate Per 100,000ProstatePancreasLiverLeukemia

Cancer Incidence Rates* for Men, 1975-2003*Age-adjusted to the 2000 US standard population and adjusted for delays in reporting.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.ProstateLung & bronchusColon and rectumUrinary bladderNon-Hodgkin lymphomaRate Per 100,000Melanoma of the skin

All sites 331.0239.21.4

Prostate 65.1 26.72.4

Larynx 5.1 2.22.3

Stomach 12.4 5.42.3

Myeloma 8.6 4.42.0

Oral cavity and pharynx 6.9 3.81.8

Esophagus 10.7 7.61.4Liver and intrahepatic bile duct 9.6 6.31.5

Small intestine 0.7 0.41.8

Colon and rectum 33.6 23.71.4

Lung and bronchus 98.4 73.81.3

Pancreas 15.7 12.01.3

Cancer Sites in Which African American Death Rates* Exceed White Death Rates* for Men, US, 1999-2003*Per 100,000, age-adjusted to the 2000 US standard population.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

SiteAfrican AmericanWhiteRatio of African American/White

All Sites6857 11Breast (female)9077 13Colon 6654 12Esophagus1712 5Leukemia5039 11Non-Hodgkin lymphoma6456 8Oral cavity6240 22Prostate10098 2Rectum6659 7Urinary bladder8365 18Uterine cervix7566 9Uterine corpus8661 25Cancer Survival*(%) by Site and Race,1996-2002*5-year relative survival rates based on cancer patients diagnosed from 1996 to 2002 and followed through 2003. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2006.

SiteWhite% DifferenceAfricanAmerican

Five-year Relative Survival (%)* during Three Time Periods By Cancer Site*5-year relative survival rates based on follow up of patients through 2003. Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2006.Site1975-19771984-19861996-2002All sites505366Breast (female)757989Colon 515965Leukemia354249Lung and bronchus131316Melanoma828692Non-Hodgkin lymphoma485363Ovary3740 45Pancreas23 5Prostate6976100Rectum495766Urinary bladder737882

Recent* Prostate-Specific Antigen (PSA) Test Prevalence (%), by Educational Attainment and Health Insurance Status, Men 50 Years and Older, US, 2001-2004*A prostate-specific antigen (PSA) test within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System Public Use Data Tape (2001, 2002, 2004), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2002, 2003, 2005.

Recent* Digital Rectal Examination (DRE) Prevalence (%), by Educational Attainment and Health Insurance Status, Men 50 Years and Older, US, 2001-2004*A digital rectal examination (DRE) within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System Public Use Data Tape (2001, 2002, 2004), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2002, 2003, 2005.

Prostate GlandGland found only in menSits below the urinary bladder in front of the rectumNormal size of gland is same as a walnutCells of the prostate make fluid contained in the seminal fluid which nourishes sperm

Prostate AnatomyPelvicBone(Pubis)UrethraBladderRectumProstateSeminal Vesicle

Prostate cancer is present in about 2 million, mostly older men in the United StatesAt birth, prostate is about the size of a peaProstate experiences 2 growth spurts- at puberty - around age 50 Prostate sits at base of the bladder with urethral urine outflow tube tunneling through its centerIts function is to produce the majority of the seminal fluid that carries sperm forward with ejaculationSources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999. Facts About the Prostate

Early Diagnosis in Younger Men is More Common Today Than 25 Years Ago Increased use of early blood screening and diagnostic tests 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.Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. NEJM. 1991;324:1156-61. 1979 Prostate Specific Antigen (PSA) was discovered PSA is produced by prostate to help liquefy sperm Low level of PSA in bloodstream is normal PSA between 4ng/ml - 10ng/ml: 22% cancer rate PSA above 10ng/ml: 67% cancer rate1970s-80s Digital Rectal Exam/Finger-Guided Needle Biopsy Once found, cancer was often beyond prostateMid-80s Rectal Probe Ultrasound Ability to critically examine prostate, biopsy carefully1991-92 PSA discovery confirmation Focus on earlier diagnosis

Results of Diagnostic Improvements Sources: Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. NEJM. 1991;324:1156-61. Cited in Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al.Brawer MK, Chetner MP, Beatie Jbuchner DM, Vessella RL, Lange PH. Screening for prostatic carcinoma with prostate specific antigen. J Urol. 1993;147:841-45. Cited in Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Men under age 65 29 per 100,000Numbers of Americans Diagnosed with Prostate Cancer1990Men over age 65 1,152 per 100,0002002Men under age 65 63 per 100,000Men over age 65 993 per 100,000 More cancers uncovered earlier, confined to the prostateEarlier intervention has yet to translate into improved long-term survival numbers.

History of the ProstatectomyHugh Hampton Young (Johns Hopkins) pioneered a systematic technique and performed the first radical perineal prostatectomy in 1904.1943 - Theodore Millin introduced the retropubic prostatectomy approach.1983 Patrick Walsh described a modified nerve-sparing retropubic approach to preserve potency.

The Nerve BundlesCross-Section of ProstateUrethraRectumNeurovascular Bundles of WalshProstate

RRP: The Surgical ApproachBladderProstateUrethraRectum1.5-4 hours, usually epidural anesthesia.

Incision:Begins just below navel and extends to pubic bone.

Remaining Urethra is sewn to bladder neck over a catheter.Surgical ApproachPelvicBone(Pubis)

RRP: ComplicationsSevere or life-threatening complications are rare.Incontinence (Urinary Control): complete incontinence is uncommon, although a significant number of patients experience some stress-incontinence. Usually improves with time.Impotence (Erectile Dysfunction): if both neurovascular bundles were spared, potency rates range from 30-86%, depending on institution. Usually improves over time, and other ED treatments can work.

RRP: AdvantagesWhole prostate - and thus the entire tumor - can be examined histologically.Surgeon has access to regional lymph nodes to test if prostate cancer cells have left the tumor.Surgical margin can be examined. Negative Surgical MarginPositive Surgical MarginNot all of tumor removedOR

Radical Perineal ProstatectomyBladderProstateUrethraRectumSurgical ApproachVery similar to Retropubic protocol (nerve sparing, sewing of urethra, etc.)

Incision:Between Anus and base of Scrotum.

PelvicBone(Pubis)

Perineal ProstatectomyComparison with RRP: Comparable cure rates as well as similar urinary and potency complications.

Disadvantages: Cannot access regional lymph nodesSlight increase in risk of rectal injury and associated complications.

Emerging Therapy: Laparoscopic Radical ProstatectomyEliminates the need for a large incision by using a telescopic instruments called a laparoscopes.

Small camera attached to the laparoscope allows the surgeon to view inside the abdomen.

Laparoscopic ProstatectomyAdvantages:Less blood loss.No large incision.Shorter hospital stay and earlier return to activities.Disadvantages:Longer procedureVariable surgical margins rates.Slower return of urinary continence.Variable potency rates.

General Procedure: EBRT and BrachytherapyEBRT:Map precise area that will receive radiation.Multiple treatments ~5 days/week for ~8 weeks. Each treatment takes about 10 minutes and no anesthesia is required.Brachytherapy40-100 rice-sized radioactive seeds are implanted into the prostate via ultrasound-guided needles. Anesthesia is required.All radiation inside the pellets is generally exhausted within a year.

History of Radiation Therapy1898 The first use of newly discovered X-rays was to alleviate the pain of pelvic bone metastases.Early use of external beam radiation therapy was limited because of power necessary to reach deep-seated cancers such as prostate cancer.1950s New and more powerful isotopes and machines were discovered and built. Today Computers and improved radiation technologies allow high-dose and high-precision treatment of prostate tumors.

History of Brachytherapy1909 Minet first placed a radium tube in a catheter to irradiate prostate cancer. 1970s Real interest occurred when Whitmore described an implant technique using I-125. Inconsistent dose distribution was a problem.1985 Holm and Ragde used TransRectal UltraSound (TRUS) to position Pd-103 implants and established a national brachytherapy implant course.

CryotherapyDestroys prostate cells by freezing tissue.Old idea that is making a comeback due to greater precision and better methods of imaging and temperature monitoring.Method: insertion of sub-zero cryoprobes into prostate perineally (between scrotum and anus).As yet unresolved how effective cryotherapy is compared to surgery or radiation.

***[title appears] Prostate cancer is a remarkably common disease with many remaining unanswered questions. [bold line and first bullet appear] While the natural history of this cancer, [second bullet appears] its prevalence and [third bullet appears] patterns of spread are well understood, [second bold line and question marks appears] open questions surround [first bullet appears] the universal use of screening tests, [second bullet appears] choices of therapy, [third bullet appears] and contributing factors such as genetics and diet. *[title, photo and first bullet appear] As men age, the cells that make up the prostate gland are increasingly likely to turn cancerous. In fact, [second bullet appears] autopsies of [first subbullet] men age 30 to 40 show cancer cells in 29 percent of their prostates and [second subbullet] for those age 60 to 70, 64 percent are effected.1 [blue box and bad news appears] Over a lifetime, an American male has a 16.7 percent risk of being diagnosed with prostate cancer.3 Thats the bad news. [good news appears] But in most cases, the cancer cells are slow growing and occur late in life. As a result, only 3.5 percent of males die from prostate cancer in the United States. *[title and 1st blue text line appear] To begin with, death rates from prostate cancer are comparatively low considering its prevalence. [first bullet] While 1 in 6 men in a lifetime will be diagnosed with the cancer, [second bullet] fewer than 1 in 33 have traditionally died from it.2 In fact, due to its slow growth, [third bullet] the 5-year survival rate is 98 percent. [second blue text line] Thus far, the diagnostic and therapeutic advances have improved quality of life, but not necessarily the years of life. [first bullet] Risk of having prostate cancer is clearly tied to age. [first subbullet] Overall incidence of the disease is 17.7 cases per 100,000 U.S. men. [second subbullet] But for men age 75 to 84, there are 248 diagnoses per 100,000 and [third subbullet] for those over 85, 591 per 100,000 are affected.7 Counter-balancing this reality is the fact [bottom blue text appears] that prostate cancer cells are generally less aggressive with increasing age, leading experts to suggest that many prostate cancers detected in routine practice may be clinically unimportant. *[title appears] The use of PSA testing has proven to be a double-edged sword, [blue text appears] illustrating the challenges faced when using imperfect markers or surrogates to indicate disease. [quote appears] Clinical experts from private institutions and the National Cancer Institute declared in 2004: 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.3 [black text appears] The unresolved dilemma: [blue text line] over-treating clinically unimportant disease revealed by extensive but imperfect PSA testing [vs. and bottom text appear] versus under-treating clinically important disease that goes undetected if one forgoes the extensive use of partially reliable PSA testing. *[title appears] When PSA testing was first widely utilized in the early 1990s, the consensus was that a value above 4 nanograms per milliliter had predictive value for a diagnosis of prostate cancer.8 [top blue text appears] But it was clear that other conditions could increase PSA levels, [first bullet] including infection, [middle bullet] inflammation or [third bullet] benign growths.4 By 2002 it had become clear that a value of 2.5 nanograms per milliliter or more was as equally predictive as a value of 4. [2004 line appears] An extensive 2004 study of nearly 3,000 men whose PSA was never above 4 and who never had an abnormal digital rectal exam has further raised eyebrows. In this group, [blue titles and first line appear] 26 percent with values of 3.1 to 4.0 had prostate cancer, [second line] 24 percent with values of 2.1 to 3.0 had prostate cancer, [third line] 17 percent with values of 1.1 to 2.0, [fourth line] 10 percent with values of .6 to 1.0 and [fifth line] 7 percent with PSA values less then .5 nanograms per milliliter. To add fuel to the fire, [bottom text appears] in those who had cancer and the lowest PSA values, 12.5 percent of the cancers were aggressive, rapidly multiplying high-grade tumors most likely to spread early. *[title and blue text line appear] As for the economics, a study of the cost of treating prostate cancer annually in California revealed $180 million in direct costs and $180 million in indirect costs, or [black text line ] $360 million per year.10On the other hand, [blue text appears] the cost of universal screening as recommended by the American Cancer Society would [black text appears] likely be $12.7 billion per year.11 [blue box with text appears] The savings that might result from increased diagnosis at earlier stages, minus increased costs from pursuing false positives or missing the diagnosis of occasional high-grade tumors with false negative PSAs remains to be explored.[left hand bottom text appears] While the American Urologic Association and the American Cancer Society in 2000 stood squarely behind PSA screening of all men over 50, [right hand text appears] the National Cancer Institute and the U.S Preventive Services Taskforce were opposed.

*[title appears] What can we learn from all this? [1 line appears] First, markers are imperfect predictors requiring a strong understanding of the upsides and downsides when used. [2 line appears] Second, prevention requires screening, and screening often relies on markers. [3 line appears] Third, the answer is not to throw away markers, but rather constantly learn from them, and improve on them. For prostate cancer, there remains opportunity for improvement.For Health Politics, Im Mike Magee. ****[title, photo and top text appear] The grade of a tumor is predictive of its likelihood to spread beyond the confines of the prostate, thus affecting curability. [12% info appears] Low-grade tumors, 12 percent of the time, grow beyond the confines of the prostate within 10 years. [33 info appears] Medium grade tumors spread 33 percent of the time within 10 years. [61 info appears] And high grade tumors spread 61 percent of the time within 10 years. *********Lung cancer is, by far, the most common fatal cancer in men (31%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death. *From 2003 to 2004, the number of recorded cancer deaths decreased by 1,160 in men and by 1,854 in women, resulting in a total decrease of 3,014 total cancer deaths. This drop was significantly larger than the 369 fewer deaths reported from 2002 to 2003, which marked the first decline in actual number of cancer deaths since 1930, when nationwide mortality data began to be compiled.

The decrease in the number of Americans dying from cancer is a result of declining cancer death rates outpacing the impact of growth and aging of the population. *Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.4 million new cases of cancer will be diagnosed in 2007. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women. *This slide shows trends in cancer incidence for all sites combined, for the years 1975-2003. Incidence rates stabilized in men from 1995 to 2003 and increased in women by 0.3% per year from 1987 to 2003. *Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing. Stomach cancer mortality has decreased considerably since 1930. Death rates from prostate and colorectal cancers have also been declining. *Between 1988 and 1992, prostate cancer incidence rates increased dramatically due to earlier diagnosis with prostate-specific antigen (PSA) blood testing, after increasing steadily from 1975 to 1988. Incidence rates for both lung and colorectal cancers in men have declined in recent years.*African Americans have higher cancer death rates than whites for numerous cancer sites. Death rates for myeloma and cancers of the prostate, larynx, stomach, oral cavity, esophagus, liver, small intestine, colon and rectum, lung and bronchus, and pancreas are all higher in African-American men than in white men.

*The 5-year relative survival rate from cancer is 68% for whites and 57% for African Americans (taking normal life expectancy into consideration). For many sites, survival rates in African Americans are 10% to more than 20% lower than in whites. This is due, in part, to African Americans being less likely to receive a cancer diagnosis at an early, localized stage, when treatment can improve chances of survival. Additional factors that contribute to the survival differential include unequal access to medical care and tumor characteristics. *The survival rates for all cancers combined and for certain site-specific cancers have improved significantly since the 1970s, due, in part, to both earlier detection and advances in treatment. Survival rates markedly increased for cancers of the prostate, breast, colon, rectum, and for leukemia. With new treatment techniques and increased utilization of screening, there is hope for even greater improvements in the not-too-distant future. *This graph shows that the percentage of men who have had a PSA test within the past year decreased by 6 percentage points from 2001. Men with less than a high school education and men with no health insurance were less likely to report a PSA test than all men 50 and older. *This graph shows that the percentage of men who have had a DRE within the past year decreased by approximately seven percentage points from 2001. Men with less than a high school education and men with no health insurance were less likely to report a DRE than all men 50 and older. The American Cancer Society suggests that men speak with their physician to make an informed decision on prostate cancer screening. *[title and first bullet appear] Prostate cancer is believed to be the most common cancer in the United States -- currently estimated to be present in some 2 million, mostly older men.2 [second bullet appears] At birth, the prostate is little more than the size of a pea, [third bullet appears] experiencing two growth spurts, [subbullet appears] one at puberty, [second subbullet] the other at around 50 years of age. [fourth bullet appears] The organ sits at the base of the bladder with the urethral urine outflow tube tunneling through its center. [fifth bullet appears] The organs function is to produce the majority of the seminal fluid that carries sperm forward with ejaculation. *[title appears] Early diagnosis of often latent, slow growing and less aggressive cancer cells in somewhat younger men is much more common today than it was 25 years ago. [first text line] This is the result of the increasingly common use of early blood screening and minimally invasive diagnostic tests.3 [1979 line appears] In 1979, Prostate Specific Antigen or PSA was first discovered. [first bullet] PSA is a naturally occurring substance that is produced by the prostate to help liquefy sperm.2 [second bullet] It is normal to have low levels of PSA in the blood stream. In 1991, a study of 1,653 men revealed [third bullet] that men with PSA between 4 nanograms per milliliter and 10 nanograms per milliliter had a 22 percent incidence of prostate cancer and [fourth bullet] those with levels above 10 had a 67 percent incidence.4With these findings, the approach to diagnosing prostate cancer radically changed. [70s-80s line appears] In the 1970s and 1980s, physicians relied on digital rectal exams, which allowed them to feel for bumps on the back of the prostate where most cancers arise. When they felt one, they performed a finger-guided needle biopsy. [first bullet] If cancer was detected, it was often already beyond the confines of the prostate, aggressively growing, and frequently beyond treatment. Logic dictated that if you could detect the cancer sooner, you could change the course of the disease.[mid80s line appears] In the mid 1980s, the use of rectal probe ultrasound [bullet appears] allowed physicians to more critically examine the entire prostate and more carefully direct the needle biopsy of a mass. [1991-92 line appears] When the association between PSA elevations was uncovered in 19914 and confirmed in 1992,5 it served [bullet appears] to focus both physicians and patients attention on earlier diagnosis.

*[title and first text line appear] In part, as a result, the numbers of Americans diagnosed with prostate cancer increased over the next 15 years. [1990 appears] In 1990, rates in [text line and bullet appear] U.S. men under age 65 were 29 per 100,000 while [right hand text line and bullet appear] those for men over 65 were 1,152 per 100,000. [2002 appears] By 2002, [left hand text and bullet appear] rates in those under age 65 had risen to 63 per 100,000 while [right text and bullet appear] rates in those over 65 had declined to 993 per 100,000.6 [bullet appears] Not only are more cancers being uncovered earlier, but more of them are confined to the prostate. [blue box and text appear] Yet the earlier intervention has yet to translate into improved long-term survival numbers.