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Trends in Relative 5 Year Survival RateTime Period Survival Rate1975-1977 68%1987-1989 83%2002-2008 100%
Prostate Cancer…more men die with it than of it 80% found at autopsy 16% diagnosed during their lifetime 3% will die of it
Risk Factors for Prostate CancerAgeFamily HistoryHormonesRaceDietary FatMultivitamin useDairy and Calcium IntakeCadmium Exposure (-)Dioxin Exposure (-)
Can you PreventProstate Cancer?Based on solid evidence, chemoprevention withfinasteride and dutasteride reduces the incidenceof prostate cancer, but the evidence is inadequateto determine whether chemoprevention withreduces mortality from prostate cancer.
Prostate Cancer Prevention Trials•(PCPT) Prostate Cancer Prevention Trial the 24.8% reduction ofprostate cancer prevalence over a 7-year period in those mentaking the 5alpha-reductase inhibitor, finasteride (Proscar 5mg perday)•REDUCE study using dutasteride (Avodart) (-23%)•CombAT Trial (Avodart + Tamsulosin (Flomax) (-40% and noincrease in high grade cancers)•SELECT study using vitamin E and selenium (worse, Viy Eincreased prostate cancer by 17%)•Physicians Health Study (PHSII) beta-carotene, Vit E, C ormultivitamins (no benefit)
Vitamins E and C in the Prevention of Prostate and Total Cancer in Men ThePhysicians Health Study II Randomized Controlled Trial JAMA. 2009;301(1):52-62
Age Distribution of Men Diagnosed with Prostate Cancer 2000-2010 39%40%35% 28%30% 22%25%20%15% 7%10% 3%5% 1%0% 30 40 50 60 70 80 90 Age
The evidence is insufficient to determinewhether screening for prostate cancerwith prostate-specific antigen (PSA) ordigital rectal exam (DRE) reducesmortality from prostate cancer.
Men who have at least a 10-y life expectancyshould have an opportunity to make aninformed decision with their health careprovider about whether to be screened forprostate cancer. Asymptomatic men whohave less than a 10-year life expectancybased on age and health status should not beoffered prostate cancer screening.
Median Life Expectancy in Men by Health (poor, average or excellent)
? Proven Benefit from PSA Screening ERSPCEuropean Randomized Screening for Prostate Cancer (ERSPC)Trial, 182,000 men age 50-74y, PSA yearly for 4 yearsMedian follow up of 11 years Screen No ScreenDiagnosis of prostate cancer 7.4% 5.1%Deaths from prostate cancer 299 462Death risk prostate cancer 0.79 1.00Conclusion: screen lowers the death rate by 21%, butyou would need to screen 1,055 men and treat 37 toprevent one death
Mortality results from the Göteborgrandomized population-basedprostate-cancer screening trial.University of Göteborg, Sweden.Lancet Oncol. 2010 Aug;11(8):725-32. Epub 2010 Jul 2. 20,000 men, age 50 to 64, half PSA every 2 years 14 year follow up Screen Control prostate cancer 12.7% (1.64) 8.2%Screening had 44% lower 0.5% (0.56X) rate so had prostate death prostate death 0.9%to screen 293 and treat an additional 12 to save 1
? Proven Benefit from PSA Screening PLCO StudyProstate, Lung, Colorectal, Ovary US Study, n = 76,693 , annual PSA for 6 years and DRE 4 years, with 13 years follow up Screen No ScreenIncidence cancer 1.22 1prostate cancer death 50 44mortality rate/100,000 2 1.7
Prostate, Lung, Colorectal, and Ovarian (PLCO) CancerScreening Trial on prostate-cancer mortality. NEJM.org March 18, 200976,693 men at 10 U.S. study centers, Men in the screening group wereoffered annual PSA testing for 6 years and digital rectal examination for 4years.Incidence 22% higher Mortality was 13% higher (not lower)
Long Term PLCO Trial• Those who had 2 or more early PSA screenings had 25% lower prostate cancer mortality• Those with minimal comorbidities had a 44% reduction in prostate cancer mortality. Treat an additional 5 to save 1 Prostate Cancer Mortality No screen screen JCO February 1, 2011 vol. 29no. 4 355-361
Prostate Cancer ScreeningMata-analysis of 6 trials ( n = 387,286)• Odds of diagnosing prostate cancer = increased by 46%• Odds of being in stage I = increased by 95%• Impact on prostate cancer mortality = none• Impact on overall survival = none BMJ. 2010 Sep 14;341:c4543
Prostate Cancer ScreeningMata-analysis of 6 trials ( n = 387,286) Favor Screening Favor Control BMJ. 2010 Sep 14;341:c4543
Check for a baseline PSA at age 40 and if 1 orover go to annual (if less than 1 start screeningat 50) Median PSA for Men age 40 – 49 median 0.5 to 0.7 75th percentile is 0.7 to 0.9
• If PSA is > 2.5 or higher or velocity is 0.35/y consider biopsy or check Free-PSA• If PSA 4-10 get biopsy or at least free-PSA• If over 10 get biopsy
Probability of finding cancer in men withclinically normal prostate glands but PSAbetween 4 – 10 using Free PSAPSA Cancer % Free PSA Age 50 - 64y Age 65 - 75y0.5 6.60% 0 - 10% 56% 55%.6-1 10% 10.1 - 15% 24% 35%1.1-2 17% 15.1 - 20% 17% 23%2.1-3 24% 20.1 - 25% 10% 20%3.1-4 27% > 25% 5% 9%4-10 25-30%>10 42-64%
Prostate Cancer Biopsy Predictor http://www.aboutcancer.com/prostate_calc_main_page.htm
Positive High Grade Biopsy by Age, Race and PSA80%70%60%50% W5540% W7030% B55 B7020%10%0% 2.5 4 10 20 50
Radical Prostatectomy versus Observation for Localized Prostate CancerProstate Cancer Intervention versus Observation Trial (PIVOT).From November 1994 through January 2002, we randomly assigned 731men with localized prostate cancer (mean age, 67 years; median PSAvalue, 7.8 ng per milliliter) to radical prostatectomy or observation andfollowed them through January 2010.Patients had to be medically fit for radical prostatectomy and to havehistologically confirmed, clinically localized prostate cancer (stage T1-T2NxM0) of any grade diagnosed within the previous 12 months.Patients also had to have a PSA value of less than 50 ng per milliliter, anage of 75 years or less, negative results on a bone scan for metastaticdisease, and a life expectancy of at least 10 years from the time ofrandomization. NEJM 2012; 367:203
Death from Any Cause During the median follow- up of 10.0 years, 47.0% assigned to radical prostatectomy died, as compared with 49.9% assigned to observation absolute risk reduction, 2.9 percentage points). Among men assigned toDeath from Prostate Cancer radical prostatectomy, 5.8% died from prostate cancer or treatment, as compared with 8.4% assigned to observation absolute risk reduction, 2.6 percentage points NEJM 2012; 367:203
Incidence of death from prostate cancer in a randomized trial thatcompared radical prostatectomy with watchful waiting.Only the young men (< 65 years) did poorly without activetreatment Death from Prostate Cancer
Patient Reported Dysfunction at 2 YearsDysfunction Surgery ObservationUrinary 17.1% 6.3%IncontinenceErectile 81.1% 44.1%DysfunctionBowel 12.2% 11.3%Dysfunction NEJM 2012; 367:203
Treating prostate cancer Surgery? Radiation?Or Watchful Waiting?
Prostate Cancer Treatment120 in 2008 from NCDB100 80 Surgery 60 Radiation Watchful Waiting 40 20 0 18-64 65-74 75-85
Choices with Prostate Cancer1. Depending on the man’s life expectancy and the nature of the specific cancer (Gleason score) is treatment necessary?2. If treatment is appropriate how to choose between surgery or radiation?
Watchful Waiting or Active Surveillance NCCN appropriate for: 1. Very low risk cancers and life expectancy < 20 y 2. Low Risk and life expectancy < 10 y
Very Low Recurrence Risk1. Stage T1c2. Gleason 6 or lower3. Less than 3 cores positive and none over 50%4. PSA density < 0.15 (so PSA was 5 and volume 35g then density would be 0.14 or 5/35)
Watchful Waiting, the odds that untreated prostatecancer would cause death related to the age and the GleasonScore
Active Surveillance• Limited to men with low risk cancer and shorter life expectancy• PSA every 3 to 6 months• DRE every 6 to12 months• Repeat biopsy may be considered every 12 months up to the age of 75• Repeat biopsy if increased PSA or PSA velocity Considered Disease Progression and Reason to Initiate Therapy • If Gleason Grade 4 or 5 is found on repeat biopsy • If prostate volume increase (number of + biopsies or the extent of the cancer)
Partin Tables: calculate the risk that thecancer is already outside the capsuleprior to therapy
Laparoscopic Prostate Surgery The surgeon tries to dissect the prostate away from the rectum, bladde r, the neurovascular bundle (nerves) and penile urethra
Radiation Fields with Prostate CancerA Low Dose Large Area (Phase 1) With radiation it is possible to include a wider area around the prostate to cover any cells that may have escaped After the highest safe dose is reached, the radiation target will be made smaller
Radiation Fields with Prostate CancerA High Dose Large Area (Phase 2) The final, high dose radiation target will be focused very precisely only on the prostate gland
Prostate Cancer Risk Groups combine all 3 things, thestage, the PSA level and the Gleason score•Low risk: (T1c, T2a Gleason 6, PSA <10)•Intermediate risk: (T2b, T2c, Gleason 7, PSA 10-20)•High risk: (T3, Gleason 8-10 or PSA > 20)
Cure Rates with Radiation versus Surgery forEarly Stage Prostate Cancer are the same from the Cleveland Clinic. Kupelian. JCO Aug 15 2002: 3376-3385
10 Year Cure Rates for Patients with High Risk Prostate Cancer (PSA >20 or Gleason 8-10 or T3)Treatment Number Cure RateRadical Prostatectomy 1,238 92%Radiation/Hormones 344 92%Radiation 265 88% Mayo Clinic Study (Cancer Jan 10, 2011)
Long-Term Functional Outcomes after Treatment for Localized Prostate Cancer The Prostate Cancer Outcomes Study (PCOS), comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis• Urinary Incontinence: worse with surgery at 2 and 5 years but the same by 15 years• Erectile Dysfunction: worse with surgery at 2 and 5 years but the same by 15 years• Bowel Urgency: worse with radiation at 2 and 5 years but by 15 years the same N Engl J Med 2013; 368:436-445
Sexual Function afterRadiotherapy orSurgery N Engl J Med 2013; 368:436-445
Quality of Life / Medicare Survey Prostate Cancer PatientsSymptom Surgery RadiationWear Pads 30% 7%Potent (< 70y) 11% 33%Potent (>70y) 12% 27%More frequent bowel 3% 10%movements J Clin Oncol 14 (8): 2258-65, 1996
Potency Rates after Surgery can range from 2% to70%) Did they have a ‘nerve sparing’ prostatectomy? Hold old is the man? How high was the PSA? How good was their sexual function before? JAMA. 2011;306(11):1205-1214
Potency Results after ExternalRadiation can range from 16% to 92% Did they get hormone therapy along with the radiation? How high was the PSA prior to radiation? How good was their sexual function before?
Responded to ViagraSurgery: 43%Radiation: 70 – 91%General Population: 80% from other studies in the literature
Choosing Treatment Prostate Cancer Urologist with experience and a good outcome with the procedureExperienced RadiationOncologist withModern Technology(IGIMRT) and goodoutcome data
The experience of the surgeon is a criticalfactor associated with a successful outcomeOpen prostatectomy the learning curve did notplateau until a surgeon had performed at least250 retropubic radical prostatectomies Theprobability of biochemical recurrence at fiveyears was significantly lower (10.7 versus 17.9percent)
Minimally invasive prostatectomy – In aseries of 4,702 men who were managed withlaparoscopic prostatectomy by one of 29surgeons at seven centers,the five-year risk of recurrence progressivelydecreased with increasing experience (17, 16,and 9 percent with 10, 250, and 750 priorlaparoscopic procedures)
Using the proper dose of radiation “It may be a bit over-exposed”
Prostate Cures Rates by Treatment,The Radiation Dose is Critical External beam > 72Gy Surgery or Seeds External beam < 72Gy IJROBP 2004; 58:25 Months
Cure Rate (PSA cure) in 2991 Men By Therapy Best results with high dose external
Prostate Cancer Relapse Rate by Radiation Dose < 72Gy 72 - 82Gy 82Gy Years Kupelian. IJROBP 2008:71:16
Goal = radiation zone precisely around the prostate cancer with small margin bladder prostateRadiation zone rectum
IMRT (intensitymodulatedradiation therapy) using 7 different beamsto target the prostateThe computer candetermine the optimalnumber of beams todeliver the radiationdose to hit the target andavoid other structures
After IMRT was established then IGRT(image guided) was introduced
Lower Risk of Side Effects with ImageGuided IMRT compared to IMRT
Better Cure Rates with Image Guided IMRT compared to IMRT for Prostate Intermediate Risk High Risk
The most sophisticated technique for image guided IMRT is Tomotherapy.Combine a CT scan and linear accelerator to ultimate intargeting (IGRT) and ultimate in delivery (dynamic, helicalIMRT) ability to daily adjust the beam (ART or adaptiveradiotherapy)
There is significant movement of the prostate gland based on daily gas in rectum Planned target No Rectal gasPlanned target,missed badly ifrectal gas pushesthe prostate Rectal gasforward
Expose the patient’s activated T cells to cancer antigen targetsThen re-infuse thepatient’s activated cells(atc’s) back into themwhich will attack prostatecancer cells
FDA Approval 4.29.10median OS of 25.8 months compared to 21.7months for patients who received the controltreatment There was no difference in time-to-progression.The total cost for three courses of treatmentwith Sipuleucel-T is $93,297.60
Phase 3 TROPIC clinical study involving 755 patients with mHRPC previously treated with a docetaxel-containingMedian overall survival in the patients receiving JEVANA + prednisone was 15.1 months compared to 12.7 monthstumor response rates were 14.4% and 4.4% for cabazitaxel-treated and mitoxantrone-treated patients respectively, FDA Approval 6.18.10
Xgeva the first and only RANK Ligand inhibitor toprevent SRE (skeletal related events in cancer)FDA Approval 11.19.10
Recent advances have demonstrated thatandrogen-based pathways continue to have aclinically significant role in the progression ofcastrate-resistant prostate cancer. In addition to androgen production by theadrenal gland and testis, several of the enzymesinvolved in the synthesis of testosterone anddihydrotestosterone, including CYP17, are highlyexpressed in tumor tissue
ZYTIGA is an oral androgen biosynthesis inhibitor that works by inhibiting the CYP17 enzyme complex, which is required for the production of androgens at these three sources.FDA Approval 4.28.11
Zytiga and prednisone combination had a median overall survival of 14.8 months compared to 10.9 months for patients receiving the placebo and prednisone combination.
August 2012In clinical trials, men who received the drug, which waspreviously known as MDV3100, lived a median of 18.4months, nearly five months longer than the median of13.6 months for those who received a placebo. Before2004, the only drug shown to prolong the survival of menwith advanced prostate cancer wasthe chemotherapy drug docetaxel. Now there are fourothers on the market — Jevtana, Provenge, Zytiga and
Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is asecond generation androgen receptor antagonist drug for the treatment ofmetastatic castration-resistant prostate cancer.Enzalutamide has approximately fivefold higher binding affinity for theandrogen receptor (AR) compared to the antiandrogen bicalutamide(Casodex)
www.aboutcancer.com Cancer Information Cancer Videos Tomotherapy Cyberknife Other Topics Dr. Miller
www.aboutcancer.comCancer Information •Basic Cancer Information •General Cancer Statistics •Most Common Cancers * brain * breast * colon/rectum * gynecologic * lung * prostate •Other Specific Cancers Radiation or Chemotherapy •All Other Cancer Topics •Other Topics •Best Web Sites
Robert Miller MD Medical Channelbone metastasesbrain metastasesbreast cancer: understanding the disease, treatment decisionshead and neck cancer (mouth, throat, larynx understanding the disease, radiation treatmentlung cancer: understanding lung cancer, radiation treatmentsprostate cancer: understanding the disease, treatmentdecisions, radiation therapyskin canceruterine (endometrial cancer) aboutcancer.com/you_tube_videos