Prostate Cancer Screening, Evaluation and Treatment Jamison S. Jaffe, D.O. Director of Minimally Invasive Urologic Surgery Director of Robotic Surgery Drexel University College of Medicine Hahnemann University Hospital

Objectives Prostate cancer background Screening in 2010 Prostate cancer prevention Current treatment options Robotic explosion

Prostate Cancer Definition Histology An uncontrolled growth of cells in the prostate gland Histology Adenocarcinoma is most common

Prostate Cancer Statistics Prostate cancer is the most common non- skin cancer in America A nonsmoking male is more likely to get prostate cancer than the next 7 most common cancers combined

Etiology Genetics Race Diet Hormones Strong familial predisposition Higher risk of developing prostate cancer Presents 6-7 years earlier HPC1 gene and PCAP gene are on chromosome 1 Race African American men have a higher prevalence and more aggressive prostate cancer than white men Diet A high-fat diet may lead to increased risks, while a diet rich in soy may be protective? Hormones Data implicating hormonal causes are indirect evidence ?

Prostate Cancer Symptoms Pre-PSA era Urinary retention - 20-25% Back or leg pain - 20-40% Hematuria - 10-15% PSA era Urinary frequency - 38% Decreased urine stream - 23% Urinary urgency - 10% Hematuria - 1.4% * None of these complaints are unique to prostate cancer

Screening Controversial American Urological Association American Cancer Society National Comprehensive Cancer Network

Screening It is inherent that as we maximize the detection of early prostate cancer we will increase the detection of both non-aggressive and aggressive prostate cancers The challenge is to identify the biology of the cancer that is detected and thus identify cancers that, if treated effectively, will result in a significant decrease in morbidity and mortality NCCN Practice Guidelines 2009

Screening The decision to participate in an early detection program for prostate cancer is complex for both the patient and physician Important factors that must be considered when beginning an early-detection program include Patient age Life expectancy Family history Race Previous early detection test results. NCCN Practice Guidelines 2009

Screening Digital rectal exam (DRE) Prostate specific antigen (PSA)

PSA Screening There has been a gradual but steady decline in prostate cancer mortality in the U.S. of approximately 30%. This trend began fairly soon after the introduction of PSA testing Ries et al: Posted to the SEER web site, 2008 Hankey et al: J Natl Cancer Inst, 91: 1017, 1999 Etzioni et al: Cancer Causes Control, 19: 175, 2008

AUA Screening Guideline All men starting at 40 years old should be screened Life expectancy of 10 year Annual screening Screening should be stopped at 75 years old The decision to use PSA for the early detection of prostate cancer should be individualized Patients should be informed of the known risks and the potential benefits

ACS Screening Guidelines Men have a chance to make an informed decision with their health care provider about whether to be screened for prostate cancer Uncertainties, risks, and potential benefits of prostate cancer screening need to be discussed Men should not be screened unless they have received this information Men without symptoms of prostate cancer who do not have a 10-year life expectancy should not be offered testing since they are not likely to benefit

ACS Screening Guidelines Screening should take place at age 50 for men who are at average risk of prostate cancer Screening should take place starting at age 45 for men at high risk of developing prostate cancer African Americans Men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65) Screening should take place at age 40 for men at even higher risk (those with several first-degree relatives who had prostate cancer at an early age)

ACS Screening Guidelines Men who choose to be tested who have a PSA of less than 2.5 ng/ml, may only need to be retested every 2 years. Screening should be done yearly for men whose PSA level is 2.5 ng/ml or higher

Mortality results from a randomized prostate-cancer screening trial Randomized 76,693 men at 10 U.S. study centers Annual screening Control group (usual care) 7 years of follow-up No statistically significant difference between the mortality rates of the two groups Heavily flawed Short follow-up Unusually high contamination rate (40-52% in the control) Andriole GL et al N Engl J Med. 2009;360:1310-1319

European Randomized Screening for Prostate Cancer Study 182,000 men between the ages of 50 and 74 Study groups PSA screening Average of once every 4 years Control group 20% “contamination” Death from prostate cancer was the primary outcome Schroder et al: N Engl J Med. 2009;360:1320-1328

European Randomized Screening for Prostate Cancer Study Incidence of prostate cancer was 8.2% in the screening group versus 4.8% in the control group 214 prostate cancer deaths in the screening group compared to 326 in the control Conclusions Screening program reduced mortality from prostate cancer by 20% High risk of over-diagnosis 1,410 men would need to be screened and 48 additional men would need to be treated to prevent one death from this malignancy Schroder et al: N Engl J Med. 2009;360:1320-1328

Prostate Specific Antigen PSA is a glycoprotein produced by the prostate gland Serum PSA levels are normally very low Disruption of the normal prostatic architecture allows greater amounts of PSA to enter the general circulation Elevated serum PSA level has become an important marker of many prostate diseases – including benign prostatic hyperplasia, prostatitis, and prostate cancer

Prostate Specific Antigen PSA Absolute Normal < 4.0 ng/mL Most urologists now use < 2.5 ng/mL Free PSA < 20% higher probability of cancer Only used after someone has been biopsied Velocity > 0.75 change in 1 year in worrisome Density PSA/Size of the gland > 0.15 worrisome

Thompson IM et al : N Engl J Med 2003 Jul 17; 349(3): 215-224

Diagnosis Any abnormality in the PSA or DRE will require Transrectal ultrasound of the prostate Biopsy of the prostate

Gleason Grading System Prostate cancer graded on appearance of cancer cells Gleason grading system Gleason grade ranges from 1 (least aggressive) to 5 (most aggressive) Gleason score (2-10) Most common cell grade (first) added to second most common cell grade i.e. Gleason 7 (3+4)

Prostate Cancer Prevention 5 Alpha Reductase Inhibitors Finasteride Dutasteride Vitamin E Selenium Lycopene Omega 3 fatty acid Zinc

The Influence of Finasteride on the Development of Prostate Cancer 18,882 men randomized 55 years or older Normal DRE and PSA Study groups Finasteride (5 mg per day) or placebo for seven years Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the digital rectal examination was abnormal Thompson IM et al : N Engl J Med 2003 Jul 17; 349(3): 215-224

The Influence of Finasteride on the Development of Prostate Cancer Prostate cancer detection Finasteride group - 803 of the 4368 men (18.4 %) Placebo group - 1147 of the 4692 men (24.4 %) 24.8 % reduction in prevalence over the seven-year period P < 0.001 Tumors of Gleason grade 7, 8, 9, or 10 were more common in the finasteride group (280 of 757 tumors (37.0 %) than in the placebo group (237 of 1068 tumors (22.2 %) P = 0.005 Thompson IM et al : N Engl J Med 2003 Jul 17; 349(3): 215-224

Effect of Dutasteride on the risk of prostate cancer 8122 men enrolled Looked at men at high risk of developing prostate cancer PSA from 2.5-10 Previous biopsy Men were biopsied at the start of the study and at year 2 and 4 Andriole GL - N Engl J Med - 1-APR-2010; 362(13): 1192-202

Effect of Dutasteride on the risk of prostate cancer Results Cancer detection Dutasteride group - 659 of the 3305 men (20 %) Placebo group - 858 of the 3424 men (25%) Risk reduction of with dutasteride of 22.8% (P<0.001) No increase in high risk tumors seen in the dutasteride group overall Higher rate of high grade tumors in the dutasteride group at years 3 and 4 Andriole GL - N Engl J Med - 1-APR-2010; 362(13): 1192-202

Treatment Options Watchful waiting / Active surveillance Radiation Therapy Surgery

Active Surveillance Appropriate for men with very low risk prostate cancer when life expectancy < 20 years or men with low risk prostate cancer when life expectancy < 10 years Expectation to intervene if the cancer progresses Need regular follow up More rigorous in younger men than older men Follow up should include PSA every 3 months DRE every 6 months Repeat biopsy at 1 year if all other factors stable

Active Surveillance 23% - 42% of all U.S. screen-detected cancers are over treated PSA detection was responsible for up to 6.9 years of lead-time bias Draisma G et al: J Natl Cancer Inst. 2009;101:374-383

Active Surveillance Advantages Disadvantages Avoid possible side effects of definitive therapy that may be unnecessary Quality of life/normal activities retained Risk of unnecessary treatment of small, indolent cancers reduced Disadvantages Chance of missed opportunity for cure Risk of progression and/or metastases Subsequent treatment may be more complex with increased side effects Increased anxiety Requires frequent medical exams and periodic biopsies Uncertain long-term natural history of prostate cancer

Radiation Therapy External Beam Radiation Therapy Brachytherapy (Radioactive seeds) High dose brachytherapy Proton beam therapy

External Beam Radiation Advantages Excellent cancer control with higher doses Avoids complications of surgery Low risk of incontinence Disadvantage 8-9 weeks of treatments Acute bowel and bladder problems Chronic Salvage therapy very complex Risk of erectile dysfunction

Brachytherapy Placing radioactive seeds into the prostate Surgical procedure Used for low risk prostate cancers May be combined with external beam in higher risk cancers Not as effective as external beam therapy Main advantage is treatment is given in 1 day Minimal down time

Proton Beam Radiation Theoretically, protons may reach deeply- located tumors with less damage to surrounding tissues Not recommended for routine use at this time Clinical trials have not yet yielded data that demonstrates superiority or equivalence of proton beam compared to conventional external beam therapy NCCN Guidelines v3.2010, 7/16/10

Surgical Therapy Open Surgery Conventional Laparoscopic Surgery Robotic-Assisted Laparoscopic Surgery Cryosurgery

Cryosurgery Not recommended by either the AUA or the NCCN practice guidelines in the primary management of prostate cancer It is not offered as primary therapy in our practice May be useful as a salvage technique?

Surgical Therapy Appropriate for tumors confined to the prostate Must have a 10 year life expectancy Excellent cancer survival 15-year prostate cancer-specific mortality of 12% in patients who underwent radical prostatectomy 5% for low risk patients Stephenson AJ et al: J Clin Oncol. 2009;27:4300-4305

Surgical Therapy Multiple techniques Open Laparoscopic Robotic High volume surgeons have superior results

Why robotic surgery? Decreased postoperative pain Improved cosmetics Quicker recovery Decreased length of hospital stay Quicker return to baseline activity Less bleeding Campbell’s Urology, 8th edition, 2002

Effects of Marketing Percent of prostatectomies performed with the da Vinci® in Philadelphia in 2008 85% Patients are requesting robotics Searching out centers with robots Increasing number of hospitals acquiring robotic technology Surgeons are pressured to adapt their techniques

Masters in Urology Meeting July 31, 2008 RALP very surgeon-dependent as learning curve is over 100 cases RALP has lower blood loss RALP in the US is the most common form of surgical treatment of CaP Biochemical recurrence shown to be 17.9% in the first 10 RALP cases on the learning curve, becoming 10.7% after 250 cases Centers of excellence vs. everyone in practice??

da Vinci Surgical System

Benefits of the da Vinci® Surgical System Three-dimensional vision 12x magnification Instruments with six degrees of freedom Tremor filtration Ergonomic surgeon console to limit fatigue

Comparing Incisions

A multi-institutional comparison of radical retropubic prostatectomy, radical perineal prostatectomy, and robot-assisted laparoscopic prostatectomy for treatment of localized prostate cancer pT2 Disease pT3 Disease Robotic Prostatectomy 4 % 36 % Radical Prostatectomy 14 % 53 % Perineal Prostatectomy 19 % 90 % p-values 0.03 0.015 Coronato et al. J Robotic Surg, 2009 3:175–178

Multiple Learning Curves? 293 consecutive RALP Data collected Operative time Blood loss Length of stay Margin status Two learning curves were observed First break – 12 cases Second break – 189 cases Jaffe et al. UROLOGY 73: 127–133, 2009

Multiple Learning Curves? Jaffe et al. UROLOGY 73: 127–133, 2009

Multiple Learning Curves? Jaffe et al. UROLOGY 73: 127–133, 2009

“Surgical Robot Examined in Injuries” May 4, 2010 “Some surgeons with extensive robotic experience say it takes at least 200 surgeries to become proficient at the da Vinci and reduce the risks of surgical complications” “That's difficult for surgeons at smaller hospitals to achieve“ Article suggests the establishment of specialized “CENTERS OF EXCELLENCE”

Our Expected Outcomes of RALP Hospital stay – 1 day Minimal blood loss Minimal narcotic use Foley duration – 5 to 7 days Continence returned within 1 year * Potency returned within 18 months * CANCER FREE

Conclusions Prostate cancer is very prevalent Screening is not as straight forward as once believed We may be able to prevent prostate cancer Lots of treatment options Patients do better we high volume surgeons Centers of excellence

Jjaffe@UCSEPA.com 215-762-3200 (office) 267-992-0523 (mobile)