Prostate Cancer: from Beginning to End

Prostate Cancer: from Beginning to End Matthew D. Katz, M.D. Assistant Professor Urologic Oncology Robotic and Laparoscopic Surgery University of Arkansas for Medical Sciences Winthrop P. Rockefeller Cancer Center

Anatomy Genitourinary System Campbell-Walsh UROLOGY, 9th edition

Anatomy of the Prostate Campbell-Walsh UROLOGY, 9th edition

Prostate Cancer Prostate Cancer most common non-skin cancer in men Second leading cause of cancer death in U.S. men About 25% of prostate cancers are thought to be clinically significant Most common type of CaP is adenocarcinoma Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

New Cases and Death Estimates Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4.

Lifetime Risk of Developing CaP Probability of Developing Invasive Cancers Within Selected Age Intervals by Sex, United States, 2004 2006* BIRTH TO 39 (%) 40 TO 59 (%) 60 TO 69 (%) 70 AND OLDER (%) BIRTH TO DEATH (%) All sites Urinary bladder Male 1.43 (1 in 70) 8.42 (1 in 12) 15.61 (1 in 6) 37.84 (1 in 3) 44.05 (1 in 2) Female 2.10 (1 in 48) 8.97 (1 in 11) 10.18 (1 in 10) 26.47 (1 in 4) 37.63 (1 in 3) Male 0.02 (1 in 4,741) 0.39 (1 in 257) 0.95 (1 in 106) 3.66 (1 in 27) 3.81 (1 in 26) Female 0.01 (1 in 10,613) 0.12 (1 in 815) 0.26 (1 in 385) 1.01 (1 in 99) 1.18 (1 in 84) Breast Female 0.49 (1 in 206) 3.75 (1 in 27) 3.40 (1 in 29) 6.50 (1 in 15) 12.08 (1 in 8) Colorectum Leukemia Male 0.08 (1 in 1,269) 0.91 (1 in 110) 1.48 (1 in 67) 4.50 (1 in 22) 5.39 (1 in 19) Female 0.08 (1 in 1,300) 0.72 (1 in 139) 1.07 (1 in 94) 4.09 (1 in 24) 5.03 (1 in 20) Male 0.17 (1 in 603) 0.21 (1 in 475) 0.33 (1 in 299) 1.19 (1 in 84) 1.51 (1 in 66) Female 0.13 (1 in 798) 0.15 (1 in 690) 0.20 (1 in 504) 0.78 (1 in 128) 1.08 (1 in 92) Lung & bronchus Male 0.03 (1 in 3,461) 0.95 (1 in 105) 2.35 (1 in 43) 6.71 (1 in 15) 7.73 (1 in 13) Female 0.03 (1 in 3,066) 0.79 (1 in 126) 1.75 (1 in 57) 4.83 (1 in 21) 6.31 (1 in 16) Melanoma of the skin Male 0.16 (1 in 638) 0.64 (1 in 155) 0.72 (1 in 138) 1.77 (1 in 56) 2.67 (1 in 37) Female 0.28 (1 in 360) 0.55 (1 in 183) 0.36 (1 in 274) 0.79 (1 in 126) 1.79 (1 in 56) Non-Hodgkin lymphona Male 0.13 (1 in 782) 0.44 (1 in 225) 0.59 (1 in 171) 1.71 (1 in 58) 2.28 (1 in 44) Female 0.09 (1 in 1,172) 0.32 (1 in 315) 0.44 (1 in 227) 1.39 (1 in 72) 1.92 (1 in 52) Prostate Male 0.01 (1 in 9,422) 2.44 (1 in 41) 6.45 (1 in 16) 12.48 (1 in 8) 15.90 (1 in 6) Uterine cervix Female 0.15 (1 in 648) 0.27 (1 in 374) 0.13 (1 in 755) 0.19 (1 in 552) 0.69 (1 in 145) Uterine corpus Female 0.07 (1 in 1,453) 0.73 (1 in 136) 0.83 (1 in 121) 1.23 (1 in 81) 2.53 (1 in 40 Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4.

Lifetime Risk of Dying from CaP Risk of dying from prostate cancer is ~3% Once metastatic disease develops there is no cure Prior to PSA screening only 25% of CaP presented confined to prostate vs. 91% since 5 year CSS rates increased from ~70% to 100% (from 1980s to early 2000s) Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4. Comprehensive Textbook of Genitourinary Oncology, 3rd edition Catalona et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270(8):948

Prostate Mortality Rates Men are living longer As such CaP mortality risk should be on rise Yet mortality rates have continued to drop No identified environmental link (diet, ect ) to explain this such as decline in smoking/lung Cancer deaths Is decline due to screening, stage migration (due to screening), better treatment, or unknown environmental link? Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4.

Presentation Most patients are asymptomatic Diagnosed due to elevated PSA or abnormal DRE Advanced cancer may present with bone pain, unintentional weight loss, hematuria, worsening LUTS, urinary retention, hydronephrosis, LE weakness/leg numbness/difficulty with ambulation Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Risk Factors Age + Family history African American Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Prevention PCPT (Prostate Cancer Prevention Trial) 18,000 men randomized to placebo vs. Proscar 5mg qday 7 year follow-up Decreased risk of prostate cancer by 25% Found small increase in high-grade cancer development Further subset analysis did NOT show this to be true Thomson IM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med, 349, 2003 Kaplan SA et al. PCPT- Evidence that finasteride reduces the risk of most frequently detected intermediate and grade (Gleason score 6 and 7) cancer. Urology, 73, 2009

Prevention REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) 8,000 men >50 yrs old were randomized to placebo vs. Dutasteride 0.5mg qday Follow-up 4 years Decreased risk of developing Gleason score 5-6 cancer by 27% Did not reduce risk of Gleason 7-10 cancer Did not increase risk of developing high grade cancer Enhanced ability of PSA to detect high grade cancers Andriole GL et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 362, 2010

Screening Guideline Age to start CaP screening Suggested Screening Tests AUA 2009 40 PSA and DRE NCCN 2010 40 PSA and DRE EAU 45 PSA and DRE ACS 2010 40-50 (depends on risk) PSA with or without DRE American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010

Screening Intervals What age should you stop screening? Some advocate men >75 should not be screened* AUA and NCCN guidelines state that screening should be individualized based on overall health (life expectancy >10yrs, FH of longevity, minimal competing medical comorbidities) American Urological Association 2009, National Comprehensive Cancer Network 2010, European Association of Urology 2009, American Cancer Society 2010 *U.S. Preventative Service Task Force Guidelines, 2008

Screening Controversial Does PSA-based screening lead to decrease in risk of death from prostate cancer? Advantages May prolong survival and save lives Save men from long painful death with little effective treatments available (costs?) Disadvantages Overdiagnosis Overtreatment Potential decrease in QOL from treatment (costs?) Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

USPSTF To Downgrade PSA Screening From "I" to "D" As In "Don't Do It" U.S. Preventative Service Task Force this past Friday recommended NOT to use PSA to screen for men for prostate cancer Based on meta-analysis done of available literature The Cancer Letter, Oct. 7, 2011

Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force ABSTRACT Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages, when treatments might be more effective. Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer. Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists. Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of perioperative harms. Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed quality using predefined criteria. Conclusions: After about 10 years, PSA-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary. The Cancer Letter, Oct. 7, 2011

Screening Two large trials done recently looking at survival benefit from screening: PLCO screening trial (U.S.) and ERSPC screening trial (European) These two RCT were largely basis for USPSTF recommendations Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009 Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

PLCO (US trial) Prostate, lung, colorectal, ovarian Cancer screening trial (U.S.) 76,693 men randomized Ages 55-74 included After 7 years risk of death same Significant flaws in study makes conclusions questionable Found no survival benefit for PSA based screening Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

PLCO trial flaws Significant rates of screening in control arm 52% contamination (men were screened prior to study) Relatively low rate of biopsy in men who had abnormal screening results in screen arm Less than 50% of men in screened arm with indication had biopsy done Short follow-up (less than 10 yrs) Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009

ERSPC screening trial (European) European Randomized Study of Screening for Prostate Cancer 182,000 men randomized Ages 50-74 included Median f/up of 9 years there was 20% reduction in CaP deaths in screened group 41 % reduction in metastases at presentation Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

ERSPC screening trial (European) flaws Numerous sites of trial entry (7 countries) Mortality reduction of 20% came with large investment To prevent one cancer death, need over 1400 men to be screened over decade and 48 men would require treatment Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

Screening Problems with both studies Short follow-up <10 years (mortality from CaP is very low in first 10 years) Subset analysis not done for high risk men (i.e. those with +FH, AA) Andriole GL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J Med, 360 (13): 1310, 2009 Schroder FH et al. Screening and prostate cancer mortality in a randomized european study. N Engl J Med, 360 (13): 1320, 2009

Göteborg Screening Trial Göteborg randomized population-based prostate screening trial 20,000 men randomized Ages 50-64 included (median 56) Median follow-up 14 years Found 44% risk reduction in CaP specific death in screened group NNT analysis revealed that 293 men needed to be screened and 12 men need to be diagnosed in order to prevent 1 death Hugosson et al. Mortality results from the Göteborg randomised Population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725-32.

Diagnosis PSA can be elevated secondary to BPH, prostatitis, recent ejaculation, prostate trauma (massage, biopsy, urethral instrumentation, cycling, etc ) Use of age and ethnicity adjusted PSA values Age Caucasian African-American Asian-American 40-49 0-2.5 0-2.0 0-2.0 50-59 0-3.5 0-4.0 0-3.0 60-69 0-4.5 0-4.5 0-4.0 70-79 0-6.5 0-5.5 0-5.0 Campbell-Walsh UROLOGY, 9th edition

Diagnosis PSA not perfect and can only be used to define risk of prostate cancer NOT diagnosis No universally accepted threshold value Decision to biopsy based on many different criteria (age, PSA velocity, PSADT, FH, race, etc ) Other tests may help make decision to biopsy PCA3, total and free PSA (use for PSA between 4-10) Campbell-Walsh UROLOGY, 9th edition

Indications for Prostate Biopsy Suspicious DRE Age, ethnicity, +FH Abnormal total PSA Abnormal change in total PSA Abnormal PSA velocity Abnormal Total and Free PSA (use when PSA between 4-10) Campbell-Walsh UROLOGY, 9th edition

When to Perform Imaging to Evaluate for Metastatic Disease Bone scan Indicated when PSA>20, Gleason score 8, Bone pain Pelvic CT/MRI Indicated when PSA>20, Gleason score 8 Newer data suggests fused PET/CT with 11 C- Acetate may be much better at detecting +LN Campbell-Walsh UROLOGY, 9th edition Oyama et al. 11 C-Acetate PET imaging of prostate Cancer: detection of recurrent disease at PSA relapse. 2003. J Nuc Med. 44; 549

When to Perform Imaging to Evaluate for Metastatic Disease Total PSA Probability of +Bone Scan <10 2.3% 10-20 5.3% 20-50 16% >50 >35% Biopsy Gleason Score Probability of +Bone Scan 7 5.5% 8 28% Campbell-Walsh UROLOGY, 9th edition

Pet Imaging in Prostate Cancer

Example of Positive LN

Prostate Cancer Indolent vs. Aggressive? Risk based on individual results PSA DRE Gleason Score: major score + minor score = sum score (1-5) + (1-5) = (2-10) Number of + biopsies Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Prostate Cancer Indolent vs. Aggressive? Low Risk PSA < 10 Gleason score 6 Intermediate Risk PSA 10-20, Gleason 7 or Gleason 6 with PSA >10 High Risk PSA > 20, Gleason 8-10 Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Treatment options for Localized Prostate Cancer Active Surveillance Androgen Deprivation Therapy (ADT) Surgery Radiation Cryoablation Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Active Surveillance Not discussed enough in this country Strict selection criteria Low risk: ct1-2a, PSA<10, life expectancy <10yrs, Gleason 6 or less Very low risk: ct1-2a, PSA<10, life expectancy up to 20yrs, Gleason 6 or less, <3 cores +, <50% of each core involved Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Androgen Deprivation Therapy Not a good choice for localized prostate cancer Significant side effects Depression/impaired memory, increased risk of CV events, bone loss, hot flashes, penile shortening, glucose intolerance, central obesity, ED and libido, gynecomastia Useful in select cases of advanced disease, +LN or combined therapy for locally advanced disease with radiation Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Cryoablation (freezing of prostate) Cancer-specific outcomes not as mature as surgery or radiation Almost all men will have significant ED after Tx Not good option for locally advanced or high risk patients Useful for men with previous pelvic radiation, rectal disorders, or inflammatory bowel disease Good salvage therapy option for men with recurrent disease after radiation, brachytherapy or cryoablation Campbell-Walsh UROLOGY, 9th edition

Radiation Various delivery methods XRT (external beam radiotherapy) Whole pelvis, 3-D conformal, IMRT (intensity modulated radiation therapy) Brachytherapy (radioactive seeds) Temporary high dose rate (usually combined with XRT boost) permanent low dose rate Campbell-Walsh UROLOGY, 9th edition

Radiation For low risk disease IMRT or Brachytherapy good treatment choices No need to add ADT For intermediate risk disease should add ADT 2 months before, during, and for 6 months after XRT For high risk disease should add longer course of ADT Just before, during, and for 3 years after XRT No randomized prospective trials comparing surgery to radiation D Amico et al. Androgen suppression and radiation vs. radiation alone for prostate cancer. JAMA, 299, 2008 Bolla et al. Three years of adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy. N Engl J Med, 337, 1997

Surgery Different approaches to remove prostate Open Laparoscopic (use straight instruments) Robotic (use wristed instruments with 7 degrees of freedom) Campbell-Walsh UROLOGY, 9th edition Comprehensive Textbook of Genitourinary Oncology, 3rd edition

Open vs. Robotic Incisions

The da Vinci Robotic System

Robotic Prostatectomy Literature comparing Robotic vs. Open: Less blood loss Shorter stay Faster return to normal activity Equivalent cancer control Equivalent incontinence rates Equivalent ED rates Experience and proper training important Most Urologist performing in community don t have fellowship training

Surgery Only form of treatment with randomized trial revealing CSS and OS advantage when compared to surveillance Survival benefit was seen for men <65 yrs of age Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group 4 randomized trial. J Natl Cancer Inst, 100, 2008

Surgery Authors of that study recently published updated 15 year follow-up data Again found CSS and OS benefit for men undergoing RP vs. surveillance in <65 yrs of age Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

PIVOT (Prostate cancer Intervention Versus Observation Trial) Randomized men 75yrs old with CaP to radical prostatectomy vs. expectant management with all-cause mortality as primary end-point (trial closed recently after accruing 731) Will be different than Scandinavian trial that looked at same thing, but essentially in pre-psa era Wilt et al. The prostate cancer intervention versus observation Trial: VA/NCI/AHRQ cooperative studies program #407 (PIVOT) Contemp Clin Trials 2009;30:81-87 Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 364, 2011

ProtecT (Prostate testing for cancer and Treatment) RCT of treatment effectiveness in UK Opened 2001 and closed 2008 111,000 men randomly assigned to surveillance, radiation, or surgery Primary end-point will be CSS at 10yrs With numerous secondary end-points including QOL analyses Donovan et al. Prostate testing for cancer and treatment (ProtecT) feasibility study. Health Technol Assess 2003; 7:14

Conclusions Prostate cancer very common problem Need to know which men to offer screening, when to begin and end, and how often to offer screening Currently we overtreat prostate cancer in U.S. Desperately need to find better ways to delineate aggressive forms of prostate cancer from indolent disease in order to offer treatment to men who will benefit and spare those who will not