PROSTATE CANCER: A Primer of Diagnosis and Treatment Jay C. Lee, MD, FRCSC Clinical Associate Professor University of Calgary
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What is the prostate? Bladder Penis Prostate Urethra
What does the prostate do? Urinary control Muscle in prostate has gripping effect around urethra Fertility Glands in prostate secrete fluid that helps activate sperm cells by liquifying semen Infection Protects against infection of bladder Growth and function of prostate is driven by hormone, testosterone
Prostate Cancer Commonest cancer in men Third commonest cancer killer Incidence: 18% lifetime risk (1 in 6): rising Mortality: 3.6% lifetime risk 1 in 3 to 4 die because of the cancer 3 of 4 die of cancer if diagnosed < 65 yrs Mortality rate falling since 94 5 year survival ( 2008 Alberta) 93%
Incidence vs. Prevalence of Prostate Cancer Autopsy studies show a prevalence of prostate cancer of 30-50% in 50 y.o. men, increasing to >75% in 75 y.o. men Prevalence data consistent throughout the world, although clinical incidence varies widely from country to country Prostate cancer
Prostate Cancer Incidence c. 1995 Approx. 16,000 new cases in Canada/year 2006: Est. 23,200 new cases in Canada Approx. 4,000 deaths from CaP/year Est. 3000 deaths in Canada Ratio 1:4 Ratio 1:8 Prostate cancer
Risk Factors Age Family History of Prostate Cancer Race Obesity/Diet IGF-1 Prostate cancer
What is PSA? PSA is a protein made by the prostate, released into semen fluid and blood Blood test is very accurate Excellent marker to measure activity of prostate gland Used both for screening and for monitoring False positives
Age specific PSA Oesterling, 1993 Age Range Normals 40-49 < 2.50 50-59 < 3.50 60-69 < 4.50 70-79 < 6.50 Better sensitivity in younger men (at cost of more neg. biopsies) Better specificity in older men (fewer treated for low grade disease) Prostate cancer
Influences on serum PSA levels BPH Prostate manipulation: DRE,massage Catheterization, cystoscopy Biopsy Infection Urinary retention Drugs Finasteride, dutasteride Anabolic steroids Prostate cancer
TO SCREEN OR NOT TO SCREEN
Screening for Prostate Cancer: The PSA Dilemma Undoubtedly detects Prostate cancer at an earlier stage, with better chance of cure, but?overdetects the indolent disease, leading to overtreatment Can be normal despite presence of prostate cancer Is often elevated in the absence of prostate cancer, leading to unnecessary biopsies, complications, anxiety, etc Prostate cancer
Recommendations for Prostate Cancer Screening American Cancer Society, American Urological Association : Annual PSA (and DRE) all men > 50 start at age 40 if at risk Canadian Urologic Association : DRE and PSA, no age or frequency recommendation counsel patients on risks and benefits However, if DRE normal and PSA < 1.00: Biannual O.K. Prostate cancer
U.S. Preventative Services Task Force the current evidence is insufficient to assess the balance of benefits and harms of prostate cancer screening in men under 75 years recommends against screening for prostate cancer over 75 years of age.
PSA Screening Trials Breast, Lung, Colon, Ovary Trial (PLCO U.S.A.): 76,693 men Screened (PSA, DRE annually for 6 yrs) Vs Usual clinical care European Randomized Prostate Cancer Screening Trial: 182,000 men Screened (PSA every 2 to 4 yrs) Vs No PSA Malmo Preventative Project (population based cohort, 27 yr f/u) 21,227 men
PLCO No difference in mortality at 11 yrs Problems: 52% of control arm screened 85% study arm screened 25% difference in mortality of patients who had 2 PSA at entry, compared to those who did not have a PSA test
ERSPC 32% reduction in CaP mortality at 13 (51% in compliant cases) 32% reduction in metastatic disease (9yrs) N N Test to save 1 life: 392 (293 Goteborg) N N Treat to save 1 life: 24 (12 Goteborg) Minnesota Colon Ca Study (occult blood): 41000 cases, 30 yr f/u 32% reduction Colon Ca mortality (annual test)
N N Screen Mammography: 1339 (50-59 y.o) (11-20 yrs) Nelson et al Ann Int Med 2009 (US Preventative task force meta analysis) Haemoccult: 1173 (10 yrs) Towler et al, BMJ 1998 Flexible sigmoidoscopy: 489 (11 yrs) Atkin et al Lancet 2010 PSA: 392 (13 yrs) ERSPC 293 (14 yrs) Goteborg
PSA pluses Early diagnosis Higher incidence of organ confined disease Lower incidence of high grade disease Lower incidence of metastases Can predict the future risk
PSA negatives Non specific Anxiety Increased number of biopsies Overdiagnosis (indolent disease) Overtreatment
Malmo Preventative Project 21277 men (27-52 y.o.) 1974-84, + 6 yrs. Median F/U 27 yrs PSA 1.6 (45 50 y.o.) risk CaP death PSA 2.4 (50 55 y.o.) risk CaP death If PSA < 1.0, only test 45, 50 and 60 yrs old
Breast Cancer Commonest cancer in women Second commonest cancer killer in women Incidence: 11.2% lifetime risk (1 in 9) Mortality: 4% 1 in 3 die because of the cancer Mortality rate falling since 90 5 year survival (alberta) 88%
Canadian Cancer Statistics Breast Prostate Incidence per 100,000 104.5 118.5 Mortality per 100,000 25.9 26.66 5 year survival rate (Alberta) 75% (92) 88% (08) 69% (92) 93% (08)
Comparison of Mammography and PSA Positive predictive value Mammography --10% Positive predictive value PSA -- 31%
DIAGNOSING AND STAGING PROSTATE CANCER
How is prostate cancer diagnosed? Testing (Screening) during routine visit to doctor Found by chance during other prostate surgery Transurethral resection of prostate (TURP/TUPR) Rarely, presents with symptoms
Prostate Cancer Testing Looks for cancer before symptoms ever appear, in order to find cancer as early as possible, when treatment is most likely to be curative Tests Prostate-Specific Antigen Digital Rectal Exam
DRE
Contraindications to Digital Rectal Examination (DRE) No rectum No digit Any questions? Prostate cancer
>70% of patients with prostate cancer have a normal DRE (T1c) Diagnosis made due to elevated PSA The higher the PSA, greater the risk of cancer The higher the PSA, more advanced the cancer
Symptoms of Prostate Cancer Most diagnosed cases are asymptomatic because of early diagnosis with PSA Advanced prostate cancer can present with bone pain, uremia, paralysis, lymphadenopathy, or generalized weakness and weight loss Prostate cancer
Signs of Prostate Cancer Only sign is palpable induration or nodularity of the prostate Therefore, any prostatic abnormality found on digital rectal examination should be biopsied Hematuria (and obstructive symptoms) are uncommon signs of prostate cancer Prostate cancer
Indications for Biopsy Elevated PSA Significant rise in PSA from one test to the next Abnormal DRE
Diagnosis of Prostate Cancer Transrectal Ultrasound (TRUS) guided needle biopsy: -local anesthetic -usually 12 cores taken -antibiotic coverage Prostate cancer
Confirming the Diagnosis Trans-rectal Ultrasound (TRUS) Guided Biopsy
Assessing Localized Prostate Cancer Stage (T stage) How big is the tumor? Grade (Gleason Scoring System) How aggressive does the cancer look?
Gleason Grade Nearly normal arrangement of cells Highly abnormal arrangement Grade
Prostate Cancer Grading Grade indicates cancer s aggressiveness - how fast it is likely to grow & spread Grading system was developed by Gleason (Gleason Grade and Gleason Score) Pathologist looks at the 2 largest sections of cancer in the tissue specimens and assigns a Gleason Grade (2-5) If 3rd area of cancer pattern, reported as Tertiary grade
Gleason Score These two numbers are added to give an overall Gleason Score (eg. 3+4=7) Tertiary Gleason Score Sometimes pathologists will report a 3 rd grade of cancer if sufficient volume of that cancer is seen Eg. Gleason 3+4=7, with tertiary pattern 5 This additional information is taken into account when we discuss treatment options with patients
Gleason Grade vs. Progression Natural history ( progression ) correlates closely with Gleason grade. i.e. gr. 4 -- clinical progression in 5-7 years gr. 3 -- clinical progression in 10-12 years gr. 2 -- clinical progression in? 15 years Prostate cancer
Stages of Prostate Cancer TNM System T1 (a,b,c): TURP or PSA detected; normal feeling gland T2 (a,b,c): Palpable abnormality, confined to gland T3 (a,b,c): Palpable abnormality, beyond gland TxN+M+: Spread to lymph nodes (N+), or bone (M+) Prostate cancer
T1c T2a T2b T3
How does cancer spread? Locally Through capsule of prostate Into seminal vesicles Beneath the bladder Into rectum or wall of pelvis To lymph nodes Via tiny lymphatic vessels First to nodes in pelvis Later to more distant nodes To other parts of the body Bone (Liver) (Lung)
Staging of Prostate Cancer DRE Subjective Understaging common CT Only for suspected lymphdenopathy» I.e. PSA >20; Gleason score>7 Sensitivity 50-75% MRI For higher grade disease may help identify those with local progression For active surveillance Anterior tumours not caught on standard biopsy Prostate cancer
Staging of Prostate Cancer Pelvic Lymphadenectomy Surgical removal of pelvic lymph nodes Most accurate means to detect lymph node mets Samples nodes from obturator fossa Open or laparoscopic techniques used Combining PSA and Gleason score can give accurate estimate of probability of node involvement: % probability=2/3 PSA + 10(G.S.- 6) Prostate cancer
Staging of Prostate Cancer Plain Xrays Osteoblastic bone Prostate cancer
Osteoblastic Metastases Normal Bone Osteoblastic Metastases Prostate cancer
Bone Scans Normal Scan Ca Prostate metastases Prostate cancer
Nomogram Example: Probability of extracapsular extension (ECE) Prostate cancer
Risk Groups LOW INTERMEDIATE HIGH PSA <10 10-20 > 20 Gleason score and <=6 7 8-10 and T- Stage T1-T2b T2c T3,T4 or or or or RX. Options Surveillance Prostatectomy EBRT Brachytherapy Cryotherapy Prostatectomy EBRT (+/- hormones) Cryotherapy Brachytherapy (a subset of pts.) Surveillance EBRT &hormones Prostatectomy Cryotherapy Hormones only
TREATMENT OPTIONS
Management of Localized Prostate Cancer Active Surveillance Radical Prostatectomy Brachytherapy External Beam Radiation Cryosurgery
WHY? & WHO? Active Surveillance (No treatment for now) Prostate cancer is a common problem and is slow growing in many men A desire to avoid or delay dealing with the side effects and risks of treatment Other health problems may be more significant for a patient Patient choice Age
Active Surveillance (No treatment for now) HOW? Check ups, & DRE with your urologist Repeat PSA (every 6 months) Repeat biopsy
Active Surveillance (No treatment for now) What determines when treatment is necessary? Changes in DRE, PSA or biopsy results Patient choice
Management of Localized Prostate Cancer Active Surveillance Radical Prostatectomy Brachytherapy External Beam Radiation Cryosurgery
WHO? RADICAL PROSTATECTOMY (Surgical removal of the prostate) Disease confined to the prostate Fit for surgery Life expectancy more than 10 years PSA less than 20 Patient choice
HOW? RADICAL PROSTATECTOMY (Surgical removal of the prostate) Open or Robotic General anesthetic, supplemented with spinal anesthesia Nerve sparing surgery Lymph node dissection
RADICAL PROSTATECTOMY (Surgical removal of the prostate) What to expect Hospital stay usually 2-3 days Minimal discomfort (spinal anesthesia) Catheter to drain urine: 1-2 weeks 3-6 weeks off work
Advantages RADICAL PROSTATECTOMY (Surgical removal of the prostate) Well tolerated Lymph nodes can be examined and sampled, if appropriate Assessment by pathologist of surgical specimens Psychological relief
RADICAL PROSTATECTOMY (Surgical removal of the prostate) Advantages Excellent long term results Low risk of serious complications Calgary results identical to Hopkins, Duke, Sloan Kettering, Baylor
RADICAL PROSTATECTOMY (Surgical removal of the prostate) Side Effects and Risks Erectile Dysfunction: 50-60% Incontinence (stress): 15-20% Severe incontinence: <1% Bladder neck scarring: 1-7% May require dilatation Rectal Injury: rare
Management of Localized Prostate Cancer Active Surveillance Radical Prostatectomy Brachytherapy External Beam Radiation Cryosurgery
Brachytherapy What is it? Permanent insertion of radioactive seeds into the prostate gland A way of focusing radiation on the prostate gland and delivering more radiation
Brachytherapy WHO? Low grade disease Some patients with intermediate grade disease may be candidates Prostate gland cannot be > 50 gms Patient choice
Brachytherapy
Brachytherapy Advantages A day surgery procedure, (general or spinal anesthetic required), 1.5-2 hours Bladder catheter removed the following day Quick recovery Most patients back to work in 3-4 days
Brachytherapy Side Effects and Risks Early (< 6 months) Irritation of the bladder and urethra Frequency, urgency, dysuria Late Erectile dysfunction: 20 50/100 men (Age, health and time related) Urethral stricture: 1/100 men May require dilatation Altered bladder habit
Management of Localized Prostate Cancer Active Surveillance Radical Prostatectomy Brachytherapy External Beam Radiation Cryosurgery
External Beam Radiation ( High energy x-rays ) WHO? Any patient with localized prostate cancer is potentially eligible Patients ineligible for surgery Patient choice
External Beam Radiation ( High energy x-rays ) WHO NOT? Inflammatory bowel disease Previous radiation to the pelvis Previous extensive pelvic surgery
External Beam Radiation What to expect CT Scan for treatment planning with bowel and bladder prep Image-guided RT (IGRT) 3 gold marker seeds are implanted in the prostate before the planning CT scan (similar procedure to prostate biopsy)
External Beam Radiation What to expect Daily x-rays on treatment machine before treatment, adjusting position of beams if necessary ( aim before you shoot ) Daily outpatient treatments Monday Friday, 5 treatments/ week 45 60 minutes at the cancer clinic daily 12 minutes on treatment machine daily 37-40 treatments (8 weeks)
External Beam Radiation Advantages Outpatient treatment Treatment times can be flexible No anesthetic required Usually no side effects for 2 3 weeks Patients often continue to work during therapy Treatment directed at the prostate and a narrow rim around the prostate (potential to eradicate cancer cells outside the gland)
External Beam Radiation Early Side Effects and Risks Fatigue of varying degrees Irritation of the lower bowel and bladder (frequency of urination, diarrhea) Usually easily managed Recovery within 4-6 weeks of finishing
Late External Beam Radiation Side Effects and Risks Erectile Dysfunction 40-60% (Risk related to age and other health issues) Bladder complications (frequency, bleeding, urgency) Rectal bleeding (5%) Secondary cancers (low risk)
Management of Localized Prostate Cancer Active Surveillance Radical Prostatectomy Brachytherapy External Beam Radiation Cryosurgery
Cryosurgery What is it? Insertion of needles into the prostate through which a cooling agent is introduced (procedure similar to brachytherapy) Prostate gland is frozen, allowed to thaw, and frozen again
Cryosurgery WHO? Older men Other health concerns (increased risk with surgery) All grades of cancer PSA < 20 Prostate gland volume < 60 gms
What to expect 1.5 2 hours Cryosurgery Spinal or General Anesthetic Supra Pubic Catheter for 2 3 weeks Minimal Pain One Night in the Hospital Quick return to work
Cryosurgery Advantages Well tolerated Overnight stay in the hospital Minimal Incontinence
Cryosurgery Side Effects and Risks Early Urinary retention (2 to 3 weeks) Swelling of scrotum and penis Discomfort with sitting (< 2 wks) Aggravation of hemorrhoids
Late Cryosurgery Side Effects and Risks Erectile dysfunction: 100% 30/100 men may be capable of intercourse by 1-3 years post treatment Incontinence: 5-10 /100 men TURP needed: 1-5 /100 men
METASTATIC PROSTATE CANCER
Management of Pelvic Recurrence After radical prostatectomy: Always associated with rising PSA Treated with full dose radiotherapy After radiotherapy: ~20% of patients, but usually associated with distant disease as well Salvage prostatectomy very difficult, so usually started on hormone therapy (or offered salvage cryotherapy) Prostate cancer
Metastatic Disease Incurable (60-80% hormone sensitive) Hormone therapy: Orchidectomy LHRH agonist: intermittent continuous LHRH antagonist Chemotherapy: Taxotere Abiraterone / Enzalutamide Prednisone Palliative Radiation
Palliative Treatment For symptomatic hormone resistant disease Localized radiotherapy to painful bony metastases Strontium 89 for diffuse bony metastases Potent bisphosphonates to prevent fractures Chemotherapy Docetaxel/prednisone Mitoxantrone/prednisone Prostate cancer