NIMIRA ALIMOHAMED MD, FRCPC

M E D I C A L O N C O L O G I ST, T O M B A K E R C A N C E R C E N T R E

C L I N I C A L A SS O C I AT E P R O F E SSO R , T H E U N I V E R S I T Y O F C A L G A RY

Prostate Cancer for Primary Care Physicians

Objectives

Review epidemiology of prostate cancerReview management options for early stage

diseaseReview recent advancements in the

management of advanced prostate cancer

Epidemiology

Canadian Cancer Statistics 2015

Incidence = the number of new cases per specified time period

Prostate cancer- Cancer with the highest

incidence in males- Estimated 24% of all new

cancer cases in men in 2015

Canadian Cancer Statistics 2015

Mortality

Prostate cancer- accounts for 10% of estimated cancer deaths in men in 2015

Canadian Cancer Statistics 2015

Prevalence = proportion of cases in the population at a given time• Indicates how widespread the disease is (vs. incidence which

indicates how likely it is to develop the disease

• Prostate cancer has a high prevalence AND incidence

Canadian Cancer Statistics 2015

Prognosis of Prostate Cancer

Early-Stage disease Organ confined “potentially curable”

Advanced disease Rising PSA (2-10 years) Metastatic disease

Castration sensitive state Castration resistant state

DeathSurvival 2-5 years

5 year survival rate ~100%

“POTENTIALLY CURABLE” DISEASE

Early-Stage Prostate Cancer

Detection of Early-Stage Disease

80% of men are diagnosed based on abnormal serum PSA levels PSA screening

PSA can be falsely elevated – lack of specificity for prostate cancer

Not all detected cancers require treatment – overtreatment of many men

HOWEVER: targeted screening in an optimal population AND a pre-screening discussion can temper these concerns

Detection of Early-Stage Disease

Digital rectal examination Suggestive of prostate cancer: asymmetry, frank

induration, hard nodules Suggestive of BPH: symmetric enlargement and

firmness of the gland Can detect tumors in the peripheral (posterior and

lateral aspects) zone

An abnormal DRE should prompt a biopsyRegardless of PSA level!

Symptoms of Early-Stage disease

Most men will not have symptoms attributable to the cancer

Urinary frequency, urgency, nocturia, hesitancy Usually attributable to underlying BPH (benign

prostatic hypertrophy)

Hematuria, hematospermia Uncommon

www.uptodate.com

Diagnosis of Early Stage Disease

Refer to UROLOGY for PROSTATE BIOPSY if: Abnormal DRE Elevated PSA*

Transrectal prostate biopsy typically performed with transrectal ultrasound guidance (TRUS) Areas of concern on TRUS are typically hypoechoic TRUS is used to guide biopsy 12 cores are typically taken

MRI guided biopsy currently being evaluated in specific situations Example: Previous negative biopsies

Risk Stratification for Localized Prostate Cancer

PSA Stage (T stage)

How big is the tumor?

Grade (Gleason Scoring System) How aggressive does the cancer look?

Tumor Staging

T1

T3

T2

T4

Clinically inapparent Organ confined

Extension through prostatic capsule Fixed or invades adjacent structures

Detailed Tumor StagingT1 Cancer in prostate only. Cannot be felt and is not visible by imaging.

T1a Discovered on prostate resection (TURP), less than 5% prostate tissue affected

T1b Discovered on prostate resection, more than 5% prostate tissue affected

T1c Cancer detected by elevated PSA only

T2 Cancer in prostate only, though more advanced. Detected during DRE.

T2a One half or less of one side

T2b More than half of one side

T2c Both sides

T3 Cancer spread to nearby areas (blood vessels, nerves, seminal vesicles).

T3a Has spread outside prostate, but not to seminal vesicles

T3b Has spread to seminal vesicles

T4 Cancer spread into wall of pelvis.

Prostate Cancer Grading

Grade indicates cancer’s aggressiveness - how fast it is likely to grow & spread

Pathologist looks at the 2 largest sections of cancer in the tissue specimens and assign each a Gleason Grade ( 2 to 5 / 5 )

The two grades are added to give an overall Gleason Score (e.g. 3 + 4 = 7 /10)

Risk Group Stratification

Using the T stage, Gleason score and PSA result, we can classify men with localized prostate cancer into risk groups: Very-Low Risk Low Risk Intermediate Risk High Risk Very-High Risk

Very Low Risk disease

VERY LOW RISK T1 AND Gleason < 6 AND Serum PSA < 10 AND Limited disease within the gland

< 3 positive biopsy cores < 50% involvement of any one core PSA density < 0.15

Management options: Active surveillance reasonable (if life expectancy < 20 years Any other option if life expectancy > 20 years

Low Risk Disease

LOW RISK localized prostate cancer T1 – T2a Gleason < 6 PSA < 10

Management options: Active surveillance Radiation therapy

External beam radiation Brachytherapy

Radical prostatectomy (Cryotherapy)

Intermediate Risk Disease

Intermediate Risk localized prostate cancer T2b-T2c (extensive disease localized within the gland) OR Gleason 7 OR PSA between 10 and 20

Management options: Radiation therapy

External beam Brachytherapy (Gleason 3+4)

Radical prostatectomy (Active surveillance not indicated unless limited life expectancy) (Cryosurgery in some)

High Risk Disease

High-risk localized prostate cancer T3a (extracapsular extension) OR Gleason 8-10 OR PSA > 20

**Need staging investigations (CT abdo/pelvis, Bone Scan) to evaluate for metastatic disease

Management options Radiation therapy

External beam + Androgen Deprivation Therapy (ADT) Radical prostatectomy +/- ADT (Cryosurgery)

Very High Risk Disease

Very high-risk localized prostate cancer T3b or T4 disease Gleason 8-10

Primary Gleason grade 5 4+ cores with Gleason 8-10

**Need staging investigations (CT abdo/pelvis, Bone Scan) to evaluate for metastatic disease

Management options Radiation therapy

External beam + Androgen Deprivation Therapy (ADT) Radical prostatectomy +/- ADT (Cryosurgery)

“Doc, what should I do?”

Example: 68 year old man with intermediate risk (Gleason 3+4=7/10) disease Options: Prostatectomy, External beam radiation

therapy, brachytherapy, cryosurgeryNo randomized controlled trials comparing

these approachesRetrospective data reports similar outcomes

The PREFERE trial will hopefully shed more light on this Large, phase III trial ongoing Comparing radical prostatectomy, EBRT, brachytherapy,

active surveillance in patients with low or intermediate-risk prostate cancer

Choice of therapy depends on: Risk stratification Informed patient choice:

Estimated outcomes with different treatment options Potential complications with each treatment approach

Patient’s general medical condition, age, comorbidities

Online risk calculator Decisionhelp.truenth.ca

“Doc, what should I do?”

AC T I V E S U R V E I L L A N C E P RO S TAT EC TO M YB R AC H Y T H E R A P Y

E X T E R N A L B EA M R A D I AT I O NC RYO S U R G E RY

Management of Localized Prostate Cancer

The Prostate Gland

Understanding this anatomy is important if one is to understand the side effects and risks of prostate cancer treatment

BladderPubic Bone

Prostate

Rectum

W H Y ? & W H O ? A D E S I R E T O AV O I D O R D E L AY D E A L I N G W I T H T H E S I D E E F F E C T S A N D

R I S K S O F T R E AT M E N T

O T H E R H E A LT H P R O B L E M S M AY B E M O R E S I G N I F I C A N T F O R A PAT I E N T S U C H A S : D I A B E T E S , H E A R T D I S E A S E , A L C O H O L I S M

I N F O R M E D PAT I E N T C H O I C E

A 2 0 1 2 S T U D Y W I T H 1 2 Y E A R F O L L O W U P S H O W S FAV O R A B L E R E S U LT S ( P I V O T- N E W E N G L A N D J O U R N A L O F M E D I C I N E )

T H E R E I S A N A C T I V E S U R V E I L L A N C E P R O G R A M AT T H E P R O S TAT E C A N C E R C E N T R E F O R M O N I T O R E D F O L L O W U P.

Active Surveillance(No treatment for now)

HOW ?

CHECK UPS, & DRE WITH YOUR DOCTOR

REPEAT PSA

REPEAT BIOPSIES

A CHANGE MAY LEAD TO INTERVENTION

Active Surveillance(No treatment for now)

W H O ?

D I S EA S E C O N F I N E D TO T H E P R O S TAT EF I T F O R S U R G E RYP S A L E S S T H A N 2 0I N F O R M E D PAT I E N T C H O I C E

PROSTATECTOMY (Surgical removal of the prostate)

WHERE?ROCKYVIEW HOSPITALUNIT 82 (POST OPERATIVELY)

PROSTATECTOMY (Surgical removal of the prostate)

HOW?OPEN OR ROBOTICUNDER ANESTHESIA NERVE SPARING SURGERY

PROSTATECTOMY (Surgical removal of the prostate)

HOSPITAL STAY USUALLY 2-3 DAYS MINIMAL DISCOMFORT FOLEY CATHETER IN PLACE: 1-2 WEEKS 3-6 WEEKS OFF WORK

PROSTATECTOMY (Surgical removal of the prostate)

ADVANTAGESW E L L TO L E R AT E DLY M P H N O D E S C A N B E E X A M I N E DA S S E S S M E N T O F M A R G I N S BY PAT H O LO G I S T P SYC H O LO G I C A L R E L I E FE XC E L L E N T LO N G -T E R M R E S U LT SE R EC T I L E F U N C T I O N M AY R E T U R N OV E R S E V E R A L W E E K S TO Y EA R S

PROSTATECTOMY (Surgical removal of the prostate)

SIDE EFFECTS AND RISKS E R EC T I L E DYS F U N C T I O N : 5 0 - 6 0 / 1 0 0 M E N - T R EATA B L E I N C O N T I N E N C E ( S T R E S S ) : 1 5 / 1 0 0 M E N - T R EATA B L EL E S S C O M M O N S E V E R E I N C O N T I N E N C E : < 1 / 1 0 0 M E N B L A D D E R N EC K C O N T R AC T U R E : 1 - 7 / 1 0 0 M E N R EC TA L I N J U RY: R A R E

PROSTATECTOMY (Surgical removal of the prostate)

Robotic Prostatectomy

Robotic Prostatectomy

State-of-the-art robotic technology

3-D Visualization

Prostatectomy access

Open Surgical Incision Robotic Prostatectomy Incision

WHAT IS IT? P E R M A N E N T I N S E R T I O N O F R A D I O AC T I V E S E E D S I N TO T H E P R O S TAT E G L A N D

C O M P U T E R G U I D E D

A WAY O F F O C U S I N G A N D D E L I V E R I N G A H I G H E R D O S E O F R A D I AT I O N

Brachytherapy

WHO?LO W R I S K G RO U P

S O M E PAT I E N T S I N T E R M E D I AT E R I S K G RO U P

Gleason 3+4, PSA <10 / Gleason 3+3, PSA<15

P RO S TAT E G L A N D L E S S T H A N 5 0 C C

I N F O R M E D PAT I E N T C H O I C E

Brachytherapy

Brachytherapy

Brachytherapy

What to expectPreoperative consult with anesthesiologistPrescriptions for:

Flomax: Started 1 week prior to procedure Antibiotic: 7 days- Start 1 day prior to procedure

Diet and bowel cleansing 1 day prior to treatment

Brachytherapy

Half life of seeds: 2 monthsPrecautions:

Carry a wallet card for securityHolding childrenSleeping with partnerVoiding seeds

Time (months)

Amount of Radiation Left (%)

Brachytherapy

AdvantagesA day surgery procedure 1.5 - 2 hoursBladder catheter removed the following

dayQuick recovery

Brachytherapy

Side Effects and Risks

Early (1- 6 months)Irritation of the bladder and urethra

Burning, frequency, urgencyLate

Erectile dysfunction: 20 – 50/100 men Urethral stricture: 1/100 men

May require dilatation

External Beam Radiation( High energy x-rays )

WHO?Any patient with prostate cancer Patients ineligible for surgeryInformed patient choice

External Beam Radiation( High energy x-rays )

WHO NOT? Ulcerative colitis, Crohn’s disease, Diverticulitis Previous radiation to the pelvis Previous extensive pelvic surgery

External Beam Radiation

What to expectImage-guided Radiation TherapyCT Scan for treatment planning with bowel

and bladder prep

External Beam Radiation

What to expectDaily x-rays on treatment machine for targetingDaily outpatient treatments

Monday – Friday, 5 treatments/ week30 minutes at the cancer clinic daily 12 minutes on treatment machine daily37- 40 treatments (8 weeks)

External Beam Radiation

AdvantagesOutpatient treatmentTreatment times can be flexibleNo anesthetic requiredPatients often continue to work during therapyTreatment beamed at the prostate and the immediate

surrounding area

External Beam Radiation

Side Effects and RisksEarly

Fatigue Irritation of the bowel and bladder

(frequency of urination, burning, diarrhea) Easily managed Recovery within 4-6 weeks of finishing

External Beam Radiation

Side Effects and RisksLate

Erectile Dysfunction 40-60 / 100 menBladder complications (frequency, urgency)Rectal or bladder bleeding (15-20/ 100 men)Bleed requiring treatment 1/100

Cryosurgery

What is it?Insertion of hollow needles into the

prostate used to freeze the prostateProstate gland is frozen, allowed to thaw,

and frozen again

WHO? U S UA L LY O L D E R M E N A L L G R A D E S O F C A N C E R , P S A < 2 0 P RO S TAT E G L A N D VO LU M E < 6 0 C C S A F E O P T I O N F O R M E N W I T H OT H E R H EA LT H C O N C E R N S I N F O R M E D PAT I E N T C H O I C E

Cryosurgery

WHAT TO EXPECT 1 . 5 – 2 H O U R S S P I N A L A N E S T H E T I C M I N I M A L PA I N O N E N I G H T I N T H E H O S P I TA L Q U I C K R E C O V E R Y 2 - 3 W E E K S

Cryosurgery

Cryosurgery

What to Expect AfterSuprapubic catheter for 2-3 weeksMust lie flat for 2 hrs each afternoonAnti-inflammatory and antibiotic used

for 7-10 days

Cryosurgery

Side Effects and RisksEarly Swelling of scrotum and penis Discomfort with sitting (less than 2 wks) Erectile dysfunction-potential for recovery 30% over

time

Cryosurgery

Side Effects and RisksLate Stress incontinence: 5 /100 men TURP needed: 2-3 /100 men

Management of Localized Prostate Cancer

Side effects/risks of treatmentThe side effects and risks of treatment relate to the fact that

the prostate gland sits very close to bowel, bladder and nervesAll treatments result in infertilityTreatment of Prostate cancer does not mean the end of a

healthy sex life An erection , orgasm and climax are still possible although

dry.

Risk GroupsLOW INTERMEDIATE HIGH

PSA <10 10 - 20 > 20

Gleason score <=6 7 8-10

T- Stage T1-T2b T2c T3,T4

Treat-mentOptions

- Surveillance- Prostatectomy- Brachytherapy- EBRT- Cryotherapy

- Prostatectomy- EBRT (External Beam Radiation Therapy) - Cryotherapy- Brachytherapy(a subset of pts.)- Surveillance

- EBRT & ADT- Prostatectomy- Cryotherapy

and

and

or

or

or

or

• EXAMINATION (DRE) • PSA

Expect undetectable levels at 3 months for surgical treatments

(prostatectomy and cryotherapy) Falls over months to 3 years for radiation

treatment ( EBRT and Brachytherapy)

How Do We Assess Whether Treatment is Working?

Surveillance post-treatment

Recommend PSA testing q6months x 5 years * then annually

DRE annually (if radiation therapy received) DRE required if PSA detectable in patients after

surgery

Active surveillance patients should have a repeat prostate biopsy Usually 1 year after initial diagnosis then at selected

intervals

Disease Recurrence

All initial treatments have a backup treatment plan if necessary for local recurrence Open/Robotic: EBRT Brachy: Cryo EBRT: Cryo Cryo: Cryo again, EBRT

Advanced Prostate Cancer

Evolution of Prostate Cancer

Localized disease Typically cured with above approaches Many men will die of other causes ~15% will go on to develop advanced disease

PSA recurrence Rising PSA level can indicate local recurrence or distant

metastatic disease “Rising PSA” state may start years after initial diagnosis and

persist for years without evidence of metastatic disease Androgen Deprivation Therapy may be initiated at this time

Metastatic/Advanced disease ~10% of all cases of prostate cancer will present with metastatic

disease Bone and lymph node metastases are most common

Medscape Education - Oncology

PSA recurrence

Investigations required: Repeat PSA test (doubling time is important) May need prostate bed biopsy Bone Scan CT scan

Androgen Deprivation Therapy

Testosterone is the primary driver of prostate cancer growth

Androgen deprivation therapy (ADT) is the mainstay of medical treatment for patients with prostate cancer High-risk localized prostate cancer

Combined with RT (total of 2 years) Rising PSA state

Intermittent or continuous therapy Metastatic prostate cancer *

Goals of therapy in advanced prostate cancer

Quantity of lifeQuality of life

Improvement in pain, obstructive symptoms, time to skeletal-related events

Androgen Deprivation Therapy

Can be achieved by: Surgical orchiectomy Medical ADT

Typically consists of continuous GnRH agonist therapy Example: Leuprolide (lupron), Guserelin (Zoladex) Delivered by subcuteneous injections q3-6months Combined initially with an antiandrogen to prevent testosterone flare

• Example: bicalutamide (Casodex) x 1 month Mechanism:

Bind to GnRH receptors, cause initial LH/FSH release and testosterone flare, the downregulation of GnRH receptors, then a decrease in production of LH/FSH and testosterone.

GnRH antagonists Example: Degarelix (Firmagon) Delivered by MONTHLY sc injections New, efficacious, prevent need to block the testosterone flare GnRH agonists remain preferred agents due to funding issues, frequency

of injections

ADT – side effects

Sexual dysfunction Loss of libido Erectile dysfunction Management:

Couples counselling prior to ADT initiation, therapy, pharmacologic strategies

Osteoporosis Osteoporotic fractures can be detected in 20% of men on ADT

at 5 years Management:

Lifestyle interventions Calcium and Vitamin D supplementation Bone Mineral Density testing at initiation of ADT Consider osteoclast inhibition with bisphosphonates or denosumab

ADT – side effects

Vasomotor symptoms Hot flashes, nausea, sweating, sleep disturbances Management:

Medroxyprogesterone, cyproterone acetate, venlafaxine and gabapentin have all been evaluated with varying degrees of success and side effects

Gabapentin: Phase III trial evaluated 223 men with hot flashes 900mg gabapentin vs placebo reduced frequency and

intensity of hot flashes and was well tolerated Acupuncture

Loprinzi CL et al Ann Oncol 2009)

ADT- side effects

Body composition Loss of lean body mass, increased body fat, decreased muscle strength,

decreased insulin sensitivity Management:

Moderate exercise regimen Increased screening for diabetes and elevated cholesterol

Cardiovascular effects Conflicting studies regarding the impact on ADT on cardiovascular health Those with a previous history of CVD are at increased risk Management:

Counseling and risk reduction

Fatigue Anemia Gynecomastia Emotional and cognitive changes

Chemotherapy in prostate cancer

Administered in the castration-sensitive and castration-resistant states

Examples: Docetaxel IV q3weekly with daily prednisone Cabazitaxel IV q3weekly with daily prednisone

Given for up to 10 cyclesSide effects:

Fatigue Cytopenias (anemia, febrile neutropenia) Infections Neuropathy Alopecia Fluid retention, edema

Novel hormonal strategies

Castration-resistant prostate cancer When the PSA rises despite ADT Due to resistance mechanisms

Intratumoral testosterone production

Abiraterone Acetate CYP17 inhibitor, decreases testosterone production Oral administration, along with prednisone 5mg BID Side effects: fluid retention, HTN, hypokalemia, LFT

abnormalities

Novel hormonal strategies

Enzalutamide Novel, potent androgen-receptor blocker Oral administration Side effects: fatigue, gynecomastia, hot flashes

Many other agents currently in development: Oral hormonal agents Immunotherapy Radiopharmaceuticals

Each therapy is used in sequence, survival gains can be significant.

Many questions remain: Optimal sequence of therapy, selection of patients, biomarkers

Bone-Targeted Therapy

Bisphosphonates and Denosumab have been found to improve outcomes in patients with metastatic prostate cancer Decreases time to skeletal-related events

Hypercalcemia, spinal cord compression, fractures, pain requiring palliative RT

Often prescribed in conjunction with other treatments and continued indefinitely

Monitor for impaired renal function, hypocalcemia and osteonecrosis of the jaw

KEY POINTS

Summary

Prognosis for most men with prostate cancer is excellent. Prostate cancer survivors have a higher chance of death from

other causes

90% of patients will present with localized disease Due to widespread PSA screening However, concerning symptoms should prompt a work-up (bone

pain, urinary tract obstruction, hematuria)

There are a few reasonable treatment options for early-stage disease. Decision making depends on risk stratification, age, comorbidities, and patient’s informed choice.

Summary

Each treatment modality may result in late side-effects .

Sexual dysfunction is common after treatment for prostate cancer.

Patients treated with ADT should have careful assessment and monitoring of cardiovascular health. Other complications include impaired glucose metabolism and osteoporosis.

Psychosocial resources should be offered to patients, and their partners.

A rising PSA post-treatment warrants a prompt discussion with the oncology team.

Summary

Patients with advanced prostate cancer are living longer with more treatment options.

The quality of life of these patients is often improved with treatment, despite the side effects of treatment.

Pain is often a major component of morbidity due to advanced prostate cancer.

Communication between the oncology team and primary care physicians is paramount to ensure quality care (oncology, supportive, palliative).

QUESTIONS?