Consequences of

prostate cancer

treatment Dr Tharani Nitkunan, consultant urologist

Dr Alison Tree, consultant oncologist

COI

Alison Tree

• Honoraria from Ferring (Degarelix), Astellas, Janssen and

Bayer

• Research funding from Elekta, MSD and Accuray

Tharani Nitkunan

• Honoraria from Astellas, Allergan and Contura International

Overview of this session

• Brief summary of the logistics of radiotherapy, surgery and

hormone therapy for prostate cancer

• How to manage the consequences of treatment (case studies)

1. Lower urinary tract consequences

2. Bowel consequences

Break for questions

3. Erectile dysfunction

4. Androgen deprivation therapy side effects and management

strategies

When to treat prostate cancer

Low-risk Intermediate-risk High-risk

PSA <10ng/ml 10-20ng/ml >20ng/ml

Gleason score/ISUP Gleason < 7/ISUP Grade 1

Gleason 7/ISUP Grade 2/3

Gleason >7/ISUP Grade 4/5

Clinical stage cT1-2a cT2b cT2c

ISUP (International Society of

Urological Pathology 2014 grades)

Gleason

1 2-6

2 7 (3+4)

3 7 (4+3)

4 8 (4+4 or 3+5 or 5+3)

5 9-10

Radiotherapy- myth busting

• Equivalent to surgery for cancer cure

Radiotherapy myth-busting

Logistics

• Start ADT first

• Once PSA has dropped to around 1, start planning

radiotherapy

• For prostate radiotherapy insert gold seeds into prostate for

image guidance (like TRUS but faster)

Risks

• Pain

• Bleeding (GI, GU, Haematospermia)

• Infection

• Rectal swab, targeted antibiotics

• IF FEVER – STRAIGHT TO A +E, NEED IV Abx (risk 0.3%)

8

• CT scan (possibly MR scan) 1 week after seeds inserted)

• Whole radiotherapy planning pathway takes around 4 weeks,

but patient only needed twice

Daily treatment – used to be 7.5 weeks,

now mostly 4 weeks, ??soon 5 days 10

Quick discussion

• If you were going to have prostate radiotherapy, what would

you be most worried about?

Daily treatment

• Fill bladder, may use enema

• Change into gown

• Patient lies on the couch

• Radiographers line up to pin-point tattoos

• Mini-CT (called cone beam CT)

• Shift patient to ensure prostate exactly aligned

• Radiographers leave the room – patient is alone

• Treat – takes about 2 minutes with VMAT

• Patient goes home, no restrictions on lifestyle

1 slide on PSA follow up

• PSA should be checked 6 monthly until 5 years after

radiotherapy

• Annually thereafter

• After radiotherapy, PSA “failure” occurs at nadir PSA+2 ng/ml

• Actually easier to say 2 ng/ml in general

• Off ADT Testosterone will usually return to normal, PSA will rise

a little. Don’t panic.

• Any questions about PSA – please write to us or call us. If

unsure, repeat PSA in 3 months.

Surgery

Surgery

Eradicate cancer

Preserve continence

Preserve potency

RALP = robot-

assisted laparoscopic

prostatectomy

Surgery – pre-operative preparation

Surgical counselling

Patient seminar

Surgery – pre-operative preparation

Pelvic floor muscle training

• hammock of muscles

• 10 squeezes 3x/d

Exercise

• 30mins 5x/week

Avoid driving 2-4 weeks after surgery

No high impact exercises for 6 weeks

Ensure no constipation

Surgery

Apical dissection

Posterior Reconstruction

Anatomy- Membranous urethral length

Previous LUTS

Experience

Retzius Sparing

Nerve-sparing

• Contraindicated in high risk of extracapsular disease

• cT2c or cT3 PCa,

• any GS > 7 on biopsy

Surgery – Post-operative care

Home at 24-48 hours

Catheter for 7-10 days

Analgesia

Ensure bowels opening

VTE prophylaxis

• Low molecular weight heparin

• TED stocking 28 days

Surgical complications – BAUS

• No semen all

• Erectile dysfunction (incl penile shortening) almost all

• Incontinence 3-5%

• Bleeding req transfusion or further surgery 2-10%

• Urinary leak 2-10%

• Pain, infection or hernia of port sites 2-10%

• Lymph node collection 2-10%

• Anaesthetic complications 0.5-2%

• Conversion to open surgery 1%

• Rectal injury 0.5-2%

Surgical complications - Potency

• Bilateral nerve sparing and good prior erectile function

• Men <60 yrs - 75% recovery

• Men >60yrs – 50% recovery

• Negative factors – obesity, diabetes, hypertension, poor pre-

operative erections

Cahill personal communication

Surgical complications - Continence

Causes

• Stress urinary incontinence 32-100%

• Sphincter incompetence 40-92%

• Urethral sphincter length >15mm – less incontinence

• Detrusor overactivity 4-40%

• Detrusor compliance 12-82%

• Stricture 24-67%

Surgical complications - Continence

• 4-8% rates of incontinence

• Better with time

• 12months

PSA follow-up post radical surgery

• 2 consecutive PSA rises >0.2ng/ml

• PSA should be undetectable within six weeks post surgery

• Rapidly increasing PSA suggests distant metastases

• Slowly increasing PSA suggests local recurrence.

ADT

When do we give ADT?

• With radiotherapy – increases cure rates

• In metastatic disease – prolongs survival

Castration

28

LHRH Agonists/analogues eg

Zoladex/Prostap/Decapeptyl

• Castrate testosterone levels achieved in around 2 weeks

• May raise testosterone in first 1-2 weeks (potential for tumour

flare). Co-treatment with Bicalutamide for first month necessary.

• Equivalent efficacy to castration in trials

• Licensed preparation

Goserelin (Zoladex) 3.6mg q 4w or 10.8mg q 12w

Leuprorelin (Prostap) 3.75mg q 4w or 11.25mg q 12w

Triptorelin (Decapeptyl) monthly, 3 or 6 monthly

• Nearly everyone responds

How to start ADT - usually

• Bicalutamide 150mg od for 28 days

• LHRH analogue injections starting 7-14 days after starting

Bicalutamide

• Start monthly, can switch to 3 monthly preparations if long term

ADT is required

• Caution

– Uncontrolled cardiac disease (ischaemic or failure)

– Diabetics with poor control

When 1 month and when 3 month

depots?

• Total length of ADT in localised disease depends on risk

• 3 month depots – 9 months to testosterone recovery

• Good risk – 6 months

• Locally advanced/node positive – 3 years

• Metastatic – lifelong

Side effects of LHRH analogues

• Hot flushes

• Fatigue

• Loss of muscle bulk

• Loss of libido and ED

• Mood change

• Insulin resistance

• Cardiac effects?

• Osteoporosis

• Acupuncture, MPA,

Tamoxifen

• Exercise

• Exercise

• Not much ?vacumn pumps

• Monitor BM

• BP, cholesterol, Exercise

• Start Alendronate

NICE guidance on Osteoporosis

Degarelix effect on testosterone levels

Van Poppel EU (54) 805-815, 2008

Overall survival

Klotz et al, Eur Urol 66, 1101-1108, 2014

37 deaths in

all, 4 due to

prostate cancer

Patients with a history of CV disease (n=708)

Risk of cardiac event or death

Degarelix

6.5%

LHRHa

14.7 %

NICE guidance

“Degarelix is recommended as an option for treating advanced

hormone- dependent prostate cancer in people with spinal

metastases, only if the commissioner can achieve at least the

same discounted drug cost as that available to the NHS in June

2016.”

Reality in my experience – Degarelix started in hospital for those

with spinal mets, switched to random LHRH, often without

Bicalutamide cover, in the community.

LUTS management

Urinary incontinence

LUTS management

• When do you talk about LUTS in your patient cohort– Pre- treatment

– Post-treatment

• History

• Investigations

• Management

• Cases

History - LUTS

• Storage

– Frequency

– Nocturia

– Urgency

– Urge incontinence

Voiding–Hesitancy–Straining to void–Stop/start flow–Incomplete emptying

Post-micturition dribbling

Red flag symptoms

History

• Stress incontinence

• Pad use

• How much does this affect your life?

• Fluid intake - caffeine

• Bowels

Assessment

Frequency/volume chart

Uroflowmetry

IPSS or EPIC

IPSS/EPIC

• EPIC

• expanded prostate cancer index composite

• 5 questions on urinary symptoms

• Other domains – bowel function/ sexual function

• IPSS

• 7 questions on symptoms + 1 quality of life question

EPIC

1. Over the past 4 weeks, how often have you leaked urine?

More than once a day/About once a day/More than once a week/About once a week/Rarely or never

2. Which of the following best describes your urinary control during the last 4 weeks?

No urinary control whatsoever/Frequent dribbling/Occasional dribbling/Total control

3. How many pads or adult diapers per day did you usually use to control leakage during the last 4 weeks?

None/1 pad per day/2 pads per day/3 or more pads per day

4. How big a problem, if any, has each of the following been for you during the last 4 weeks?

Dripping or leaking urine /Pain or burning on urination/Bleeding with urination/ Weak urine stream or incomplete emptying/ Need to urinate frequently during the day

5. Overall, how big a problem has your urinary function been for you during the last 4 weeks?

No problem/Very small problem/Small problem/ Moderate problem/Big problem

IPSS

Score:

1-7 mild

8-19 moderate

20-35 severe

IPSS

Quality of life question

If you were to spend the rest of your life with your urinary

condition just the way it is now, how would you feel

about that?

0 delighted, 1 pleased, 2 mostly satisfied, 3 mixed, 4

mostly dissatisfied, 5 unhappy, 6 terrible

Urine dipstick

Signs of UTI – wcc and nitrites

Haematuria – to follow haematuria pathway

Diagnosis

History Anatomy

Storage Bladder• Bladder compliance

• Detrusor overactivity

Voiding Urethra

• Stricture

• Stress urinary incontinence

Voiding

• Tamsulosin 400mcg od

• Offer finasteride or a 5alpha reductase inhibitor to men

with prostate volumes >30g or PSA >1.4ng/ml

Management of storage symptoms

Bladder training, caffeine reduction

Antimuscarinics

Mirabegron

Combinaton

Botox

Management of storage symptoms

- bladder training

Antimuscarinics

NICE guidelines

• Offer one of the following

oxybutynin immediate release or

tolterodine immediate release or

darifenacin

• If the first treatment is not effective or well tolerated, offer

another drug with the lowest acquisition cost.

• Do not offer oxybutynin immediate release to frail elderly

Antimuscarinics – per NICE

• Offer one of the following

oxybutynin immediate release or £1.76 to £1.06

tolterodine immediate release or £1.18

darifenacin. £30.58

• If the first treatment is not effective or well tolerated, offer

another drug with the lowest acquisition cost.

Trospium chloride XL (Regurin XL 60mg) £23

Fesoterodine (Toviaz 4 and 8mg) £28.62

Solifenacin (5 and 10mg) £29.70 to £38.64

Antimuscarinics

Risks

• Increase in cognitive impairment

• OR=1.45, 95% CI 1.16 to 1.73

• Increase in falls

• all-cause mortality relative to score on the Anticholinergic

Cognitive Burden (ACB) scale

• a system that scores drugs with anticholinergic effects from 1 (possible

anticholinergic effects based on in vitro data) to 3 (known anticholinergic

effects that may cause delirium).

• an increase of 1 point on the scale approximately doubling risk (OR=2.06,

95% CI 1.82 to 2.33)

Mirabegron

• Beta 3 adrenoceptor agonist

• Enables bladder relaxation

• £27.06

• SCORPIO - RCT comparing mirabegron to tolterodine XL

4mg and placebo for 12 weeks4

• Reduced number of incontinence episodes and micturition

episodes

• contraindicated in severe uncontrolled hypertension (systolic

blood pressure ≥180 mm Hg or diastolic blood pressure ≥110

mm Hg, or both)

Investigations – flow rate and scan

Flow rate and scan

Urodynamics

Urinary incontinence - management

History Anatomy Management

Storage Bladder• Bladder compliance

• Detrusor overactivity

Intradetrusor Botox

Clam cystoplasty

Urinary diversion

Voiding Urethra Urethral stricture Optical urethrotomy

Stress urinary

incontinence

Pelvic floor muscle training

Sling

Artificial urinary sphincter

Case 1

Mr AK 76

Locally advanced CaP, DXT (ProSpare Trial) in 2011

Hypertension, NIDDM

Referred in April 2014

Storage LUTS and penile tip pain

Solifenacin 20mg od and on tamsulosin

Voids 2 hly day and nigh

GA cystoscopy 2013 normal.

Case 1

Changed to regurin

Some improvement

Changed to Mirabegron

Urodynamics

Case 1

Not obstructed on CMG, DO only

Reflux bilaterally to mid ureter at 90mls

MDT

Combination treatment – mirabegron + Regurin

Ensure regular USKUB

Content with LUTS

Case 2

Mr RR 77

DXT for CaP 2011 Gleason 4+5 5/12 T2N0, PSA

7.3

Urgency and Frequency

Urodynamics

Botox

Worked well

Botox Nov 2012, Sept 2015, Nov 2016

Case 3

Mr AW 84

Prostate brachytherapy 2006

LHRH analogues since 2009

Bicalutamide 2013

Dexamethasome Nov 2013- Aug 2015

CRPC

Frequency, urgency, weak stream, urge incontinence

D – 15, N- 4

IPSS QoL 5/6

Started on Tamsulosin at RMH – helped Sx

Started on Fesoterodine

Bladder diary and uroflowmetry

Residual

166ml

Case 3

TURP March 2016

Less frequent and urgent but more

incontinence

Urodynamics

Cystoscopy + urethral dilation Nov 2016

Rigid small prostate

Short bulbar stricture

Normal bladder

Case 4

Mr AP 67

RARP

Stress urinary incontinence

Pelvic floor muscle training

Male sling or artificial urinary sphincter

Boston Scientific

Bowel symptoms

Case history

• 72 year old man

• PSA 18, Gleason 4+4 (Grade group 4), T3a (capsular invasion)

N0M0 prostate cancer

• Radical radiotherapy 2 years ago – 60 Gy in 20 fractions

• PSAs well controlled around 0.5 ng/ml

• Now in GP PSA follow up

• Comes to see you with a 6 week history of flecks of blood on

the toilet paper

• Since radiotherapy minor increase in bowel frequency (2/day).

• No other symptoms

Please discuss – 5 minutes

• Correct investigation and management of this

• Most likely causes

• Appropriate treatments for these

2 week rule always applies (first time

round)

• Use usual referral criteria

• Most likely he has rectal telangiectasia from previous

radiotherapy

• Often require no treatment

• If persistent or heavy bleeding, can use sucralfate enemas,

formalin application.

Severe rectal telangiectasia

Same patient comes back 2 years later

• Bleeding has spontaneously improved, but now has loose

stools 3-4 times per day coming on gradually over the last 12

months.

• Some faecal urgency

What do you do?

5 min break and/or

questions

Erectile dysfunction

Erectile dysfunction

Pre-procedural potency is important

History

• Sexual function using IIEF (International Index of Erectile

Function)

• Medical history

• Assess cardivascular risk

Erectile dysfunction – cardiovascular

risk

Low risk – treat ED

High risk – refer to cardiologist

Erectile dysfunction

Diagnostic tests

• Glucose-lipid profile

• Testosterone

Management

• Lifestyle changes and risk factor modification

• manage hypertension, diabetes, weight

Erectile dysfunction – PDE5 inhibitors

• Viagra (Sildenafil), Levitra (Vardenafil), Cialis (Tadalafil)

• Cause smooth muscle relaxation – vasodilation

• How to take them

• Take at lease 30 minutes before sexual activity (45 mins for Viagra).

• Avoid heavy meals 2 hours prior to taking Viagra (not a problem with Cialis).

• Will require sexual stimulation / intimacy to acquire an erection.

• May require up to 8 doses to gain optimum effect (on separate days).

Side effects

Vacuum constriction device

• Blood drawn into the penis using a vacuum device and

constriction ring

• Blood drawn into the penis using a vacuum device and

constriction ring

• Works within 5-6 minutes

• Effective in patients that cannot have PDE5 inhibitors

• Advantages – suitable for most patients,

Intracavernosal injection therapy

• Alprostadil (Caverejct)

• Relaxes smooth muscle increasing blood flow to the penis

• As the penis engorges it compresses venules preventing outflow

of blood

• Erection occurs in about 10 minutes

Intraurethral therapy

MUSE (Alprostadil)

Insert stem into urethra after urination

Erectile rehabilitation

Cialis 5mg daily (2.5-5mg) or with injection or urethral therapy

2x/week or daily vacuum therapy

Starts 6-8 weeks post-op

Patients are allowed 4 PDE5i tablets per month on NHS

ADT side effects

Further information

62 year old man, metastatic prostate

cancer, on ADT for 3 years

• Comes to see you with several complaints:

• Hot flushes waking him at night, embarrassing in the day

• Fatigue – affecting QOL

• Loss of strength (can’t dig the garden any longer)

• Reduced penile length

• Reduced self-worth, feeling low

What would you do? 5 minutes

Serenity prayer – what can we change?

God grant me the serenity to accept the

things I cannot change, the courage to

change the things I can and the wisdom

to know the difference

What side effects can we actually help

with?

Hot flushes

• Randomised trial venlafaxine 75mg od vs cyproterone acetate

100mg od vs medroxyprogesterone acetate 20mg od. MPA and

cyproterone better than venlafaxine, MPA favoured but…

• Acupuncture

Reduced penile length, reduced libido

• A side effect of ADT – no known way to improve this whilst on

LHRH analogues.

Reduced self worth, feeling low• I have a question for you here – what should I be telling the

patient to do?

Questions?