To treat or not to treat:When to treat!

A case presentation

Filip Ameye, MD,PhdUniversitary Hospitals Leuven, Belgium

Departement of Urology Prostate Center

A case presentation

• Pt. 76 y. – Mild LUTS (07/1999)• Rectal exam. and sonography: cT2c • PSA : 21 ng/ml• Transrectal biopsies

– Gleason 7 (4+3) / 8 of 12 biopsies +• Staging : CT and bone scan: negative• Definite staging : cT2cNoMo

A case presentation

• General Health Status– Comorbidities

• Mild hypertension – treated• NIDDM –compensated• Mild depression

– Other variables• Normal nutritional and cognitive status• No dependancy and/or geriatric syndromes

• Social status • Married, middle class, urban

How can we treat this patient

?

How can we treat this patient

EAU GuidelinesAUA guidelinesNCCN Guidelines....

EAU Guidelines 2007 cT2NoMo • Watchfull waiting

– Asymptomatic patients with well, and moderately differentiated tumors and a life expectancy <10 years.

– Patient who do not accept treatment related complications• Radical prostatectomy

– Standard treatment for patients with a life expectancy >10 years who accept treatment related complications

• Radiotherapy– Patients with a life expectancy >10 years who accept treatment related

complications.– Patients with contraindications for surgery– Unfit patients with 5-10 years of life expectancy and poorly differentiated

tumors.(combination therapy is recommended)• Hormones

– Symptomatic patients who need palliation of symptoms unfit for curative treatment. Antiandrogens are associated with poorer outcome compared to watchfull waiting and are not recommended

• Combination– ...NHT+ RT : better local control....Hormonal (3 years) +RT: better than RT in

poorly differentiated tumors

How should we treatthis patient

?

How should we treat this patient

Tumor characteristicsAgeGeneral ConditionLife ExpectancyPatient preference

Should we treat this patient ?

Watchfull waiting ?

• Pt. 76 y. – Mild LUTS• Rectal exam. and sonography: cT2c• PSA : 21 ng/ml• Transrectal biopsies

– Gleason 7 (4+3) / 8 of 12 biopsies +• Staging : CT and bone scan: negative• Definite staging : cT2cNoMo

D’Amico Prostate Cancer risk classification

Prostate Cancer specific mortality after treatment

Localized prostate cancer

Low risk

Intermediate risk

High risk

Radicalprostatectomy

Radiationtherapy

Only patients with high-risk disease are likely to receive curative treatment

Death of other causesDeath of prostate cancer

D‘Amico A et al. JCO 2003, 21: 2163-2172

Can we treat this patient surgically ?

Radical prostatectomy?

• Pt. 76 y. – Mild LUTS• Rectal exam. and sonography: cT2c• PSA : 21 ng/ml• Transrectal biopsies

– Gleason 7 (4+3) / 8 of 12 biopsies +• Staging : CT and bone scan: negative• Definite staging : cT2cNoMo• Good General Health – moderate operative risk

Can we treat this patient surgically ?

Radical prostatectomy?

• EAU Guidelines– Standard treatment – Life expectancy > 10 years– Accepting treatment related complications

• D’Amico data– Favorable for surgery in high risk patients

Median life expectancy

0

4

8

12

16

20

24

60 65 70 75 80 85 90 95 100

10 year

Life expectancy - PercentilesMedian/Vulnerable

6,84,6

19,65

15,611,9

8,8

14,0510,6

7,7 5,3 3,92,5

8,15,85 4

2,6 1,8 1,10

5

10

15

20

25

70 75 80 85 90 95Age (années)

nb d

'ann

ées

rest

ante

s

Frail and terminal

Fit.

Can we treat this patient surgically ?

Radical prostatectomy?• EAU Guidelines

– Standard treatment – Life expectancy > 10 years– Accepting treatment related complications

• D’Amico Data• But ........

– General Health status ?– Per and early postoperative morbidity ?– Late postoperative problems

A case presentation

• General Health Status – 76 Y– Comorbidities

• Mild hypertension – treated• NIDDM –compensated• Mild depression

– Other variables• Normal nutritional and cognitive status• No dependancy and/or geriatric syndromes

• Social status – Married, middle class, urban

Can we treat this patient safely with a Radical prostatectomy

?

This clinical case has to be considered as ‘vulnerable’

• Simplified Senior adult health status assessement.

• Lodovico Balducci, MD. & Jean-Pierre Droz, MD.

• “SIOG prostate Cancer in senior adult patients guidelines”

Senior adults with localized prostate cancer

Standard treatmentas for younger patientsexcept prostatectomy

Symptomaticmanagement including

specific treatments(hormones, RTUP…)

Readaptation

Life Expectancy Evaluation

Group 1(Healthy)

Group 2(Vulnerable, i.e.

reversible problem)

Group 3(Frail, i.e. non

reversible problem)

Group 4(Terminal illness)

• Comorbidity (CISR-G):grade 0 or 1 or 2

• Independent in IADL• No denutrition

• Comorbidity (CISR-G):at least one grade 3

• Dependent in ≥ 1 IADL• Denutrition

• Comorbidity (CISR-G):several grade 3 or at leastone grade 4

• Dependency: Impairmentof at least one ADL

• Cognitive impairment• Repeated delirium• Severe denutrition

• Terminal• Bedridden• Major comorbidities• Cognitive impairment

Standard treatmentas for younger

patients

Only palliativetreatment

The optimal treatment for this patient

Radiotherapy ?• EAU Guidelines

– Life expectancy > 10 years– Accepting treatment related complications– Unfit patients with 5-10 years of life

expectancy and poorly differentiated tumors (combination therapy is recommended)

– Patients with contraindications for surgery

The definite treatment for this patient

Radiotherapy combined with hormones

• EAU Guidelines– Combined with hormones during 3 years

• Better than RT in poorly differentiated tumors• Proven overall survival benefit

– Neo adjuvant : • better local control, no benefit in O.S

Combined RT and HT – Bolla study

Further clinical course

• Conformal Radiotherapy – 72 GY – 08/99• Hormonal treatment :

– Goserelin 10,8 every three months (Zoladex)– Bicalutamide 50 mg 1 month (Casodex)

• Oncological Follow up– Every three months – Clinical/PSA– Cyproterone 50mg (Androcur)– hot flushes

since 12/99

Biochemical recurrence

0,1 0,1 0,4 0,71,3

0,1 0,1 0,1 0,1 0,10,6 0,9 1,1 1,4

8,6

0123456789

10

01/00

03/00

05/00

07/00

09/00

11/00

01/01

03/01

05/01

07/01

09/01

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03/02

05/02

07/02

09/02

11/02

01/03

03/03

PSA

(ng/

mL)

Zoladex LA + Androcur

TAP/CT: 2 LN external left iliac artery 7 and 8 mmTc-99m bone scan: negative

What is the proposed strategy ?

1. Nothing

2. Stop Androcur and wait

3. Stop Androcur and replace immediately by Casodex 50 mg

4. Stop Androcur and replace immediately by Estracyt 50 mg (estramustine phosphate)

5. Add Avodart 0.5 mg (dutasteride)

6. Start docetaxel

Anti-androgen withdrawal syndrome

25224Total

6333BicalNieh

NR2914Bical

NR508FlutSchellhammer et al

3.32839FlutHerrada et al

3.73321FlutFigg et al

3.51582FlutSmall et al42857FlutScher et al

Duration (months)

% of patients with 50% PSA response

Patients (n)DrugTotal

Flut + flutamide; Bical = bicalutamide; NR = not recorded

Adding a second line of hormones

Second-line hormonal manipulations

NR2331High-dose bicalutamideJoyce et al

41451High-dose bicalutamideScher et al

NR1414Megestrol acetateOsborn et al

NR12149Megestrol acetateDawson et al

8.55520Ketoconazole + hydrocortisone + AAW

Small et al

3.56350Ketoconazole + hydrocortisoneSmall et al

44829Aminoglutethimide + AAW + hydrocortisone

Sartor et al

1.82934Hydrocortisone + AAWDawson et al

42281PrednisoneTannock et al

NR6138DexamethasoneStorile et al

42030HydrocortisoneKelly et al

Duration (months)

% > 50% PSA response

Patients(n)DrugTotal

AAW = anti-androgen withdrawal

Biochemical recurrence

0,1 0,1 0,4 0,71,3

0,1 0,1 0,1 0,1 0,10,6 0,9 1,1 1,4 1,1 1,4 1,6

8,6

0123456789

10

01/00

04/00

07/00

10/00

01/01

04/01

07/01

10/01

01/02

04/02

07/02

10/02

01/03

04/03

07/03

10/03

01/04

PSA

(ng/

mL)

TAP/CT: 2 LN external left iliac artery 7 and 8 mmTc-99m bone scan: negative

Stop Androcur

Zoladex LA + Androcur Zoladex LA

Clinical course after AA withdrawal

• Biochemical progression

• Asymptomatic

• Patient agreed to be included into a clinical trial - Atrasentan

• He agrees to have bone scans and CT scans every two months

Biochemical Progression

0,1 0,1 0,4 0,71,3

0,1 0,1 0,1 0,1 0,1 0,6 0,9 1,11,4 1,62,1

3,1

4,4

6,2

10,1

8,6

0

2

4

6

8

10

12

01/00

04/00

07/00

10/00

01/01

04/01

07/01

10/01

01/02

04/02

07/02

10/02

01/03

04/03

07/03

10/03

01/04

04/04

07/04

PSA

(ng/

mL)

Study drug

Zoladex LA

Atrasentan - Study M00-244

0

20

40

60

80

100

120

140

0 12 24 36 48 60 72 84

FUp (months)

PSA

ng/

ml

Non-metastaticPSA rising

Atrasentan vs. placebo

Further clinical course

18 mm

13mm

• Patient has to stop trial medication

• Strictly asymptomatic

• MRI of the axial skeleton confirms two metastases

Asymptomatic Biochemical Progression

What is our strategy now ?

1. Zometa 4 mg monthly

2. Estracyt per os

3. Docetaxel 75 mg/m² q/3 weeks

4. Surveillance until symptoms appear

Evolution to Symptomatic HRPC

• The patient initially decides to have surveillance

• He comes back after four months

• He has moderate but recurrent pain in the back.

Biochemical recurrence

0,1 0,1 0,4 0,71,3 0,1 0,1 0,1 0,1 0,1 0,6 0,9 1,11,4 1,62,13,1 4,4 6,210,1

42,6

8,6

05

1015202530354045

01/00

04/00

07/00

10/00

01/01

04/01

07/01

10/01

01/02

04/02

07/02

10/02

01/03

04/03

07/03

10/03

01/04

04/04

07/04

10/04

01/05

PSA

(ng/

mL)

Study drug

Zoladex LA

Symptomatic HRPC What is our strategy now ?

1. Zometa 4 mg monthly2. Estracyt per os3. Docetaxel 75 mg/m² q/3 weeks 4. Radionuclide drugs5. Palliative radiotherapy6. Other ?