Management of metastatic prostatic

cancerCase discussion

Dr. Daniel Radavoi

- 48 years old E.S. patient went to GP for:

- constipation- LUTS

- he was referred to a general surgery specialist: - DRE: firm rectal mass located on the anterior rectal wall : raise suspicion of a rectal cancer

- recommended a pelvic MRI scan

- tumor markers for rectum cancers

15.June.2009

• CA19-9 = 14.4 U/ml (N<27)• CEA = 4.4 ng/ml (N<4.3)

MRI:

- Right lobe prostate tumor with contralateral extension, involvement

of the rectum and invasion of the seminal vesicles

- adenopatic tumoral masses in the right obturatory fosa and bilateral on

common iliac, external iliac and presacral lymph nodes

- perirectal and perivesical nodes

21.June.2009

- Patient referred to urologist 25.June.2009

PSA = 215 ng/ml

DRE: a rigid, immobile tumor mass that extend into pelvis with adherences to the bone structures, the rectal lumen being reduced in diameter

Transrectal ultrasonography:

- a mass with the same echogenicity as the prostate gland that appeared to be arising from the prostate and who was invading the anterior wall of the rectum - a transrectal biopsy (10 cores) – PCa Mastofi grad IV, GS 4+4=8,

- 9 of 10 cores positive

Bone scan:- inflammatory-degenerative aspects on:

• acromioclavicular junctions• sternoclavicular junctions• right intercarpal joints

- 2 hot spots suggestive for metastatic lesions: vertebral bodies C3 and T8

30.June.2009

Question:Do we treat this patient immediately?

Facts on androgen deprivation therapy (ADT):

1. ADT is the best available treatment for metastatic prostate cancer- however, the impact on overall survival is yet unclear

2. The goal of ADT is to lower serum testosteron to the castrate level- Surgical castration- Medical castration: LHRH – agonists LHRH – antagonists Estrogens- Complete androgen blockade- Intermittent ADT- Androgen blockade (by AA)

3. ADT has a variety of side effects- therefore, timing is an important issue

4. ADT will ultimately fail in the majority of patients- prostate cancer will became castration resistant

Do we treat M+ patients immediately?

MRC trial suggested no difference on OS for early hormonal therapy (EHT) Less severe complications with EHT

spinal cord compression 1.9 vs. 4.9% ureteric obstruction 7 vs. 11.8% recurrent bladder outflow obstruction 13.9 vs. 30.3%

asymptomatic M+ patients – will need treatment in < 9 months.

We have to balance the avoidance of side-effects of hormonal treatment (for a mean of 9 months) against the risk of important complications.

Questions:

What kind of the treatment do we offer?

Are all kinds of ADT equally effective?

Surgical castration, 1941

LHRH – Agonists, 1985

LHRH – Antagonists, 2009

The goal of ADT is to achieve castrate levels of serum testosterone.

05.July.2009

The patient has received CAB

• TRIPTORELINUM (DIPHERELINE PR) 11,25 mg/3- months depot formula

• Bicalutamide 50 mg/day

EAU Guidelines on prostate cancer - 2012

Only 3 randomized clinical trials demonstrated a significant survival advantage of CAB (CDN-83, EORTC 30853, NCI 0036)

No study ever shoved a worse survival with CAB

According to the most recent systematic reviews and meta-analyses, at a follow-up of 5 years, CAB appears to provide a small survival advantage (<5%) versus monotherapy (castration through LHRH analogues) (LE: 1a)

The rationale of CAB is to:

1. Prevent flare-up phenomenon2. Block the stimulating effect of adrenal androgens

- responsible for 5-10% of serum T concentration - following castration, DHT tissue levels decrease by only 45%

Facts on LHRH analogue medical castration:

Patients prefer medical castration• LHRH analogue have been widely used for 25 years• 1-,3-,6- months depot formulations are available• reversible treatment

Problems with LHRH analogue medical castration• There is an initial rise in testosterone (flare up)• Some patients do not achieve castrate levels

15-35% do not achieve ≤20ng/dl 5-15% do not achieve ≤50 ng/dl

There are “ mini flares” following each administration

Testosterone breakthrough has been reported

Would you consider a supplementary treatment for bone loss and fracture protection?

What supplementary treatments would you consider?

1. no treatment - young patient unlikely to have an important bone mass lost

or

2. you would performed a bone densitometry to detect osteoporosis

or

3. Zoledronic acid (Zometa)

5 July 2009 – PSA 215 ng/mL - started CAB

21 October 2009 - PSA = 2.45 ng/mL - Serum testosteron = 24 ng/dL

15 December 2009 - PSA = 0.75 ng/ml

PSA = 0.75 ng/ml

CAB (Diphereline 11.25mg/3 months + Casodex 50 mg)

MRI:

• inhomogeneous prostatic tissue

• poor margins delineation

• without adjacent tissues infiltration

• no detectable lymphadenopathy

15 December 2009

24 December 2009

Bone scan:

1. inflammatory-degenerative aspects

•acromioclavicular junctions• sternoclavicular junctions• right intercarpal joints

2. signal abnormality suggesting metastatic lesions

• C3• T8• anterior costal arch 2

Apparently unchanged aspect on bone scan compared with June 2009 scintigraphy

What about radiotherapy treatment to the primary site in M+ patient?

“A clinically import survival benefit (HR 0.69; 95%CI, 0.61-0.79) when local treatment applied to the primary tumor”

“Addition of local radiotherapy to endocrine treatment decrease overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone”.

January 2010

• Patient received pelvic external beam radiotherapy

• wider pelvic field (46 Gy) with prostate boost (20 Gy), well tolerated;

• CAB was continued during and after irradiation

15 March 2010 PSA = 0.20ng/ml

06 May 2010 PSA = 0.062ng/ml

Continuous or intermittent androgen deprivation therapy?

EAU Guidelines on prostate cancer - 2012

Patient has opted for intermittent androgen blockade 06 May 2010

PSA = 0.062ng/ml

Advantages:- Better tolerated- Avoidance of sexual dysfunction- Avoidance of hot flushes, loss of muscle bulk- Reduction in gaining weight- Protective effect against metabolic syndrome- Reduction in osteoporosis- Reduction in cardiovascular morbidity associated with ADT- etc

- no difference in survival between continuous (CA) and intermittent arm (IA)- the greater number of cancer deaths in the IA was balanced by a greater number of cardiovascular deaths in the CA- side-effects were more pronounced in the continuous arm- men treated with intermittent therapy reported better sexual function

His PSA started to rise:

15.08.2010 – PSA 1.22 ng/ml

16.11.2010- PSA 2.75ng/ml

09.01.2011- PSA 8.45 ng/ml

15.03.2011- PSA 12.15ng/ml - patient resumed ADT

   

At what level of PSA would you resume hormonal treatment?

EAU Guideliness 2012

Treatment is resumed when the patient reaches either a clinical progression, or a PSA value above a predetermined, empirically fixed threshold. This is usually 10-15 ng/mL in metastatic patients.

Patient has opted for intermittent androgen blockade 06 May 2010 PSA = 0.062ng/ml

A new hot spot posterior costal arch 8

March 2011 - external iliac adenopathy- thickening of right seminal vesicle wall- presacral, common iliac and internal iliac adenopathies. -Right obturatory fosa and perirectal tumoral masses- Prostate with T2 hyposignal on right transitional and peripheral zone. Prostatic capsule with irregular aspect on the right, with heterogeneous signal of adjacent fat and perirectal fascia- signal abnormality suggesting metastatic lesions on T8, T12, L1 vertebrae bodies, posterior costal arch 8 and right iliac bone

Goserelinum (ZOLADEX) 10.8 mg every 3 months Bicalutamide (CASODEX) 50 mg/day, 7 days, to reduce the risk of “flare-up” phenomenon Bone related treatment? - Denosumab - Zolendronic acid

20.05.2011- PSA 2.16ng/ml

21.06.2011- PSA 1.11ng/ml

18.07.2011- PSA 1.69 ng/ml

06.10.2011- PSA 1.31 ng/ml

19.12.2011- PSA 1.21ng/ml

03.01.2012- PSA 1,10ng/ml

13.03.2012- PSA 1.10 ng/ml  

15.03.2011- PSA 12.15ng/ml - patient resumed ADT

ADT will ultimately fail and PCa will become castration-resistant

What 2nd line treatment would you offer?

- addition of antiandrogens

- Docetaxel

- Abiraterone acetate

- MDV 3100