Management of metastatic prostatic cancer

Case discussion
Dr. Daniel Radavoi

15.June.2009
- 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
CA19-9 = 14.4 U/ml (N<27) CEA = 4.4 ng/ml (N<4.3)

21.June.2009

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

- 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

30.June.2009

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

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 ureteric obstruction recurrent bladder outflow obstruction

1.9 vs. 4.9% 7 vs. 11.8% 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?

LHRH Agonists, 1985

Surgical castration, 1941

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

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) 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

The rationale of CAB is to:

1. Prevent flare-up phenomenon 2. 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. or

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

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

15 December 2009 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

24 December 2009 Bone scan:

1. inflammatorydegenerative 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

PSA = 0.20ng/ml PSA = 0.062ng/ml

15 March 2010

06 May 2010

Continuous or intermittent androgen deprivation therapy?

Patient has opted for intermittent androgen blockade 06 May 2010

PSA = 0.062ng/ml EAU Guidelines on prostate cancer - 2012

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

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

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

15.03.2011- PSA 12.15ng/ml - patient resumed ADT 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

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