prostate cancer case
DESCRIPTION
medicinaTRANSCRIPT
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