Transcript Slides

Module 3: Treatment of
Hormone-Sensitive Prostate
Cancer
Introduction
PAGE 2
Factors Influencing Treatment
Decision
• Treatment option depends on several factors:
•
•
•
•
•
Tumour grade and stage
Possible adverse events
Patient’s general health status
Patient’s life expectancy
Patient’s preferences
Prostate Cancer Treatment Options
Treatment goal defined in function of the stage of disease:
curative versus non-curative
Curative
Localised
Non-curative
Locally
advanced
Metastatic
Hormone
resistant
X
Active surveillance
or watchful
waiting*
X
Surgery
X
X
Radiotherapy
X
X
X
X
X
Hormonal therapy
Chemotherapy
*Until tumour activity increases
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 15 July 2014.
Mohler JL et al. J Natl Compr Canc Netw. 2012;10(9):1081-1087.
X
Treatment Guidelines
Treatment Guidelines: T1a Disease
Treatment
Comments
Grade
Watchful waiting
Standard treatment for Gleason score ≤6 and 7 adenocarcinomas
and <10-year life expectancy
B
Active surveillance
In patients with >10-year life expectancy, re-staging with TRUS
and biopsy is recommended
B
Radical prostatectomy
Optional in younger patients with a long life expectancy,
especially for adenocarcinomas with Gleason score ≥7
B
Radiotherapy
Optional in younger patients with a long life expectancy,
especially in poorly differentiated tumours. Higher complication
risks after TURP, especially with interstitial radiation
B
Hormonal therapy
Not an option
A
Combined therapy
Not an option
C
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
TRUS, trans rectal ultrasonography; TURP, transurethral resection of the prostate
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Treatment Guidelines: T1b-T2b
Disease
Treatment
Comments
Grade
Treatment option in patients with cT1c-cT2a, PSA <10 ng/mL,
biopsy Gleason score ≤6, ≤2 positive biopsies , ≤50% cancer
involvement of each biopsy
Active surveillance
Patients with a life expectancy <10 years
Patients with a life expectancy >10 years once they are informed
about the lack of survival data beyond 10 years
Patients who do not accept treatment-related complications
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
PSA, prostate-specific antigen
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
B
Treatment Guidelines: T1a-T2c
Disease
Treatment
Radical prostatectomy
Comments
Optional in patients with pT1a PCa. Standard treatment for patients
with a life expectancy >10 years who accept treatment-related
complications
Grade
A
Patients with a life expectancy >10 years who accept treatmentrelated complications
Radiotherapy
Patients with contraindications for surgery
B
Unfit patients with 5-10 years of life expectancy and poorly
differentiated tumours (combination therapy is recommended)
Brachytherapy
Hormonal therapy
Combination therapy
Low dose rate brachytherapy can be considered for patients at low
risk of PCa with a prostate volume ≤50 mL and an IPSS ≤12
B
Symptomatic patients, who need palliation of symptoms, unfit for
curative treatment
C
Anti-androgens are associated with a poorer outcome compared to
“active surveillance” and are not recommended
A
For high-risk patients, neo-adjuvant hormonal treatment and
concomitant hormonal therapy plus radiotherapy results in increased
overall survival
A
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
IPSS, international prostate symptom score; PCa, prostate cancer
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Treatment Guidelines: T3-T4 Disease
Treatment
Watchful waiting
Comments
Grade
Option in asymptomatic patients with T3, well-differentiated and moderatelydifferentiated tumours, and a life expectancy <10 years who are unfit for
local treatment
C
Optional for selected patients with T3a, PSA <20 ng/mL, biopsy Gleason
score ≤8 and a life expectancy >10 years
Radical prostatectomy
Patients have to be informed that RP is associated with an increased risk of
positive surgical margins, unfavourable histology and positive lymph nodes
and that, therefore, adjuvant or salvage therapy such as radiation therapy or
androgen deprivation might be indicated
C
Radiotherapy
T3 with >5-10 years of life expectancy. Dose escalation of >74 Gy seems to
be of benefit. A combination with hormonal therapy can be recommended
A
Symptomatic patients, extensive T3-T4, high PSA level (>25-50 ng/mL), PSADT<1 year
Hormonal therapy
Patient-driven, unfit patients
A
Hormone monotherapy is not an option for patients who are fit enough for
radiotherapy
Combination therapy
Overall survival is improved by concomitant and adjuvant hormonal
therapy (3 years) combined with external beam radiation
A
NHT plus radical prostatectomy: no indication
B
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
TRUS, trans rectal ultrasonography; TURP, transurethral resection of the prostate
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Treatment Guidelines: N+, M0
Treatment
Comments
Grade
Watchful waiting
Asymptomatic patients
Patient driven (PSA <20-50 ng/mL), PSA-DT >12 months
Requires very close follow-up
B
Radical prostatectomy
Optional for selected patients with a life expectancy of >10 years
as part of a multimodal treatment approach
C
Radiotherapy
Optional in selected patients with a life expectancy of >10 years,
combination therapy with adjuvant androgen deprivation for 3
years is mandatory
C
Hormonal therapy
Standard adjuvant therapy in more than 2 positive nodes to
radiation therapy or radical prostatectomy as primary local
therapy. Hormonal therapy should only be used as monotherapy
in patients who are unfit for any type of local therapy
A
Combined therapy
No standard option; patient driven
B
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
DT, doubling time; PSA, prostate-specific antigen
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Treatment Guidelines: M+
Treatment
Comments
Grade
Watchful waiting
No standard option
May have worse survival/more complications than with
immediate hormonal therapy
Requires very close follow-up
B
Radical prostatectomy
Not a standard option
C
Radiotherapy
Not an option for curative intent; therapeutic option in
combination with androgen deprivation for treatment of local
cancer-derived symptoms
C
Hormonal therapy
Standard option
Mandatory in symptomatic patients
A
Grade A recommendation: Based on clinical studies of good quality and consistency addressing the specific recommendations
Grade B recommendation: Based on well-conducted clinical studies, but without randomised clinical trials
Grade C recommendation: Made despite the absence of directly applicable clinical studies of good quality
Heidenreich A et al. EAU Guidelines 2013. Available at: http:://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Active Surveillance and Watchful
Waiting
Active Surveillance/Watchful Waiting
• Close monitoring
• Periodic testing (PSA, DRE)
• Switch to treatment when there are signs of tumour spread, pain or
other symptoms indicating that the prostate cancer becomes more
aggressive
DRE, digital rectal examination; PSA, prostate-specific antigen.
Active Surveillance (1/2)
Disease Monitoring
• Doctor visit
• PSA assessment
 every 3 to 6 months
• DRE
• TRUS-guided biopsy  once a year to once every 2-4 years
Candidates for Active Surveillance: Selection Criteria
• Low-risk PCa
• Gleason score ≤ 6
• PSA < 10 ng/mL
• Stage T1-T2a
• Selected intermediate-risk PCa
DRE, digital rectal examination; PCa, prostate cancer; PSA, prostate-specific antigen; TRUS, transrectal ultrasound.
Thomsen FB, Brasso K, Klotz L et al. J Surg Oncol 2014;109:830-835.
American Cancer Society website. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-watchfulwaiting. Accessed 23 February 2015.
Active Surveillance (2/2)
Trigger for Treatment Initiation
Treatment should be started in case of:
- rising PSA level
- change in the DRE
- abnormal ultrasound or biopsy findings (increase in Gleason score or extent of tumour)
Advantages
• Gives more time to decide on the best treatment
• Avoids common adverse events associated with treatment of PCa
• Maintains sexual function
• Saves treatment costs
Disadvantages
• Patients don’t show up for their regular monitoring, thus their cancer may evolve and
become life-threatening
• Prostate cancer might grow faster than expected and expand beyond the prostate
• Anxiety due to feeling of “not doing anything against their cancer”
DRE, digital rectal examination; PCa, prostate cancer; PSA, prostate-specific antigen.
Mohler J, Bahnson RR, Boston BB et al. J Natl Compr Canc Netw 2010;8:162-200.
American Cancer Society. Website. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-watchfulwaiting. Accessed 23 February 2015.
Watchful Waiting vs. Active
Surveillance
Watchful Waiting
• Fewer tests and
examinations
• No treatment
Active Surveillance
• Close disease monitoring
• Initiation of treatment upon
disease progression
• No curative intent
• Symptom management
American Cancer Society. Website. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-watchful-waiting. Accessed 23
February 2015.
Surgery
Radical Prostatectomy
Radical Prostatectomy
• Radical prostatectomy is the surgical removal of the prostate gland and surrounding tissue
• Used for patients with early-stage prostate cancer
• Main types of surgery:
• Radical (open) prostatectomy
• Retropubic
• Perineal
• Laparoscopic prostatectomy
• Laparoscopic prostatectomy
• Robot-assisted laparoscopic
prostatectomy
• Cryosurgery
• Transuretral resection of the
prostate (TURP)
Radical retropubic
prostatectomy
Laparoscopic
prostatectomy
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 15 July 2014
Rozet F et al. J Urol. 2005;174(3):908-911.
PSA After Radical Prostatectomy
Within 6 weeks of successful radical prostatectomy, PSA
should be undetectable2
A persistently increased PSA is indicative of PSAproducing tissue (e.g. residual cancer due to
micrometastases or residual disease in the pelvis)2
A rapid rise in PSA (high PSA velocity, short PSA doubling
time) suggests distant metastases while long PSA
doubling time and slower rise in PSA suggests local
disease recurrence2
Predictive factors distinguishing local from systemic
recurrence also include time to PSA recurrence and
tumour differentiation2
Rarely (e.g. with
unfavourable
pathology
undifferentiated tumours), both local treatment failure
and distant metastases may occur with undetectable PSA
levels2
PSA, prostate-specific antigen
1.Ahlering TE & Skarecky DW. Prostate cancer Prostatic Dis 2005;8:163-6
2.Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Survival After Radical Prostatectomy
• The cumulative incidence of death from any cause was statistically significantly
better for men treated with RP compared to watchful waiting (56.1% vs 68.9%,
p<0.001)1 [The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)]
• Cancer mortality was lower in patients with RP compared to radiotherapy or
ADT2 [CaPSURE Registry]
• In men ≤65 years with early-stage PCa, survival after RP was longer than in
patients on active surveillance
• For men >65 years, survival with RP was similar to other treatments or active
surveillance
ADT, androgen deprivation therapy; PCa, prostate cancer; RP, radical prostatectomy.
1.Bill-Axelson A. et al. N Engl J Med 2014;370:932-942.
2.Cooperberg MR, et al. Cancer 2010;116:5226-5234.
Postoperative Complications of
Radical Prostatectomy
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Prostatectomy: Advantages and
Disadvantages
Advantages
• Provided the cancer has not spread outside the prostate, surgery will remove all cancerous tissue
• Easy follow-up
• Improved survival in selected patients
Disadvantages
• General anesthesia, hospital stay and recovery time from surgery
• Risk of adverse events such as erectile dysfunction (due to nerve damage) and urinary incontinence
• Sexual function in patients 65 years old or below is particularly decreased at one year after RT1
RT, radical prostatecomy.
1.Brajtbord JS, et al. J Urol 2014;192(2):396-401.
Orchidectomy
Orchidectomy
•
Orchidectomy/orchiectomy is the surgical removal of either one or
both testes
•
Relatively short procedure (ca. 30 minutes) usually done under local or
epidural anesthesia
•
Achieves testosterone castration quickly
Orchidectomy: Advantages and
Disadvantages
Advantages
• Simple procedure1
• Free of complications1
• Can be done using local anaesthesia1
• Testosterone castration level achieved within a few hours2
• No risk of non-compliance with treatment3
• Low cost3,4
Disadvantages
• Negative psychological effect of “castration” 1,3
• Irreversible1,4
• Adverse events: osteoporosis, anemia, loss of libido/potency, hot flushes, loss of muscle mass, etc.
• Does not allow neo-adjuvant, adjuvant or intermittent therapy1
ADT, androgen deprivation therapy
1.Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 15 July 2014.
2.Lin BJ, et al. Urology 1994;43(6):834-837.
3.Loblaw A, et al. J Clin Oncol 2004;22(14):2927-2941.
4. Choi S & Lee AK Drug Healthc Patient Saf. 2011;3:107-119.
Radiotherapy
Radiotherapy
•
High-energy X-rays
•
Important alternative to surgery for curative therapy
•
Schedule consisting of a certain number of treatments courses
administered over a defined period of time (one week to several
weeks)
•
May be combined with ADT
ADT, androgen deprivation therapy
Types of Radiotherapy in Prostate
Cancer Treatment
External beam radiation therapy
Radioactive seed implantation in brachytherapy
Source: http://www.urologyassociates.com.au/WeTreat/PC/ProstateCancer-6.php
Source: Thinkstockphotos.com; Image number:157017590
http://www.thinkstockphotos.com/search/#157017590/s=DynamicRank/f=
CPIHVX
Survival of Patients with Prostate
Cancer Treated with Radiotherapy
PCa, prostate cancer; RT, radiotherapy; RPE, radical prostatectomy
1.Lee WR et al. J Clin Oncol. 1995;13(2):464-469.
2.Tewari A et al. Urology. 2006;68(6):1268-1274.
3.Sylvester JE et al. Int J Radiat Oncol Biol Phys. 2007;67(1):57-64.
Long-Term Genitourinary and
Gastrointestinal Effects of Radiotherapy
Incidence of late toxicity by RTOG grade (from EORTC trial 22863)
*Overall toxicity included GU and GI toxicity and leg oedema. As most patients had >1 type of toxicity, overall toxicity does not result from simple addition.
EORTC, European Organization for Research and Treatment of Cancer; GU, genitourinary; GI, gastrointestinal; RTOG, The Radiation Therapy Oncology Group.
Ataman F et al. Eur J Cancer. 2004;40(11):1674-1681.
Erectile Dysfunction* after Surgery
or Radiotherapy
80%
~1 year follow-up
≥2 year follow-up
Risk of Impotence
70%
75%
75% 75%
66%
60%
50%
45%
40% 40%
40%
30%
48%
24%
20%
10%
0%
N/A
Brachytherapy
Brachytherapy +
external irradiation
* Defined as inability to maintain an erection sufficient for intercourse.
N/A, not available.
Robinson JW, et al. Int J Radiat Oncol Biol Phys. 2002;54(4):1063-1068.
External
irradiation
Nerve-sparing
radical prostatectomy
Standard radical
prostatectomy
Benefit in Overall Survival with the
Addition of ADT to Radiotherapy
Jones CU, et al. N Engl J Med 2011;365:107-18
PSA Monitoring After Radiotherapy
•
PSA levels after radiotherapy decrease more slowly than after
prostatectomy
•
PSA nadir <0.5 ng/mL after radiotherapy may be associated with a
favourable outcome; the optimal cut-off value remains controversial
•
It can take up to 3 years or more before reaching PSA nadir
•
PSA increasing >2 ng/mL above the nadir value is the current definition
of biochemical failure after radiotherapy
•
After radiotherapy, PSA-DT correlates to the site of recurrence; PSA-DT
was 13 months for patients with local recurrence versus 3 months for
patients with distant failure
DT, doubling time; PSA, prostate-specific antigen
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf
Accessed 15 July 2014
Radiotherapy: Advantages and
disadvantages
Advantages
• Equivalent or superior efficacy to surgery in men with metastatic disease1
Disadvantages
• Lower efficacy than surgery in men with non-metastatic prostate cancer1
• Increase in incidence of secondary cancers in the long-term2,3
ADT, androgen deprivation therapy
1.Sooriakumaran P et al. BMJ 2014;348:g1502
2.Okajima K, et al. Int J Clin Oncol 2013;18(6):1078-1084
3.Brenner DJ et al. Cancer 2000;88(2):398-406.
Hormonal Treatments
History of Hormonal Treatments in
Prostate Cancer
The future
1938-Acid Phos.
1940 Huggins -endocrine
control Advent of
orchiectomy and
estrogen treatment
(Awarded Nobel Prize for
this discovery)
John Hunter
1780-castration
1904
First RP
1970s
Steroidal and
non-steroidal
AAs available
New androgen receptortargeted drugs. AA
vaccines, biomarkers,
genetic research
1980s
Long-acting
synthetic LHRH
agonists
2003
First GnRH blocker
(abarelix) launched
Nobel Prize:
Andrzej Schally,
Roger Guillemin
2008 & 2009
1867
1920s
1960s and 70s
RT for PC using
radium
Synthetic estrogens
developed
Degarelix approved in US & EU,
respectively
2004
First perineal
prostatectomy
performed
1960s
Figure adapted from DE Crawford
RT established
as important
treatment for PCa
2009
AR signalling inhibitors
Docetaxel in
combination with
prednisone
approved
1995
Cryosurgery accepted as a
treatment option for
recurrent cancer after RT
AA, antiandrogen; AR, androgen receptor; LHRH, luteinizing hormone releasing hormone; PCa, prostate cancer;
RP, radical prostatectomy; RT, radiotherapy.
Currently Available Hormonal
Treatments
• GnRH Agonists
• GnRH Antagonists
• Estrogens
Association Between Testosterone
Levels and Risk of Death During ADT
Predictors of survival probability according to the
Cox regression model
6mo. Testosterone
6mo. PSA
Gleason scale
Age
0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
ADT, androgen deprivation therapy; mo, months; PSA, prostate-specific antigen
Perachino M et al. BJU Int. 2010;105(5):648-651.
Clinically Relevant Castration Levels
of Testosterone
• Historically, due to limitations in analytical techniques, castration levels
of testosterone were defined as ≤50 ng/dL1
• For regulatory purposes, GnRH agonist activity is measured against a 50
ng/dL level1
• However, advances in analytical methodology (greater precision in lower
ranges) show that surgical castration levels in most studies are around
20 ng/dL2
• Thus, this has resulted in revisiting the current definition of castration;
some authors suggested that a more appropriate threshold should be
<20 ng/dL1,3
GnRH, gonadotropin-releasing hormone
1.Oefelein MG et al. Urology. 2000;56(6):1021-1024.
2.Tombal B. Eur Urol Suppl. 2005;4(5):14-19.
3.Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 15 July 2014.
GnRH Agonists
GnRH Agonists
•
Synthetic analogues of LHRH
•
Lower the production of testosterone, which in turn slows or stops the
growth of prostate cancer1 ---> androgen suppression/chemical
castration
•
Long-acting injectable products or implants (1-, 2-, 3-, 6-, or 12-month
depot)
•
Comparable efficacy with surgical castration
•
Testosterone suppression is reversible upon cessation of GnRH
agonists2
•
The most widely used hormonal treatment
1.Lepor H and Shore ND. Rev Urol 2012;14:1-12.
2.Kaku H et al. Prostate. 2006;66(4):439-444.
Pituitary Regulation of Testosterone
Production
Testosterone is produced by Leydig
cells in the testes in response to
stimulation by LH from the anterior
pituitary gland1
Hypothalamus
Testis
GnRH
GnRH
Receptor
Sertoli
Cells
Pituitary
FSH
FSH
Leydig
Cells
LH
DHT Receptor
Testosterone
Other Target
Tissues
Prostate
DHT, dihydrotestosterone; FSH, follicle stimulating hormone; GnRH, gonadotrophin-releasing hormone; LHRH, luteinising hormone-releasing hormone;
LH, luteinising hormone.
1.
Guyton AC, Hall JE. Reproductive and hormonal functions of the male (and function of the pineal gland). In: Guyton and Hall Textbook of medical physiology.
12th ed. PA: Saunders/Elsevier; 2011:973-986.
Mechanism of Action of GnRH
Agonists
The constant stimulation of the
pituitary by the GnRH agonist leads
eventually to down-regulation of
GnRH receptors and desensi-tisation
of the gland
Hypothalamus
Testis
GnRH
GnRH
Receptor
GnRH
Agonist
Sertoli
Cells
Pituitary
FSH
FSH
Leydig
Cells
LH
DHT Receptor
Testosterone
Other Target
Tissues
Prostate
DHT, dihydrotestosterone; FSH, follicle stimulating hormone; GnRH, gonadotrophin-releasing hormone; LHRH, luteinising hormone-releasing hormone;
LH, luteinising hormone.
Hellerstedt BA, et al. CA Cancer J Clin 2002; 52(3): 154-79.
Serum Testosterone Levels During
Treatment with GnRH Agonists
Mean serum testosterone concentration (ng/dL)
Testosterone profile of GnRH agonist Eligard™ (leuprolide) 7.5mg
700
600
500
400
n=117
300
200
Injection #1
Injection #2
100
Injection #3
Injection #4 Injection #5
0
0
1
2
3
4
Months post baseline
GnRH agonists generally reduce serum testosterone to<50 ng/dL within 2–4 weeks
GnRH, gonadotrophin-releasing hormone
Eligard [prescribing information]. Available at http://www.eligard.com/Docs/Pdf/TOLMAR%20Pharmaceuticals_Web_PI_05-07-14.pdf. Accessed 12 September
2014.
Survival with GnRH Agonists is
similar to Orchidectomy
Overall survival1
Goserelin 3.6 mg (n=176)
Orchidectomy (n=182)
1.0
0.9
1.0
0.8
0.9
0.7
0.8
0.6
p=0.23
0.5
0.4
0.3
0.7
p=0.42
0.6
0.5
0.4
0.3
0.2
0.2
0.1
0.1
0.0
0
24
48
72
96
120
144
Time (weeks)
1.
2.
Goserelin 3.6 mg (n=138)
Orchidectomy (n=145)
Patients surviving (%)
Estimated survival probability (%)
Overall survival2
Kaisary AV, et al. Br J Urol. 1991;67 (5):502-508.
Vogelzang NJ, et al. Urology. 1995;46(2):220-226.
168
192
216
0.0
0
40
80
120
160
Time (weeks)
200
240
280
320
Testosterone Control is not Equivalent
with GnRH Agonists and Orchidectomy
Meta-analysis of randomised trials vs. orchidectomy: patients failing to reach testosterone levels ≤50 ng/dL
15%
Proportion of patients not achieving
castration levels ≤50 ng/dL (%)
GnRH agonist not specified
10%
Leuprolide
(n=37)
Goserelin
(n=1)
Microsphere leuprolide
formulation
5%
Goserelin
0
Morote
20061
Sarosdy
19992
Oefelein
20003
McLeod
20014
GnRH agonists fail to achieve the recognised limit of castration (50 ng/dL) in 2–12.5% of patients.
GnRH, gonadotrophin-releasing hormone
1.
2.
3.
Morote J et al. Urol Int. 2006;77(2):135-138.
Sarosdy MF et al.. BJU Int. 1999;83(7):801-806.
Oefelein MG et al. J Urol. 2000;164(3 Pt 1):726-729.
Wechsel
19965
Jocham
19986
Initial Rises in Testosterone, LH and
PSA Levels with Leuprolide
Leuprolide
***
200
400
***
***
150
50
***
Serum PSA (%)
100
*
200
02 57
14
21
28
Time (days)
100
***
***
***
***
0
*
50
100
0
** **
150
300
Serum LH (%)
Serum Testosterone (%)
200
02 57
14
***
***
21
28
Time (days)
0
02 57
14
21
Time (days)
28
***p<0.001 vs. baseline, **p<0.01 vs. baseline ,*p<0.05 vs. baseline
LH, luteinizing hormone; PSA, prostate-specific antigen
Sasagawa I et al. Int Urol Nephrol. 1998; 30 (6): 745–753.
Testosterone Microsurges with GnRH
Agonists
Frequency of testosterone surge* on ≥ 1 repeat injection (microsurge)
measured on day 4 and 8 of each treatment cycle
Goserelin 3.6 mg
monthly for 48 weeks
Goserelin 10.8 mg
3-monthly for 48 weeks
34 / 126 (27.0%)
20 / 113 (17.7%)
*Testosterone levels increase from below castrate level to greater than castrate level, i.e. >18.5 ng/dL
Zinner NR et al. Urology. 2004;64(6):1177-1181.
Symptomatic Flare
• The initial GnRH agonist-induced surge causes symptomatic flares1
• Symptomatic flare in metastatic disease is a result of an acute testosteronemediated stimulation of PCa growth1
• Patients at risk: symptomatic, high-volume, bony disease2
• Flare can lead to serious clinical effects, depending on tumour size and
location of metastases1, 2
• Increased bone pain – Acute bladder outlet obstruction – Obstructive renal
failure – Spinal cord compression – Fatal cardiovascular events due to
hypercoagulation status
• Incidence of symptomatic flare with GnRH agonists: ∼11%1
• Occurrence of symptomatic flare is reduced by
• Antiandrogens to protect against testosterone surge
• Earlier diagnosis – fewer patients with metastatic disease at the time of GnRH
agonist initiation
GnRH, gonadotrophin releasing hormone; PCa, prostate cancer
1.
2.
Thompson IM. Rev Urol. 2001;3 Suppl 3:S10-S14.
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 13
August 2014.
Frequency of Testosterone
Breakthrough with GnRH Agonists
LHRHa, luteinizing hormone-releasing hormone agonist
Pickles T, et al. BJU Int 2012;110:E500-E507.
Castration Levels of Testosterone
with GnRH Agonists
Testosterone levels in patients treated with LHRH agonist
Proportion of patients (%)
50
45.1%
38.6%
40
30
20
16.3%
10
0
< 20 ng/mL
LHRH, luteinizing hormone-releasing hormone
Bertaglia V, et al. Clin Genitourinary Cancer 2013;11(3):325-330.
20 to 50 ng/mL
> 50 ng/mL
Preference for GnRH Agonists vs
Surgical Castration
Patients prefer injections to surgical castration
Patients’ preference
100
80
78%
(n=115)
60
40
22%
(n=32)
20
0
Goserelin
Orchidectomy
Testosterone suppression is reversible once GnRH agonists are withdrawn.
GnRH, gonadotrophin-releasing hormone.
Cassileth BR et al. Qual Life Res. 1992;1(5):323-329.
Testosterone Suppression is Reversible
Upon Cessation of GnRH Agonists
Testosterone levels (ng/mL)
Testosterone levels after cessation of GnRH agonist (not otherwise specified) therapy (box plot
analysis)
BF = before LHRH agonist therapy
T 2.9–10.7 mg/mL
BF, before; BL, baseline; LHRH, luteinising hormone releasing hormone; M, months; T, testosterone.
Kaku H et al. Prostate. 2006;66(4):439-444.
3M vs. baseline: P=0.0034
Hormonal Adverse Effects of GnRH
Agonists
Hot flushes1
Gynaecomastia and
breast tenderness1
Mood changes1
GnRH Agonist:
Hormonal
Side Effects
Impaired cognitive
function1
Sexual dysfunction1
Metabolic sydrome2,3
• Abdominal obesity
• Fasting hyperglycaemia
• Hypertriglyceridaemia
Osteoporosis1
Cardiovascular
morbidity/mortality2,3
GnRH, gonadotrophin releasing hormone.
1.
2.
3.
Sharifi N et al. JAMA. 2005;294(2):238-244.
Braga-Basaria M et al. J Clin Oncol. 2006;24(24):3979-3983.
Saylor PJ, et al. J Urol. 2013;189(1 Suppl):S34-S42.
GnRH Agonists:Advantages and
Disadvantages
Advantages
•
Effective lowering of testosterone level1
•
Overall survival comparable to bilateral orchidectomy1,2
•
Psychological preference over surgical castration3
•
Generally reversible
Disadvantages
•
Delay in castration due to testosterone surge
•
Flare symptoms
•
Testosterone microsurges
•
Testosterone breakthrough (testosterone levels higher than with orchidectomy)
•
Hormonal adverse events and cardiovascular effects
GnRH, gonadotrophin-releasing hormone
1.
2.
3.
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed: May 23, 2013.
Seidenfeld J et al. Ann Intern Med 2000;132:566-77.
Cassileth BR et al. Qual Life Res. 1992;1(5):323-329.
GnRH Antagonists
GnRH Antagonists
• Synthetic peptides
• Compete with natural GnRH for binding to GnRH receptors
• Inhibit LH and FSH, leading to rapid serum testosterone decrease1,2
• Devoid of agonist activity on the GnRH receptor1,2
• Reversible GnRH receptors blockage
• Earlier GnRH antagonists presented histamine-releasing properties,
insufficient potency and lack of solubility2-4
FSH, follicle stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteneising hormone
1.
2.
3.
4.
Kirby RS et al. BJU Int 2009;104:1580-1584.
Doehn C et al. IDrugs 2006;9(8):565-572.
Cook T et al. The Oncologist 2000;5(2):162-168.
Jiang G et al. J Med Chem 2001;44(3):453-467.
GnRH Antagonists: Advantages and
disadvantages
Advantages
•
Degarelix exerts a direct and immediate blockade of GnRH pituitary receptors
•
There is no initial stimulation of GnRH receptors, and therefore no testosterone surge
•
Fast reduction of LH, FSH, PSA and testosterone compared to GnRH Agonists
•
No need for flare protection with antiandrogen
Disadvantages
•
Monthly depot formulation
•
Higher risk of injection site reactions compared with GnRH Agonists
FSH, follicle stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteneising hormone; PSA, prostate-specific antigen
Klotz L et al. BJU Int. 2008;102(11):1531-1538.
Estrogens
Estrogens
•
Female sex hormones, however, small amounts are also produced by
the testes in men
•
Several mechanisms of action, including down-regulation of LHRH
secretion, androgen inactivation and suppression of Leydig cell
function
•
Inhibit androgen production by the testes in a reversible manner
•
Seldom used in the treatment of prostate cancer due to their
unfavourable safety profile
LHRH, luteinizing hormone releasing hormone.
1.
2.
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 13
August 2014.
Bosset PO et al. BJU Int 2012;110:E826-E829
Estrogen: Advantages and
Disadvantages
Advantages
•
Testosterone level lowering efficacy comparable to orchidectomy1,2
•
Simple oral therapy1,2
•
Reversible1,2
•
Low cost
Disadvantages
•
Increased risk of cardiovascular and thromboembolic toxicity 1,2
•
Gynecomastia3
•
Oedema, weight gain, and loss of libido3
1.
2.
3.
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed 13 August 2014.
Ockrim, et al. Nat Clin Pract Oncol. 2006;3(10):552-563.
Malkowicz SB. Urology 2001;58(Suppl 2A):108-113.
Antiandrogens
Antiandrogens
•
Compete with testosterone and DHT for binding to the androgen
receptors in the prostate1
•
Block the androgen receptors, reducing the ability of testosterone to
promote prostate cancer cell growth
•
Rarely used on their own to treat prostate cancer because they don’t
block androgen production, however AA monotherapy bears quality of life
benefits compared with castration due to lack of loss of libido in some
patient groups2
•
Used in combination with a GnRH agonist, prevent the initial testosterone
surge/flare often seen with GnRH agonists alone
•
The combined use of an antiandrogen with orchiectomy or a GnRH
agonist is called Combined Androgen Blockade (CAB), complete androgen
blockade, or total androgen blockade.
AA, antiandrogens; DHT, dihydrotestosterone; GnRH, gonadotrophin releasing hormone.
1.
2.
Hellerstedt BA et al. CA Cancer J Clin. 2002;52(3):154-179.
Labrie F et al. Cancer. 1993;71(3 Suppl):1059-1067.
Antiandrogens – monotherapy
Overall survival in men with locally advanced PCa
1.0
Bicalutamide 150 mg
Castration
0.9
Proportion surviving
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
200 400 600
1000
1400
1800
Time to death (days)
PCa, prostate cancer.
Iversen P et al. J Urol. 2000;164(5):1579-1582.
2200
2600
Antiandrogens: Advantages and
disadvantages
Advantages
•
Prevention of osteoporosis
•
Prevention of loss of musculature
•
Preservation of potency (non-steroidal antiandrogens)
•
Lower incidence of hot flushes compared to castration (Cyproterone acetate)
Disadvantages
•
Less effective than castration
•
Increased incidence of side effects: e.g. hepatotoxicity and CV side effects (with steroidal antiandrogens);
gynecomastia, breast pain, hot flashes (with non-steroidal antiandrogens)
•
Development of resistance to antiandrogen treatment
CV, cardiovascular; GnRH, gonadotrophin-releasing hormone
Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed: May 23, 2013.
Treatment Modalities
Combined Androgen Blockade (CAB)
• Definition:
• ADT treatment combining GnRH analogues and antiandrogen
• Rationale:
• GnRH agonists reduce serum testosterone by 90%-95% but do not suppress
adrenal androgens1
• Adrenal androgens maintain intra-prostatic concentrations of DHT at
approximately 40%2
• Antiandrogens block interaction of testosterone and DHT with prostatic
androgen receptors
• Adding antiandrogens to GnRH agonists CAB allows blockade of both
adrenal and testicular sources of androgens1
• Antiandrogen may protect against insufficient castration by agonists i.e.
microsurges1
ADT, androgen deprivation therapy; CAB; combined androgen blockade; DHT, dihydrotestosterone; GnRH, gonadotrophin-releasing hormone.
1.
2.
Labrie F. Endocr Relat Cancer. 1998;5:341-351..
Labrie F et al. Cancer. 1993;71(3):1059-1067.
Combined Androgen Blockade (CAB)(2)
• Disadvantages of CAB:
•
•
•
•
Small survival advantage vs monotherapy (<5% at 5 years)1
The relevance of this advantage to clinical practice is unclear1
Benefit appears to be limited to non-steroidal antiandrogens1
Increased incidence of side effects, e.g.gynaecomastia, breast pain and hot
flashes2
CAB; combined androgen blockade.
1. Heidenreich A et al. EAU Guidelines 2013. Available at: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf Accessed: May 23, 2013.
2. Crawford ED et al. N Engl J Med. 1989;321(7):419-424.
Intermittent Androgen Deprivation
Therapy
• Definition:
• ADT cycles interrupted by treatment-free intervals, during which
testosterone levels rise above castration levels (=testosterone recovery)
• Rationale:
• Improve tolerability
• Improve QOL
• Cost savings
• Possibly, delay time to castration-resistant prostate cancer
ADT, androgen deprivation therapy; QOL, quality of life.
Calais da Silva F, et al. Curr Opin Urol 2011;21:248–51
IAD: Improved Tolerability without
Compromising Efficacy?
Continuous ADT
Short-term AEs
Long-term AEs
Metabolic
syndrome
Fatigue
Osteoporosis/
skeletal events
Hot flashes
Arterial stiffness
CV
effects
Loss of libido
Cognitive decline
Erectile
dysfunction
ADT, androgen deprivation therapy; AE, adverse events; CV, cardiovascular; IAD, intermittent androgen deprivation
Shore N, Crawford ED. Rev Urol 2010;12:1-11.
Isbarn H et al. Eur Urol 2009;55:62-75.
Diabetes
IAD: Improved Quality of Life?
ADT can impair QoL
†
Also significant:
 testosterone
 lean body mass
 body fat
 comorbidity index
for ADT vs no ADT
*p<0.01; †p<0.001 vs no ADT (n=96)
ADT, androgen deprivation therapy; IAD, intermittent androgen deprivation; QOL, quality of life
Dacal K, et al. J Am Geriatr Soc 2006;54:85-90
IAD: Cost Savings?
% time ON and OFF therapy (meta-analysis of 1446 patients in phase II trials)1
39%
ON therapy
61%
OFF therapy
Median number of cycles = 2
In a phase III study, % time OFF therapy after 15 cycles was 49%2
Potential for cost savings by reducing medication use and the costs associated with
managing adverse events3 if outcomes are similar/better
IAD, intermittent androgen deprivation
1. Shaw GL et al. BJU Int 2007; 99:1056–65
2. Mottet N et al. Eur Urol Suppl 2009;8(4):131 (abstract 44)
3. Buchan N, Goldenberg S. Nat Rev Urol 2010;7:552–60
Module 3 – Quiz
Questions (1)
• Question 1: Name 3 types of patient that would be candidates for Active
Surveillance?
• Question 2: Name 3 postoperative complications of Radical
Prostatectomy?
• Question 3: What is the castration level of Testosterone?
a)
b)
c)
50 ng/dL
20 ng/dL
32 ng/dL
• Question 4: How is watchful waiting defined?
a)
b)
c)
Close monitoring of disease
Curative treatment in case of disease progression
Symptom management
Questions (2)
• Question 5: How long does it take to reach testosterone castration levels
after orchidectomy?
a)
b)
c)
Three to twelve hours
Five to six days
Two to four weeks
• Question 6: What is the 5-year overall survival rate in patients with
localised disease after radiotherapy?
a)
b)
c)
Less than 50%
50%-75%
> 75%
• Question 7: What is a “Flare”?
a)
b)
c)
Symptoms of an increase in testosterone
Increase in serum testosterone
A fatal cardiovascular event
Questions (3)
• Question 8: What are the long-term adverse effects of radiotherapy?
a)
b)
c)
Vascular effects
Gastrointestinal and genitourinary effects
Musculoskeletal and connective tissue effects
• Question 9: The efficacy of GnRH agonists is comparable to surgical
castration?
a)
b)
True
False
• Question 10: How do antiandrogens work?
a)
b)
c)
Down regulate the GnRH receptor
Down regulate the androgen receptor
Block the androgen receptor
Questions (4)
• Question 11: What is the most common indicator of prostate cancer
recurrence during or after treatment?
a)
b)
c)
Raised testosterone levels
Raised PSA levels
Decreased testosterone and PSA levels
• Question 12: Why are estrogens no longer used frequently?
a)
b)
c)
High costs compared to other treatments
Unfavorable safety profile
Less effective than other treatments
Quiz Answers
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
See answers on slide 17
See answers on slide 25
a
c
a
c
a
b
a
c
b
b