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Hormonal treatment in prostate cancer
D. Schrijvers, MD, PhDZiekenhuisnetwerk Antwerpen (ZNA)-Middelheim
AntwerpBelgium
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Prostate cancerA hormone-sensitive disease
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Prostate cancer: a hormone-sensitive disease
Testosteron
LHRH
Pituitary gland
Cortisol
Testis
Prolactin
Adrenal gland
Hypothalamus
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Prostate cancer: a hormone-sensitive disease
17 hydroxylase
17-20 lyase
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Prostate cancer: a hormone-sensitive disease
Debes et al. N Engl J Med 2004
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Prostate cancerHormonal interventions
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Prostate cancer: hormonal interventions
• Testosterone-lowering therapy
> Testicular production
• Surgery: bilateral orchiectomy
• Decreasing LH
>Luteinizing hormone-releasing hormone (LHRH) agonists
• Triptoreline
• Gonadoreline
• Gosereline
>LHRH antagonists
• Abarelix
• Degarelix
>Estrogens
> Testosterone production
• CYP 17 complex blocker
>Abiraterone acetate
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• Blocking dihydrotestosterone production> 5- reductase inhibition
• Finasteride• Dutasteride
• Blocking the androgen receptor
> Anti-androgens
• Non-steroidal
>Bicalutamide
>Nilutamide
>Flutamide
• Steroidal
>Cyproteronacetaat
>Megestrol acetate
>Medroxyprogesterone acetate
Prostate cancer: hormonal interventions
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• Decreasing androgen production by the adrenal gland
> Adrenalectomy
> Decreasing ACTH production
• Corticosteroids
>Hydrocortisone
>Prednisone
>Dexamethasone
• Blocking conversion of androgens
> Aromatase-inhibitors
• Aminogluthetimide
• Ketoconazole
Prostate cancer: hormonal interventions
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Hormonal interventions in early disease
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Hormonal interventions: rationale
Neoadjuvant androgen suppression
Increased cell kill
Adjuvant androgen suppression
Improved local control
Reduction in metastasis
Improved overall survival
Reduction prostate volume
Sparing normal tissues
Reduction complications
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Hormonal intervention + surgery: neo-adjuvant
Endpoint Odds ratio 95% CI p
Positive surgical margin rate 0.34 0.27-0.42 < 0.00001
Disease-free survival (5 year) 1.20 0.95-1.52 0.97
Overall survival 1.11 0.67-1.85 0.69
Kumar et al. Cochrane Database Syst Rev 2006
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Hormonal intervention + surgery: adjuvant
Disease-free survival
Overall survival
Shelly et al. Cancer Treat Rev 2009
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Hormonal intervention + radiotherapy: neo-adjuvant
Pra et al. Curr Oncol 2010
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Hormonal intervention + radiotherapy: neo-adjuvant
Shelley et al. Cancer Treat Rev 2009
Clinical disease-free survival
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Hormonal intervention + radiotherapy: adjuvant
Pra et al. Curr Oncol 2010
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Hormonal intervention + radiotherapy: adjuvant
Kumar et al. Cochrane Database Syst Rev 2006
Overall survival
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Hormonal interventions in early disease: conclusion
• Radical prostatectomy
> Neo-adjuvant hormonal therapy
• No improvement of disease-fee and overall survival
> Adjuvant hormonal therapy
• Improvement in disease-free survival
• No improvement in overall survival
• Radiotherapy
> Neo-adjuvant hormonal therapy
• Improvement in clinical disease-free survival
> Adjuvant hormonal therapy
• Improvement in overall survival
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Hormonal interventions in biochemical relapse
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Biochemical relapse: disease-specific mortality
Freedlander et al. JAMA 2005
Median survival has not been reached after 16 years
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Biochemical relapse: disease-specific mortality
Zhou P et al. J Clin Oncol 2005
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Biochemical relapse: overall survival
Outcome Immediate (%) Deferred (%) Odds ratio (95% CI)
Overall survival
1 year 88 86 1.16 (0.9-1.49)
2 year 73 71 1.08 (0.89-1.33)
5 year 44 34 1.19 (0.95-1.50)
10 years 18 12 1.5 (1.04-2.16)
Nair B et al. Cancer Treat Rev 2003
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Biochemical relapse: conclusion
• Several studies indicate that the interval between first detected rise in PSA and development of symptomatic metastases may be several years
• Only for men with rapid PSA doubling time should hormonal therapy be considered
• Measuring PSA and then not acting on the information is causing anxiety
• Converting healthy men into PSA cripples
• The solution is to stop measuring PSA!
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Hormonal interventions in metastatic disease
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Hormonal manipulations in metastatic disease
Diagnosis of stage III/IV disease (45% to 55% of new prostate cancer diagnoses)
HORMONAL THERAPY
85-90% respond (PSA decline 50%)
10-15% fail to respond
20% achieve a disease-free
statusand terminate
therapy
80% respond while continuing
therapy(mean response
duration 3 years)
Castration-resistant status
(median survival = 6 to 12 months from time of diagnosis)
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Hormonal treatment for metastatic disease: immediate versus deferred treatment
Prostate cancer-specific mortality Overall survival
Loblaw al. J Clin Oncol 2007
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Hormonal treatment for metastatic disease: maximum androgen blockade (MAB)
• Patient-based meta-analysis showed no significant benefit of MAB (> 8000 patients, 27 trials)
Prostate Cancer Trailists’ Collaborative Group. Lancet 2000
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Author (year) N° pts Setting Treatment Result
Miller (2007) 335 N+, M+ Gosereline +
bicalutamide
Same OS
Same QoL
Thun (2007) 167 Increasing PSA
after RP
Leuprolide Same time to AI
Improved QoL
Conti (2007) 1382 All stadia All types Same time PSA progression
Less side effects I
Mottet (2009) 173 M+ Leuproreline +
flutamide
Same median PFS and OS
Same QoL
Calais da Silva (2009) 626 T3-4, N+, M+ Triptoreline +
cyproterone
Same time to AI
Same QoL
Hormonal treatment for metastatic disease: intermittent versus continuous
(N°: number; pts: patients; N+: lymph node positive; M+: metastatic disease; OS: overall survival; QoL: quality of life; AI: androgen independent disease; RP: radical prostatectomy; PSA: prostate specific antigen; PFS: progression-free survival)
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Hormonal treatment for metastatic disease: conclusion
• Castration is standard treatment (orchiectomy, LHRH agonists or antagonists) in symptomatic patients
> Use of LHRH
• Start with anti-androgen for 2 weeks to prevent flair up
• Start with chemical castration with LHRH agonist
• Intermittent castration is an option after 6-9 months of treatment
> Biochemical relapse
• Stop if PSA < 0.5 ng/mL
• Restart if PSA > 4 ng/mL for 3-6 months
> Metastatic disease
• Stop if PSA < 4 ng/mL
• Restart if PSA > 10-15 ng/mL for 3-6 months
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Side effects of hormonal treatment
Side effect LHRH agonist
LHRH anta-gonist
Anti-androgen
Steroidal
Anti-androgen
Non-steroidal
Estrogen
Hot flushes + + + - +
Loss of libido + + + - +
Erectile dysfunction + + + - +
Obesity + + + + +
Gynecomastia - - + + +
Metabolic syndrome + + - - +
Allergic reactions - + - - -
Visual disturbances - - - + -
Osteoporosis + + - - -
Hepatotoxicity - - + + +
Interstitial pneumonitis
- - - + -
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Side effects of hormonal treatment
Events per 1000
person-years
Diabetes
mellitus
CHF MI Sudden
death
No treatment 20.9 61.3 10.9 9.0
LHRH agonist 29.0 72.3 13.6 12.9
Orchiectomy 24.5 63.3 13.2 12.5
>73,000 men; age>65 treated for localized prostate cancer 1992-1999, observed through 2001 >1 in 3 received ADT(CHF: chronic heart failure; MI: myocardial infraction, LHRH: luteinisinghormone-releasing hormone)
Keating. J Clin Oncol 2006
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Mechanisms of castration resistance
Debes JD, Tindall DJ. N Engl J Med 2004
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Treatment for castration-resistant disease
• Control testosterone level (< 0.5 ng/mL)
• Continue (biochemical) castration
• Addition of anti-androgen: PSA response in 33%
• Stop anti-androgen (withdrawal): PSA response in 5-20%
• Other hormonal manipulations
> Dexamethasone/hydrocortisone: PSA response in 50%
> Estrogen (DES): PSA response in + 20%
> Ketoconazole: PSA response in 25%
> Estramustine: PSA response in 24%
• Chemotherapy
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Hormonal treatment in prostate cancer
• Hormonal treatment is an important treatment modality in both early and metastatic prostate cancer
• Hormonal treatment is not without side effects
• The pros and cons of this treatment option should be discussed with the patient before starting therapy
• New drugs are being developed to interfere with the hormonal control in prostate cancer
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