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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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