Metastatic Prostate Cancer

Androgen deprivation therapy

- Basics of hormonal control of the prostate

- Therapeutic approaches to androgen deprivation therapy

1) Bilateral orchiectomy

: Within 24hours of surgical castration, testosterone levels are reduced by more than 90%

2) Inhibition of LHRH

(1) LHRH agonist

synthetic analogs of native LHRH

initial exposure to agonists of LHRH results in a flare of LH testosterone levels

: known as the ‘testosterone surge’ or ‘flare up’ phenomenon (begins within 2-3days of the first injection and lasts through approximately the first week of therapy)

: result in a severe, life-threatening exacerbation of symptoms

→ co-administration of an antiandrogen (for only 21-28 days)

Goserelin acetate (Zoladex): 3.6mg sc monthly

Leuprorelin acetate (Leuplin): 3.75mg sc monthly

Leuprolide acetate: 7.5mg sc monthly

3) Antiandrogens

Compete with testosterone and DHT for binding sites on their receptors in the prostate cell nucleus: promoting apoptosis and inhibiting prostate cancer growth

- Steroidal antiandrogens

: Cyproterone Acetate, Megesterol acetate, medroxyprogesterone acetate

- Non-steroidal or pure antiandrogen

: Flutamide (250mg tid), bicalutamide (50mg po daily), nilutamide (150mg daily)

4) Antiandrogen withdrawal phenomenon

정의: experience a decline in PSA level, objective

responses with the withdrawal of the antiandrogen from the combination with LHRH agonist

- Declines in PSA level are seen

→ within 4weeks with flutamide withdrawal

→ within 6weeks with bicalutamide, nilutamide withdrawal

- Declines in PSA level of more than 50% (15-30%), and median duration of 3.5-5months

Castration resistant prostate cancer

1) CRPC without Symptom or minimal Symptom

(1) Observation

(2) 2nd hormonal Tx

- Ketoconazole: 200mg tid+prednisolone 5mg bid

그외 Alternative antiandrogen, High dose antiandrogen, Estrogen, Glucocorticoid 등이 있음.

2) CRPC with Symptom

(1) Docetaxel+prednisolone

Docetaxel 75mg/m2+P/S 200ml IV for 1hr Day1+PRD 5mg bid po q 3wks

RR: 70% (PR: 38%, CR: 32%), median survival: 12.7 mo response rate of reduction in PSA 45%

- Ref) NEJM 2004;351:1502-1512

** Docetaxel 투여시 전처치 및 주의사항

- Prevention of hypersensitive reaction

1) dexamethasone 20mg iv before 30min of chemotherapy(Day1) 2) dexamethasone (8mg orally twice daily, Day 2-3)

steroid 전처치: hypersensitivity 감소, fluid retention 감소, asthenia 감소

3) pheniramine 1x iv

4) ranitidine 50mg iv

- Dose reduction from toxicity

1) 20% dose reduction:

prolonged grade 4 neutropenia (>7days)

grade 4 thrombocytopenia

grade ≥2 liver toxicity

grade ≥3 diarrhea

grade ≥3 cutaneous toxicity

2) Discontinue

grade > 2 renal toxicity: Clcr < 60ml/min

grade 3 liver toxicity

grade ≥ 3 neuropathy

grade 4 cutaneous toxicity

grade 3 anaphylactoid reaction

* Docetaxel chemoTx 예시 (OPD)

1. Prehydration P/S 500cc (300cc/hr)

2. dexamethasone 10mg iv

3. metoclopramide 10mg iv

4. chemo

Docetaxel 75mg/m2+P/S 200cc (200cc/hr)

5. posthydration P/S 500cc (300cc/hr)

6. med) solondo (prednisolone) 5mg bid for 21days PRN med

(2) Mitoxantrone+prednisolone (이 regimen은 pain palliation이 목적임.)

Mitoxantrone (Mitron) 12mg/m2+P/S 100ml IV Day1+PRD 5mg BID for 21days

Ref> JCO 1996;14:1756

** 새로운 약제들

1) Abiraterone acetate, androgen synthesis inhibitor (CYP 17 inhibitor)- CRPC, docetaxel 사용 전, 혹은 후 Abiraterone acetate 1,000mg once a day+prednisolone 5mg bid

OS: 14.8 month PFS: 5.6 month

Ref> NEJM 2011;364:1995, 2013;368;138

2) Enzalutamide (MDV 3,100), New androgen receptor inhibitors - CRPC, docetaxel fail 후에 Enzalutamide 160mg once a day

OS: 18.4 month

Ref> NEJM 2012;367:1187

3) Cabazitaxel- CRPC, docetaxel fail 후

Cabazitaxel 25mg/m2 iv over 1hr every 3weeks+prednisolone 5mg bid

OS: 15.1 month, PFS: 2.8 month

Ref> Lancet 2010;376:1147

** Spinal cord compression

Dexamethsone 10mg loading after 4mg q 6hr+RT