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