Ca Prostate

Dr. Edmond Wong

Ca Prostate• Epidemiology + risk factor• Diagnosis: PSA, DRE, investigation (CT, MRI, PET) • PSA screening• Chemoprevention• Management by staging

– RP: Open, Lap, Robotic (result) – RT: EBRT vs BT (result) – HT: Alone or adj setting

• Mx of CRPC: Chemo, vaccine, others

Epidemiology• Epidemiology:

– Ca Prostate in HK (2008): 1400 new case, 280 death [HK cancer registry]– Life time risk (HKCR 2008): incidence 1 in 30, death 1 in 300– Quoted life time risk: incidence 16%, death 3%– Trend: Incidence increasing (PSA, bx) , mortality static

• Risk factor: – Age: 30% in 50yo, 70% in 90yo, 75% of dx in men > 65– Region: US immigrant from Asia 20x risk– Race: Black >> caucasian >> asian– Hormonal effect

• Huggin and Hodges 1941: Demonstrate the responsiveness of CaP to androgen deprivation

• Testosterone and DHT itself is not tumorogenic but essential in tumor growth– Diet: obesity, charred meat, alfa-linoleic acid– Familial CaP: 10%

• Def: 3 generation, 3 1st degree relative, 3 <55 at dx• 1 relative 2x risk , 2 relative 5x risk• Gene: Ch 1q, 8p, X, Y, BRCA2 gene

– Others: infertility, high alcohol intake, smoking (more aggressive CaP)

PSA and diagnosis• What is PSA:

– 34kD serine protease (glycoprotein) = human kallikrein 3 (HK3)– 261 amino acid, Chromosome 19– Fxn: secreted by ductal epithelial cell, liquefy seminal coagulum

within the ejaculate– ½ life : 3 days– 3 forms:

• Free PSA: unbound • Alfa -1- antichytmotrypsin (ACT) : detect in essay• Alfa-2-macroglobulin (AMG): not detect in essay

– Detection using a monoclonal antibody essay– What’s the use:

• Dx , prognosis (risk gp), monitor post-txn, BPH

What is normal PSA? • Currently no single level can be 100% risk free of CaP , even 6% in PSA < 0.5 [PCPT 2003]• Define by lower than absolute value: <4ng/ml

– At level of 4ng/ml: SV 80% (20% in PCPT) , SP 70%, PPV 30% , NPV 80% (accuracy 50-80%)– Why 4? 97% CI of PSA for men > 40 years old [Myrtle 1986]– Chance of CaP in PSA level [Catalona]:

• 2.6-4 22% [JAMA 1997]• 4-10 25% [JAMA 1994]• >10 50% [JAMA 1994]

– PCPT result [NEJM2003] : Prevalence of CaP In men PSA<4: 15%• <0.5 6%• 0.6-1 10%• 1.1-2 17%• 2.1-3 23%• 3.1-4 26%

– PPV of PSA > 20ng/ml : 87% [Gerstenbluth JU2002]– 35% of CaP dx at PSA < 4ng/ml– PSA > 10 50% ECE– PSA> 100 100% metastasis

• Then what are the means to improve PSA performance:? – Age specific PSA: [Osterling JAMA 1993]

• 40-50 2.5• 50-60 3.5• 60-70 4.5• > 70 6.5

– Combine with DRE: abnormal DRE 50% CaP, 40% OC

What other means to improve PSAImprove in Diagnosis: • PSA velocity: PSAV

– Normal : < 0.75ng/ml/yr [Carter JAMA 1992]– At least 3 PSA result is required– PSAV = 0.5 x (PSA2-PSA1/time1 + PSA3-PSA2/time2)

• Free-to-total PSA ratio: – Normal: > 20%– F:T < 10% 60% risk , F:T > 25% 10% risk

• PSA density: – Normal: <0.15ng/ml/ml– PSA : prostate volume (dis: operator dependent) – Prostate volume: H x W x L x 0.52 (Ellipsoid formula)– PSA Transitional zone density: < 0.35ng/ml/ml

Disease monitoring: • PSA doubling time (PSADT):

– Time taken for PSA to double (in years)– < 5yr suspicious of CaP– In AS: intervene if PSADT < 2-3 yr– After RP: < 6m metastasis , > 12m local recurrence

• Can free PSA use to assess risk of CaP in all men ?– No, free PSA is restricted to level btw 4-10 ng/ml– In PSA < 4ng/ml, age specific or PSA velocity should be

use

What is PCA3?1. PCA3 (Prostate cancer gene 3 assay) (UPM3 test): PROGENSA

– A prostate specific non-coding mRNA – Over-expressed 100 times in 95% of CaP specimen than in benign prostate– Aim

1. To improve CaP detection2. To guide decision for TRUS Bx3. To differentiate clinically significant from indolent disease (?)

– Suitable scenarios 1. ↑ tPSA & -ve Bx2. ↑ tPSA 2.5-103. ↑ tPSA & concomitant urinary condition e.g. BOO/ prostatitis4. Normal tPSA & FHx

– Measure PCA3 & PSA mRNA concentration in urine collected after DRE– PCA test-> PCA3 score = PCA3 mRNA/ PSA mRNA x 1000 (abnormal if >35)– Adv

1. High sensitivity (70%) & specificity (90%) & similar in all PSA levels (Hessels)2. Not affected by prostate vol, age , previous bx, tPSA level3. Correlated with tumour vol4. May be a predictor of extracapsular extension5. Greater dx accuracy predicting outcome of repeat bx than tPSA and fPSA

Ca Prostate New Markers1. Human Kallibrein 2 (hK2)

– Product of KLK2 gene. Predictor of ECE & SV invasion2. Prostate specific membrane antigen (PSMA)3. Prostate specific antibodies4. Urokinase-type plasminogen activator receptor

(uPAR)5. Early Prostate cancer antigen (EPCA)6. GSTP-1 Hypermethylation

What is your view on PSA screening?• For screening of a disease to justify , it should fulfill the Wilson &

Junger’s criteria in 1968 with WHO• Wilson & Junger criteria:

1. Is it a important health problem? Yes (16% LTR, 3% mortality)2. Any acceptable treatment ? Yes (RP, RT, HT provide long term survival data) 3. Natural history understood? Yes & No (Chodak & Johansson, Alberston)4. Any Latent or early symptomatic stage? Yes (lead time biase > 10yr)5. Suitable and acceptable screening test ? NO (PSA is not specific enough)6. Facilities or dx and txn available? Yes7. Agree policy on whom to treat this patient? Yes8. Treatment start in early stage should more beneficial ? Problem with

overdiagnosis and overtreatment9. Cost? NO , much higher cost10. Case finding should be a continuing process and not a once-and-for all project

PSA screening• Evidence For:

– Randomised screening project (Quebec study)• 70% decrease in CSM but cross contamination and further analysis show no diff

– Tyrol (Austria): 33% decrease in the CSM seen in Tyrol compare to rest of Austria but effect was too rapid (6yr)

• Evidence against: – Seattle area (highly screened) and Connecticut (seldom screened) show NO difference in

the reduction in CSM

European Randomized Study ofEuropean Randomized Study ofScreening for Prostate CancerScreening for Prostate Cancer ERSPC : Schroder NEJM 2009• 7 European Countries• 182,000 men• Ages 50-74 Core age (55-69)• FU : median 9.0 years• Screening interval : 4 years• Sextant biopsy : PSA > 3.0ng/ml

Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening rial PLCO: Andriole NEJM 2009•10 U.S. study centers• 76,693 men• Ages 55-74•FU : mean 10 years• screening interval : annual PSA for 6 years & DRE for 4 years• No predefine bx scheme: PSA > 4 ng/ml

Results of PLCO & ERSPC

ERSPC• Relative risk (RR) of PC death 20%

relative reduction• Absolute mortality reduction : 3% to 2.4%• No overall Survival benefit• NNS: 1410 NNT: 48

Problem: • Prescreening: virtually none• Contamination in non screening gp: 6% • Non compliance to screening: 18%

PCLO• 7 yr: screened men 22% more likely to be

dx CaP• 10yr: no survival benefit in screening arm• Screening does not reduced risk of dying

from prostate cancer• Over dx in 50%

Problem: • Prescreening: 44%• Contamination in non screening gp: 52%• Non compliance to screening: 15%• 10 yr FU: premature data

Goteborg RCT• Goteborg RCT [Hugosson Lancet Oncol 2010]• Göteborg randomised population-based prostate cancer screening trial• Started in 1995, 20000 Swedish men• Age: men 50-74 yo• Screening : PSA every 2 years, DRE is not a must• PSA threshold for further uro workup : 3ng/ml• Result:

– 14 year FU : 44% fewer CaP deaths in the screening group NNS: 293 NNT: 12• Discussion:

– Much higher mortality reduction (RR of 0·56) due to– Younger men: Median 56 (gain full benefit of screening) – Lower PSA threshold 3ng/ml (vs 4ng/ml in PLCO)– Shorter screening interval 2yr (vs 4yr in ERSPC)– Higher rate of bx compliance , lower rate of prescreening and lower contamination of

control gp– Longer FU 14 yr (vs 10 PLCO , 9 ERSPC)

• However: still no effect on overall mortality & screening cause true stage migration

What can be concluded then?• EAU 2010: Wide spread mass screening for PCa is not appropriate • BMJ meta-analysis 2010: There was no signifcant effect on the risk of death from prostate

cancer or on overall mortality. • Risk of over diagnosis and over treatment (40% insignificant )• ACS (American Cancer Society) GL 2010:

– Asymptomatic men with LE > 10 can be offered PSA test, after receiving information about the uncertainties, risks, and potential benefits associated with prostate cancer screening

– Men < 10yr LE should not be offered CaP screening– For men who choose to be screened for prostate cancer :

• PSA with or without the DRE • PSA is <2.5 ng/mL, : Screen every 2 years; • PSA 2.5 to 4 screening should be conducted yearly • PSA level of >4.0 ng/mL referral for further biopsy

• Cochrane review 2011 [BJU]– Meta-analysis of 5RCT, > 300000 men– CaP screening not associate with signification reduction in CaP specific mortality– CaP screening lead to more men dx with CaP (RR 1.3)– Harm of screening: false +ve result of PSA, SE of TRUS + bx– Conclusion: benefit from CaP screening is likely to occur > 10yr men with LE < 10-15 should be

advice that screening is not beneficial and has harms• Future: Prostate testing for Cancer and Treatment PROTECT study in UK: comparing radical

txn vs WW in PSA screened population

• To consel patient: – Prostate cancer is an important health problem.– The benefits of 1–time or repeated screening and aggressive

treatment of prostate cancer have not yet been proven.– DRE and PSA measurements can have both false–positive and

false–negative results.– The probability that further invasive evaluation will be required is

relatively high.– Aggressive therapy is necessary to realize any benefit from the

discovery of a tumor.– A small but finite risk for early death and a significant risk for

chronic illness, particularly with regard to sexual and urinary function, are associated with these treatments.

– Early detection may save lives.– Early detection and treatment may avert future cancer–related

illness

What do you understand by Chemoprevention of CaP?

PCPT: Prostate Cancer prevention Trial• Thompson NEJM 2003• RCT: 18882• 5mg Finasteride vs Placebo• Type II • Inclusion:

– Men >55– PSA <3ng/ml , Normal DRE– AUA<20

• Fu 7 year• Bx: PSA > 4, DRE abn, end of study• Result:

– RR reduction CaP : 24.8% (24.4% vs 18.4%)– Increase risk of GS > 7 (6.4% vs 5.1%)– More sexual SE (libido/ejaculation/ED,

gynaecomastia)

REDUCE: Reduction by Dutesteride of Prostate Cancer event Trial

• Andrioloe NEJM 2010• RCT: 8231• 0.5mg Dutasteride QD vs Placebo• Type I and II • Inclusion:

– Men 50-75– PSA 2.5 -10– AUA < 25– 1 –ve bx 6/12 before

• FU 4 yr• Bx: indicated , radomise, 2, 4 yr• Result:

– RR reduction of CaP: 22.5% (25.1% vs 19.9%)– Increase risk of GS >8 in ¾ year (0.5% vs <0.1%)– More sexual SE (libido/ejaculation/ED), heart failure

(0.7% vs 0.4%)

• The fact that 30% of men in 50yo have histological CaP but few of clinical evidence dx suggest opportunity of preventive measure

• Diet: low fat, soy product (phyto-oestrogens), Lycopene (cooked tomato), Vit A & D (antioxidant) , pomegranite juice

• Vit E & selenium: not proven to reduce risk, rather increase risk [SELECT study JAMA 2009]

Chemoprevention• Why 5ARi decreases risk of Ca prostate?

– Shrinkage of prostate tumors or inhibit their growths– Decreased PSA level : X2

• How did 5ARI lead to more HG tumor ? [Grover]– Induced histological change mimic HG cancer (not really)– HG tumor resistant to androgen deprivation– Create environment that promote growth of HG tumor– Reduction of prostate volume and increase tumor density increase detection rate

• Why more high grade tumor detected during year 3 / 4?– Relatively more tumor detected in year 1/2 in the placebo arm and less tumour case remained in the

study to progress to higher grade in year 3/4• Then should Chemoprevention be offer to patient?

– Pros• Reduce prevalence of CaP by 25% (but only in low grade Ca)• BPH: AUR/BPH surgery/IPSS/UTI

– Cons• Possibility of high grade prostate cancer • Sexually related S/E• Cost of treatment• No evidence on mortality from high risk CaP• No agreed PSA level for biopsy• No long term data on 5 ARI

• Conclusion: [FDA Oncology Drug Advisory Committee Dec 2010][NEJM 2011]– Reduction in CaP risk with both drugs was limited to tumor with GS < 6 (80% very low risk)– One additional HG cancer in order to avert 3-4 potentially clinically relevant low-grade cancers– FDA: both 5ARI doe not have favorable risk benefit profile for the proposed used of chemoprevention of

CaP in healthy men

TRUS + bx• Indications for TRUS + bx:

– Abnormal PSA or DRE (asymmetry , nodule, fixed craggy mass, obliteration of MG)– Previous bx show HGPIN / ASAP– Previous normal bx but rising PSA or abn DRE– Confirmed txn after cryo, HIFU– PSA recurrence after RT

• Indication of TRUS only:– Estimate volume pre intervetion (PVP,TURis,OP)– Male infertility: SV, EJD obstruction, calculus, Mullerian cyst– Prostate abscess with drainage– CPPS: prostatic cyst or calculi

• Preparation: – Rule out CI: immunocompromise, bleeding tendency, aspirin/ warfarin/ plavix, active UTI– Investigation: CBP, LRFT, INR, MSU/CSU– Informed consent– Roger Kirby RCT: no need to stop aspirin before TRUS +bx [BJU 2003]

• Procedure: – Med: Antibiotic prophylaxis(Quinolone, flagyl x 3 days) , Fleet enema on morning– Analgesic : Elma Cr to peri-anal area, Preiprostatic block with lignocaine (10ml , 1%)– DRE: size, nodule, SV (cT stage) – 7.5MHz TRUS probe , bi-planar views:

• ECE or nodule: hypoechoic (50%) ,isoechoic (40%), hyperechoic (10%)– 18 gauge needle,10- 12 core lateral & peripheral directed bx (increase CDR by 15% vs 6 core [Presti

2000])• Complications: hemospermia (25%), mild hematuria (5%), PR bleeding (5%), severe PR bleed

(1%), Sepsis (<1%), AROU (1%), Death (< 0.1%)

TRUS + bx• Improvement in TRUS + bx:

– Number of core according to prostate volume (Vienna nomogram) – Saturation bx : 20-30 core under GA – Bx of Transitional zone or SV biopsy– MRI guided bx (better for apex)

• Would you recommend 2nd biopsy ?– PSA 4-10: chance of finding CaP in bx [Djavan]

• 1st 22%• 2nd 10%• 3rd 5%• 4th 4%

– 3rd and 4th detect tumor of low grade and small volume– Thus: 2nd bx if serial abnormal PSA, but more bx is associated with more indolent Ca

• High Grade prostatic intra-epithealial Neoplasm (HGPIN)– Structurally normal gland with cytological atypical cell, fragmented BM– Precursor to CaP , does not secrete PSA– Asso with 30% +ve rate in subsequent bx – EAU 2010 : not recommend repeat bx

• Atypical small acinar proliferation (ASAP) – Small (0.4mm) , atypical (line with cytological atypical cell with atrophic change) acini– Asso with 40% +ve rate in subsequent bx– EAU 2010: immediate repeat systemic biopsy

Pathology• Adenocarcinoma: 95%

– Variant: neuroendocrine, endometriooid , small cell, mucinous• 5%: TCC or sarcoma• Acinar or ductal epithelium• Basal cell layer absent , BM breach• Invasion to prostatic fibromuscular stroma• Macro: hard , white• Location: PZ (75%), TZ (25%), CZ (5%)• 85% multifocal , mean number: 7• Local extension: sphincter, corpora, SV, Bladder, hardly to rectum• Metastasis:

– Internal Iliac LN– Bone : Sclerotic– Typical axial skeleton (spine, Ribs, Pelvis) – Proximal long bone, clavicles, skull

Gleason Grading• Donald Gleason 1974• Grade 1-5 : according to glandular architecture at low magnification• Cytology feature does not have a part• Score: sum of most common and 2nd most common tumor pattern• Gleason’s grading system

– Grade 1 Well demarcated nodule– Grade 2 irregular spacing btw glands, irregular outline– Grade 3 Variability in gland shape & spacing– Grade 4 Gland fusion– Grade 5 Diffuse solid sheet of undifferentiated cells

• Gleason score: – GS 2-4 Well differentiated– GS 5-7 Moderately differentiated – GS 8-10 Poorly differentiated

• In general: 30% understage, 5% overstage• Most important prognostic indicator• Used in : bx , TURP , RP specimen• Gleason sum 4 or below should not be given for Bx specimens• For RP specimen, foci <5% should be ignored• Microscopic invasion of bladder neck = T3a but not T4• PSM at BN = T3a but not T4

Staging of CaP (AJCC 7th : 2009)T Stage: • T1: clinically not palpable or visible by

imaging– T1a: incidental < 5% of tissue resected– T1b: incidental > 5% tissue resected– T1c: Identify by bx (not palpable)

• T2: Tumor confined to prostate– T2a: < ½ of one lobe– T2b: > ½ of one lobe– T2c: Both lobe

• T3: Extend through capsule– T3a: Extracapsular extension (uni or

bilateral) – T3b: invade SV

• T4: Tumor is fixed or invades adjacent structures other than SV: , such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall

N Stage: Regional LN• Nx: Regional LN cannot be assessed• N0: no regional LN met• N1: Regional LN met

M Stage: Distant metastasis:• Mx : DM cannot be assessed• M0: no distant met• M1: Distant met

– M1a: Non-regional LN– M1b: bone– M1c: Others site

Mx of CaP• Depends on accurate staging and risk stratification• T Stage:

– DRE: very poor, correlate with pT stage < 50%– TRUS: only 60% or all Ca & 40% of T3 detected– MRI: SV 70% & SP 80% in prediction of ECE & SV invasion (confuse by recent TRUS + bx : wait 4/52)– Others: bx GS score & % of core involved– Predict by PSA level : % organ confined CaP :

• PSA <4 80%• PSA 4-10 70%• PSA >10 50%

• N stage: – Gold standard is lymphadenectomy (obtrator LN only miss 50%) – Extended LND proximally to the common iliac bifurcation (AUA BPP 2009)– CT / MRI relies on size of lymph node (>8mm) with significant under staging (50%)– CT finding of nodal disease <1% if PSA <20 – PSA: Proportion of N+ disease

• PSA <10 5%• PSA 10-20 18%• PSA >20 36%

• M stage: – ALP, Cr elevated in 70% of M1 disease– Best staging is with bone scan, Superior to XR / ALP / PAP, Radio-isotopes :Technetium diphosphonates– MRI marrow screen: more SN then bone scan but more expensive– PSA > 100, 100% PPV for M1 disease.

• Thus need combination of factors for better staging: Partin Tables

When do we need….• Bone scan ?

– PSA > 20 – GS 8-10 – cT3 / T4 regardless of PSA

• CT/ MRI ? High risk group– PSA >20-25 OR– Bx GS>/= 8 OR– cT3 disease or above

• Lymphadenectomy ?– Unnecessary in low risk CaP (PSA</=10 AND cT1/T2a AND GS </=6) : <10% LND

by Partin– LND indicated in : intermediate to high risk gp

• PSA > 20 • PSA 10-20 AND GS<6• Risk of LN met > 7% (Partin tables)

– Extend: overlying the external iliac artery and vein, the nodes within the obturator fossa cranially and caudally to the obturator nerve, and the nodes medially and laterally to the internal ileac artery

Partin Tables• Nomogram devised based on the results of RP in JHH. • It predicts the final pathological stage based on preoperative PSA,

DRE finding and TRUS GS• Latest version : 2007, based on >5700 RP in JHH from 2000 to 2005

by 22 surgeons• Determines probability of pathological OC/EPE/SV+/LN+• Changes

– Absence of GS2-4 (Epstein)– Subdivision of GS7– T1c % rose from 33% to 77% : A result of PSA screening (stage migration)– OC % rose from 48% to 73%– Inclusion of T2c (TNM version change) – Absence of T1a/b– Amongst high GS (8-10) and high cTstage (T2b/c), probabilities of OC increased

• Expanded role of surgery among these patients• Will Rogers phenomenon

Risk Stratification System• To assess risk of having metastatic disease [NICE

2008] Risk group PSA (ng/ml) GS Clinical T stageLow <10 & <6 & T1-2aIntermediate 10-20 7 T2b-2cHigh >20 8-10 T3-4

• To assess risk of biochemical recurrence after radical txn [D’Amico classification JAMA 1998]Risk group PSA (ng/ml) GS Clinical T stage PSA Failure in 5 yr

Low <10 </=6 T1c-2a <25%Intermediate 10-20 7 T2b 25-50%High >20 8-10 T2c >50%

Nomogram• Pre-treatment: to predict:

– Final pathologic stage + LN : Partin Tables [2007]– Relapse after radical txn: D’Amico Classification– T & N stage: Kattan nomogram– 5 yr CaP recurrence after RP: Kattan nomogram

• Post-treatment: to predict:– Post-RP progression free: Kattan nomogram– Post-RP BCR then receive RT, risk of progression: Kattan Nomogram– 1-2 yr survival probability after CRPC state: MSKCC

• Kattan Nomogram to predict PCSM after RP– Bx GS, PSA , year of surgery were asso with PCSM (prostate cancer specific mortality) – Few pt will die from CaP within 15 yr of RP, despite adverse clinical features

• USCF- CAPRA score:– Cancer of the Prostate Risk Assessment (CAPRA) – Develop from data of Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE)– More applicable to real world scenarios

• Use: 1. Age at dx (< 50 or > 50)2. PSA (<6, 6.1-10, 10.1- 20, 20.1- 30 , > 30)3. GS (no 4/5, 2nd pattern 4/5, 1st pattern 4/5)4. Clinical stage (T1/T2 , T3a)5. Percent of bx core involved with cancer (< 34% or > 34%)

• To predict:– Likelihood of metastasis– Cancer-specific mortality– Overall mortality

• CAPRA score: 0-10 score– 0-2 : low risk mx with AS– 3-5: Intermediate risk mx with localized txn (RP, RT, BT +/- EBRT) – 6-10 : high risk Mx with multimodality (RP + RT, RT + HT)

Imaging• Is CT useful in dx of CaP?

– No, low SV & SP, accuracy 15-65%– May have a role in dx of LN met

• Role of Prostascint?– Prostascint use Indium III capromabpendetide

(radiolabelled monoclonal Ab to prostate-specific membrane antigen)

– PSMA expressed in epithelial cells of prostate origin– Identify soft tissue site of CaP metastasis– Use to see if localized therapy is beneficial because MRI

cannot demostrate low volume metastasis & Extraprostatic disease

Watchful waiting?• Aim: to reduce risk of over treatment & associated morbidity in subgroup of pt with

insignificant disease with low risk of progression• Who are the candidate?

– LE < 10yr– Low grade (1-2) , low stage cancer < T2a– Significant morbidities

• Why? Evidence: – Grade 1-2 subgroup for T1a disease [Chodak 1994]

• 10-year DSS: 96%(G1), 94%(G2)• 10-year MFS: 92%(G1), 78%(G2)

– But may not be suitable for Pt with LE > 15 because [Johnhanson JAMA 2004]• CaP mortality rate increased from 15 to 44 per 1000 person-years during first 15 yr to beyond 15 yr• FU for 21 years overall : 40% disease progression , 17% metastasis & 16% die of CaP

– However , not all investigation agree with the progression beyond 15 yr [Albersten JAMA 2005]

• Prostate cancer progression rates do not increase after 15 years of follow-up– Possibility of difference btw Johnhanson & Albersten study

• Different classification: Johnhanson (aspiration cytology) vs Albersten (Glandular architecture GS)• Different record method : Johnhanson (Record review) vs Albersten (death certificiate)

– Thus Counseling men with >15yrs life expectancy with moderately diff (GS5-7) is the most challenging, but still recommend aggressive treatment in the time being

• FU and txn: – DRE, PSA 6/12– Palliative txn : HT if progression or preset level of PSA reach

• Final report of the Johannson study• 32 yr of follow-up,• Result:

– All but 3 (1%) of the 223 men had died. – 90 (41.4%) local progression events and 41 (18.4%) cases of progression to

distant metastasis.– 38 (17%) men died of PCa. – Cause-specific survival decreased between 15 and 20 yr, but stabilized with

further follow-up.– All nine men with Gleason grade 8–10 disease died within the first 10 yr of

follow-up, five (55%) from PCa.– Survival for men with well-differentiated, nonpalpable tumors declined slowly

through 20 yr, and more rapidly between 20 and 25 yr (from 75.2% [95% confidence interval, 48.4–89.3] to 25% [95% confidence interval, 22.0–72.5]).

– It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels.

• Conclusion: local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis.

EU Jan 2013

WW vs RP , which is better for who?• So far only two RCT address this issue1. Pre-PSA Era: Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4): Bill-Axelson • 695 pt T1-2 disease, WW (348) vs RP (347) • RP able to achieve a significant relative risk reduction of CSM

– By 44% at 10 year [NEJM 2005]– By 35% at 12 year [JNC 2008]– By 38% at 15 year [NEJM 2011]

• RP also significantly reduce local progression & risk of metastasis• Overall mortality was not statistically significantly different between group but favored radical prostatectomy [JNC

2008]• Survival benefit is confined to men < 65 yo but also in low risk group• Limitation: 5% T1c (PSA screened), 75% T2, High grade excluded, criteria for local progression (DRE/obstrutive

symptoms requiring TURP)2. PSA-Era: Prostate Cancer Intervention Versus Observation Trial (PIVOT)• More representative of men being diagnosed and treated in contemporary clinical practice than were those enrolled in

SPCG-4• RP vs WW in patients with clinical stage T1-T2 disease• 731 patients , median age of 67 years , ¾ clinical stage T1c disease• Tumor risk categorizations [D’Amico]: 43% low-risk, 36% medium-risk, 20% high-risk PCa. • FU 15 years• Result: AUA 2011

– CSM thru 12 is < 10% : affect by risk : Low risk (10%), high risk (10-20%)– RP compare with WW did not produce significant reduction in all cause mortality and cancer specific mortality (<

3% absolute difference)– However, it suggest a benefit from surgery for high PSA and high risk disease

Conclusion : • Men with LE >15yr (i.e <65) in average HK men, RP produce a significant reduction of CSM , local and

metastatic progression compare to WW. And this is true especially in high risk group.

How about Active Surveillance ?• Aim: Curative treatment

– For men with potentially curable CaP but wish to avoid the complication associated with treatment– Treating those with sign of clinical progression

• Reason: Risk of CaP death for GS6 is 20% in 20yr [Albersten 2005]• Adv:

– Avoid side effect of txn– Minimize overtreatment for indolent cancer– Retain QoL , normal activity and work schedule

• Disadv: – Risk of undertreatment for occult aggressive disease– Cancer progress and become incurable at later stage– Later txn of advance Ca may cause more morbidity– Require frequent assessment and biopsy– Anxiety of living with a cancer– No long term (>10yr) FU data

• Inclusion criteria: in general low risk diseaseRoyal Marsden EAU 2010 Esptein (insignificant) 1994

PSA < 15 <10 PSAD < 0.15GS < 3+4 <6 <6T stage T1-2 T1c-2a < T1c+ve core < 50% <50% < 50% or < 10mmNo of +ve core <2 <3 out of 10Others Age50-80 ,fit for Txn

• AS FU [LKlotz:]– DRE Q3m for 2 yrs, Q6m thereafter if PSA stable– PSA Q3m for 2 yrs, Q6m thereafter if PSA stable– TRUS Bx Q12-18m

• Trigger for Treatment – Biochemical :PSADT < 3y– Histological : GS >/= (4+3) or >50% in core– Clinical progression

What is the outcome for AS?• 450 patient, Median FU 7 yr• Good risk pt included: pT1b-pT2b, N0M0, GS <=7, PSA <=15• Intervention if: PSADT < 3yr, GS >4+3, unequivocal clinical progression• Result: 12 yr FU [Klotz JCO 2009]

• OS : 78.6%• 10 yr CaP actuarial survival: 97.2%

• At 8yr FU :34% stop AS:– 15% rapid biochemical progression (PSADT < 3 yr)– 3% clinical progression– 4% histological progression, – 12% pt preference

• Conclusion: AS for favorable risk CaP and intermediate risk in Man > 70 is feasible and safe in 10-15 yr time

• So to consul the patient about AS:– In well-selected pt with low risk disease, there is very low rate of progression and cancer

specific death– PSADT are unable to predict that a patient will be at high risk (i.e short PSADT show pt

already at high risk !!!)– There are still risk of tumor progression after AS for pt with apparently localized CaP,

esp with long LE >15yr

AS vs WW• Summary of AS vs WW

Watchful Waiting Active Survillance

Aim Avoid treatment Treat only if necessaryAvoid cx asso with intervention

Protocol Occasional PSA Frequent PSANo biopsy Frequent Biopsy

Treatment indication Symptoms Increase PSADTUpgrade GS

Treatment timing Late EarlyTreatment Aim Palliative Radical

EAU 2010 : AS

Radical Prostatectomy• Radical prostatectomy:

– Open: Perineal , Retropubic– Pure Lap: Trans/extraperitoneal– Robot: Trans/extraperitoneal

• Indication: – Localized CaP with LE> 10 yr– High risk only if there is “Realistic prospect of long term disease control”

• Is Neo-Adjuvant HT useful in localized CaP? NO– Meta-analysis: Reduce PSM rate (only in T2 but not T3), organ confinement & LN

invasion but No effect on OS or DFS [Shelly Cancer Txm rev 2009]

• Open Retropubic prostatectomy:1. Pelvic lymphadenectomy; 2. Opening of the endopelvic fascia and limited incision of the puboprostatic ligaments; 3. Suture ligation and transection of Santorini's dorsal venous complex; 4. Dissection of the urethra at the apex of the prostate 5. Transection of the urethra (sometimes the anastomotic sutures are placed at this point

in the operation); 6. Dissection of the prostate from the neurovascular bundles; 7. Securing and transection of the prostatic pedicles; 8. Transection and reconstruction of the bladder neck; 9. Dissection of the seminal vesicles and ampullary portions of the vasa deferentia10. Performance of the vesicourethral anastomosis

• eLND:– Indicated in intermediate/high risk: LN +ve > 7%– GS<7, PSA< 10: not beneficial (< 7% involve)– GS > 7, PSA >10: 25% LN +ve [Schumacher EU06]– Extend: Overlying external iliac A&V , Within obturator fossa cranially,

Obturator N caudally, Medial and lateral to internal iliac artery– Cx: Lymphoceles &lymphoedema , DVT & PE

• Complication: – Mortality: < 1%:– Infection : 5%– Bleeding: 5%– Rectal injury: 5%– Impotence: 40-60%– Incontinence: 50% early (5% long term)– Stricture , stenosis: 10%– Anaesthetic risk: 5-10%– PSM: 10%– Conversion 5%

• Clinical pathway in John Hopkins: – Day 0: fluid diet, PCA – Day 1: advance diet, off PCA , ambulation – Day1 or 2: discharge based on (tolerating regular diet, pain control, ambulating)– Duration of Cath base on patient specific factor and physician discretion (usually 14 day with

cystourethrogram)• Fu schedule:

– Day 14 : Off foley, start PFE– 1st FU 6 weeks: assess recovery , early cx , review histology, ensure PFE, offer PDE5-1– Discuss Progression free survival by using Kattan Nomogram– 2nd FU 3 months: PSA < 0.1, assess incontinence and impotence– Then 6 monthly FU

• Impotence: – Risk factor: Age (>65), pre-op IIEF, co-morbidities, NS perform– Nerve Sparing: potency 50% (uni) , 60% (bi) – CI to NS: palpable disease, apical tumor, GS > 8– Txn: early penile rehab, PRN PDE5-I, IU/IC PGE-1, VCD– No benefit of daily vardenafil vs PRN [Montorsi Eu 2008]

• Incontinence: – Improved in 18m– Risk factor: ,Age, blood loss, BN stenosis– Prevention: Pre-op PFE, treat DO– Txn: urethral bulking agent, Bulbourethral sling , AUS

• BNS: 5%– Presentation: 3-9m , poor flow, frequency with urgency – Risk factor: bleeding, post-op urinary leakage– Txn: TUBNI

• LRP / LaRP vs Open RP [Ficarra EU 2009 Review]• Adv:

– Shorter Length of stay– Lower blood loss and transfusion rate & cath time– Similar PSM & BPFS rate– Fewer reps and surg complication and stricture

• Dis: – More time consuming (initial steps of learning curve)– More GU complications, incontinence and ED– Similar post-op use of additional cancer therapy– Higher need of slavage therapy (EBRT / ADT) within 6m

• No available data to prove superiority of any surgical approach interms of fxn & oncological outcome

• Advantage of LaLRP: 1. 3 dimensional magnified visualization (10-15x)2. Elimination of intention tremor3. In ease of wrist movement (270 degree)4. Less physically and technically demanding then pure Lap5. Lower average IO blood loss then ORRP, no diff in transfusion rate

• Disadvanatge of LaLRP: • COST !!!• Higher frequency of stricture • No long term result

Advantages disadvantages

Perineal -less blood loss-shorter operative time

-no pelvic lymph node dissection-higher rate of rectal injury/fecal incontinence- Higher PSM than RRP

Retropubic -low risk of rectal injury/fecal incontinence-Preservation of neurovascular bundles-lower risk of +ve margins vs perineal

Laparoscopic -similar oncological outcome-field magnification 10-15-less bleeding/post-op pain-comparable incontinence and stricture

-heat from electrocautery can damage cavernous nerves-difficulty hemostasis in neurovascular bundles-higher +ve margins-lack of long-term results for adequacy of cancer control

Robotic -greater technical ease-three dimensional visualization

• What is the Cancer control result after open RP ?• JHH/Patrick Walsh series

1982-97, N=2404, mean FU 6.5yr (26% 10y)10YCSS 96% 15YCSS 90%10YBPFS 74% 15YBPFS 66%10YMFS 90%10 OS 95%

• Ways to improve continence:– Walsh 2002: Butressing sutures to prevent passive opening of BN with filling (BN

intussuception) 3mo continence 82% vs 54%– Recapitulation of normal support of Urethra and BN

• “Rocco stitch” JU06: suturing posterior striated sphincter to the Denovilliers fascia posterior to the bladder wall earlier recovery of continence

• Tewari “Total restoration technique ”Uro07• Menon JU08: 2-layer anastomotic reconstruction in RALRP no difference compare to 1 layer

• Ways to improve Sexual function: – Kaul BJU06: high intrafascial nerve release along the length of prostate

• 95% have intercourse at least 1x in 4 weeks• 70% return to baseline erectile function at 1 year

– Nielsen JU08: High anterior release (HRA) of the levator fascia in RRP• High release done more toward the apex of prostate and in plane btw levator fascia and

prostatic fascia, rather than btw prostatic fascia and capsule of the prostate • Earlier potency (93%vs 77% at 12 mo)• Improved return to baseline (70%vs 54%)• Compare to standard nerve sparing

• Why need early Penile Rehab?– Erection depends on cavernosal smooth muscle content and fxn– SM integrity and fxn depends on tissue oxygenation– Hypoxia collagen accumulation (fibrosis) thru action of TGF-

Beta– Collagen deposit penile shortening and reduce girth– Also venous occlusion and further ED– After RP Neurapraxia + vasular injury and SM damage

decrease erection + tissue hypoxia – PGE1 reduce expression of TGF-b maintain oxygenation and

prevent hypoxia • Result:

– Early adm of intracavernous injection– Early use of PDE-5 inhibitors– 30-70% improvement in rate of spontaneous erection– Combination of PDE-5i + VCD is most user friendly, cost-effective

and patient compliant

• Is there role for Adj-HT in localized CaP?– Trend of improved 5yr OS & DFS but not at 10 yr [Cochrane review ]– NO improvement in OS is local/LA CaP [EPC McLeod 2006]

• N+ post RP : [EOCG 3886 Messing Lancet Onco 2006 ]– N+ After RP : immediate ADT vs delay ADT– Immediate ADT has improvement in: OS , CSS , BPFS– Early ADT benefit pt with N+ disease with RP + PLND– Immediate hormone FU 11yr improved CSS (80%) and OS

• If PSA < 0.1 on 1st FU: continue FU– Post txn 1st year: Hx , PSA, DRE 3, 6, 12 months– Then: every 6 months after until 3 year– Then: Annually

• What if pathology R1 or T3 (ECE) or persistent raised PSA > 0.2?– Explained: 50% T3 will be biochemical progression in 5yr– Adjuvant RT (immediate):

• when compare to salvage RT: • Improve BPFS at 5yr by 22% (72% vs 50%) [EORTC 22911 Bolla Lancet 2005]• Improve BPFS by 18% (72% vs 54%) [ARO 96-02 German [Wiegel JCO 2009]• Improve: 10-yr MFS 10% (71% vs 61%) & 10-yr OS 8% (74% vs 66%) [SWOG 8794 Thompson 2008]

– Advantage:• RT before PSA > 0.5ng/ml will have undetectable PSA level again in > 60% • 5yr progression free survival: 80%• Severe late toxicity is rare • Highest impact in case of PSM (EAU 2010)

– Or wait until PSA progression then salvage RT• EAU 2010 : can offer immediate RT OR clinical monitoring and salvage RT when PSA >0.2 but <0.5• NICE 2008: do not recommend immediate RT• Ongoing trials:

– RADICALS: Radiotherapy and Androgen deprivation in combination After Local Surgery : Access Adj vs salvage RT and duration of HT

Biochemical recurrence Post-RP• Definition: 2 consecutive values of 0.2 ng/mL or greater [Eu consensus IJCP 2004]• After PSA rise post RP: if left untreated [Pound JAMA 1999]

– Median time to metastasis: 8 yr– Median time to death after met : 5 yr

• Why investigate: To stratified patient into:– Candidate for salvage therapy or not– Local salvage txn vs systemic therapy

• What investigation: – PSA– Bx of VU anstomosis not indicated : low SV & SP in PSA < 1ng/ml– Bone scan: No additional value unless PSA > 20ng/ml or PSA velocity > 2ng/ml/yr– MRI : not routine– PET: 11C-acetate PET : High SV &SP for local recurrence in PSA > 1ng/ml

• No definite modality to differentiated local or systemic recurrence , base mainly on PSA kinetics

Local recurrence Systemic recurrence

Time of PSA increase (yr) > 3 < 1

PSA velocity (ng/ml/yr) <0.75 (90%) >0.75 (50%)

PSADT (months) > 11 months <4 -6 months

Pathological stage < pT3a N0, pTx R1 pT3b, pTxN1

GS on prostate specimen < = 6 8-10

Biochemical recurrence Post-RP• Local recurrence: Salvage RT

– ASTRO consensus: dose of at least 64Gy when PSA level is < 1.5ng/ml after RRP– EAU 2010: Dose of 64-66 Gy , before PSA reach 0.5ng/ml post RP– PSA level at time of salvage RT affect outcome:

• 6yr BPRF survival: PSA <0.5 (48%) vs PSA > 1.5 (18%) [Stephenson JCO2007]– As per discussed : RT improved MFS & BPFS [EORTC, SWOG & ARO]– Conclusion: Adjuvant RT when PSA< 1.5ng/ml will give advantage on: BPFS (15% in

5yr) , MFS in 12 yr & CSS – Dosage: 64-66 Gy– Local toxicity:

• EORTC: 3% interrupted due to diarrhea• Grade 3-4 toxicity: 2x in adj arm• Urethral stricture and incontinence

• In systemic recurrence: HT– EAU 2010: PSA recurrence indicative of systemic relapse is best treated by early ADT

result in decrease frequency of clinical metastasis– LHRHa or Orchidectomy or Casodex 150mg can be used

• Or observation: until clinical evidence of metastatic disease is a viable options in : – GS <7– PSA recurrence > 2yr after surgery – PSA DT > 10m [EAU 2010]– Quote Pound JAMA 1999

RT• What is RT and how it works?

– RT: High-energy photons (produced by linear accelerators) with good tissue penetration – X-ray pass thru tumor – Interaction of photons & outer atoms cause formation of free radical (e.g OH-) – Result in DNA damage & double-strand breakage

• Optimisation & effect of RR– Repair: Fractionation result in more cell entering sensitive phases of cell cycle &

arresting cell repair– Reoxygenation: As cell die, more O2 available for free radical formation– Reassortment: Cells more susceptible in G2 & S phase. Damage may not be appreciable

until cell division has occurred– Repopulation: Further cell division result in tumor growth & compormises efficacy

• Type of RT: – EBRT: linear accelerator to produce high energy x-ray– 3D-Conformal RT – radiation beam conform to the shape of treatment target– Intensity modulated RT – CRT using extremely advanced software, specialized

personnel, and hardware adaptations to linear accelerators, so that treatment can be maximized over the target and minimized to the surrounding tissue (>80Gy)

– Brachytherapy

RT• No randomised studies comparing RP with EBRT or brachytherapy for localised prostate cancer• National Institutes of Health (NIH) consensus set up in 1988

– EBRT offers the same long-term survival results as surgery– EBRT provides a quality of life at least as good as that provided by surgery

• In localized prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. There is fairly strong evidence that low-, intermediate- and high-risk patients benefit from dose escalation (LE 1a)

• Indications for RT:– Clinically localized prostate cancer

• Localized prostate cancer low risk (T1a-2a, GS < 6, PSA, 10)– EBRT ≥74Gy, Brachytherapy ≥140Gy

• Localized prostate cancer, intermediate risk (T2b , GS 7, PSA 10-20)– 6m ADT with RT (> 75Gy) improve OS by 13% vs no ADT (D’Amico JAMA 2004)

• Localized high risk (T2c, GS> 7, PSA >20) / Locally advanced prostate cancer– Dose: >75Gy, External irradiation with dose escalation is mandatory improve 5yr BDFS– Concomitant and/or adjuvant HT provide longer time-to-disease progression and longer OS than RT alone

followed by ADT at progression (LE : 1b)• Prophylatic RT to Pelvic LN:

– Pelvic LN metastasis require systemic txn because RT alone is not sufficient– In high risk case: Prophylatic RT (50Gy) to Pelvic LN has NO benefit – Evidence : RTOG 7706 study, Standford study , GETUG-01 trail– PLND needed to improve pt selection for RT based on Partin’s tables and Roach formula– Should be consider when Risk of N+ disease > 15 %

• Roach formula: 2/3 PSA + (10 x [GS-6])– For example: Pelvic irradiation for pN1 pt with long term ADT

• CI to EBRT: • Severe LUTS• Inflammatory bowel disease• Previous pelvic RT

• Complication with EBRT: • Cystitis/hematuria 20%• Proctitis 20% (3% long term) • Urethral stricture 5%• Urinary incontinence 1% long term• Lower limb edema 5%• ED 30-60% (occur over years due to vascuologenic )• 2nd cancer 1 in 300

• Oncological outcome –conformal RT series: 5yrs BFS• 85% (low risk), 60% (int. risk), 40% (high risk) (Zelefsky) (Campbell)

Intensity modulated radiotherapy (IMRT)• Increase RT dose to 86Gy within target vol , while respecting the

tolerance doses in organs at risk• The Only safe means in dose escalation (80Gy) & hypofractionated RT• Largest Experience: MSKCC

– Zelefsky JU 2006• Localized CaP , RT 81 Gy• 8 yr PSA relapse –free survival: good (85%), intermediate (76%) poor (72%) risk

group (ASTRO 97)– Cahlon Int Jrn Rt Oncol Bio Phy 2008:

• Organ confined CaP , RT 86Gy• 5yr PSA relapse-free survival: good (98%), Intermitedate (85%) , Poor (70%) risk

group (ASTRO 2004)• Ongoing trial for comparing dose escalation using IMRT and 3D-CRT :

UK NCRI , MD Anderson, Fox Chases, Ottawa Health Research Institute)

• Evolving technique : – Image- guided RT (IGRT): organ movement detected and corrected at real time– Tomotherapy: like spiral CT scanning

Transperineal Brachytherapy (EAU 2010)• Permanent: iodine-125 (standard), palladium-103 (for less differentiated tumor with high

PSADT)• Non-permanent: iridium-192 (high dose rate)• Patient with low risk CaP – favorable for low dose brachytherapy• For intermediate and high risk localized CaP, brachytherapy with supplemental external

beam RT or neoadjuvant ADT may be considered• Use Stranded seeds better seed retention• Dosage: 140Gy (D90: dosage cover 90% as calculated by CT scan) • Indication : low-risk patient

– cT1b-T2a– Gleason score </= 6 on sufficient number of random Bx– PSA <10ng/ml– <50% tumor occupying Bx specimen– Prostate volume <50cm3– IPSS </=12

• Contraindication: – LE< 5yr – Coagulation disroder– Previous pelvic RT– Any GS 5– Previous TURP increase risk of urinary incontinence – Large Prostate > 50gm or Large median lobe (difficult seed implantation) – Moderate to severe LUTS ( risk of worsening LUTS and retention)

Brachytherapy• Complications

– Urinary retention 20%– post-implant TURP 8.7%– Urinary incontinence 10% (> EBRT)– Proctitis (Grade II/III) 10%– Erectile dysfunction 40%– Perineal hematoma occasional

• Results – 7 year BPFS : low risk (80%), intermediate risk (70%), high risk

(60%)– 10 year BPFS: low risk (60%)– Cleveland Clinic and MSKCC experience, 5Y BRFS for

brachytherapy is comparable to EBRT and RP– BT + EBRT 15yr BPFS: low/intermediate risk (80%), high risk (50%)– Not recommended for intermediate and high risk patient

Proton bean therapy

• Advantage of Proton beams: – deposit all RT dose at the end of particle’s path in tissue (the

Bragg peak) vs RT (deposit along their path) – Sharp fall-off beyond deposition depth – More DNA damage compare to RT

• Disadvantage: – Highly sensitive to change in anatomy (bladder or rectal filling) – Deliver with lateral beams

• Loma Linda/Massachusetts General Hospital trial– Using protons for boost dose for dose escalation

• Still consider experimental

RT alone vs RT+ADT• EORTC 22863 (Bolla, Lancet 2002)

– High risk localised or locally advanced patient, 3yrs ADT– 5yrs PFS improved from 40% to 74%– 5yrs overall survival improved from 62% to 78%– 5yrs cancer specific survival improved from 79% to 94% – [Bolla IROBP 2008]

• Higher 10 yr OS (58% vs 40%), PFS (47% vs 22%)• Higher 10 yr CSS : 31 % vs 11%• Higher 10 yr CVS mortality: 11% vs 8 %

Short term ADT vs Long term ADT• EORTC 22961 (Bolla, NEJM 2009)

– Randomized trial, 6m ADT vs 3yrs ADT + RT– Overall survival and CSS benefit in 5 yrs – 3.8% and 1.5% (p 0.65)– Conclusion: advise to the long term ADT+RT for high risk patient

LN+ve prostate cancer (very high risk) • EBRT + immediate Long term HT• Indication:

– PLN lower than iliac regional node– < 80 yr– WHO PS 0-1– No severe co-morbitidy

• RTOG 85-31 [Lawton JCO 2005]– Randomized phase III trial, RT to Pelvis + immediate HT vs RT + HT

at relapse – Improve OS, CSS, MFS and progression– Improve PFS from 10% to 54% in 5yrs

• No role in prophylactic pelvic irradiation (EAU 2010)

RTOG 94-08: RT + Short term

ADT (4m)• Whether short term ADT (4m) improve OS + DSS in

localized CaP txn with RT ?• Inclusion: <=T2b, PSA <= 20ng/ml• 1979pt: RT alone (992) vs RT + ADT (987)• ADT: given 2m before and during RT (4m in total) • Result: FU 10yr, RT+ ADT vs RT able to

– Improve Overall survival : 62% vs 57% (HR 1.17 P=0.03)– Reduce DFM : 8% vs 4% (P= 0.001)– Reduce biochemical failure , metastasis, rate of +ve bx at 2yr

• ADT Grade 3 SE: <5%• Conclusion: RT+ ADT improve OS + DSS. Benefit mainly

seen in intermediate , but not low-risk men

FU Post RT• History:

– Psychological aspects– Signs of disease progression– Treatment related complication

• Examination: – PSA– DRE– TRUS + bx: Only warrant if the finding of local recurrence affects treatment decision

• PSA– PSA level falls slowly after RT to a nadir (mean time : 9m)– PSA bounce : rise of PSA after initial fall (should remain < 1.5ng/ml)– Interval to reach nadir can be very long (up to 3 years)– PSA nadir <0.5ng/ml asso with favorable outcome [Ray 2006]

– PSADT correlated to site of recurrence [Hancock JU1995]• 13 months local recurrence• 3 months distant failure

• CT/MRI not indicated unless PSA>20ng/ml• Bone scan not require in asymptomatic patient

Post RT biochemical recurrence• Definition of biochemical failure after RT:

– ASTRO 1996: three consecutive increases in PSA– RTOG-ASTRO 2006 [Phoenix consensus conference]: a

rise of 2 ng/mL above the post-treatment PSA-nadir (lowest value)

• In the absence of salvage procedure, mean time form biochemical to clinical progression ~3 yr

• Options: – ADT (main choice)– Local procedure: salvage RP, Cryotherpay & Interstitial

radiation therapy

Salvage RP post RT• Offer potential ncurative options for salvage txn of OC recurrence disease post RT• Accurate pre-surgical staging is not defined after RT • If TRUS+Bx is plan, it should be at least 18m after EBRT• Indication:

– Low co-morbidity– Life expectancy of > 10yr– Organ- confined CaP < T2– GS < 7– Pre-surgical PSA < 10ng/ml

• Result: – 10 yr : CSS 70%, OS 60% in 100 salvage RT pt [Stephenson JU 2004]– Very low peri-op complication rate– But urinary incontinence can be up to 20% [Heidenreich EU 2010]

• There is increase risk of – Ant & total extirpation procedure– Associated complication– Decrease long-term disease specific survival

Other salvage procedure• Cryotherapy:

– Transperineal USG guided placement of cryoprobes– Argon or liguid nitrogen (temp: -20 to -40)– 2 cycle of freeze-thaw cycle cellular necrosis– USG monitor diameter of ice ball– Warming transurethral warming device for protection of urethral , sphincter and rectum– GA, day case

• MOA: – Cellular dehydration & protein denaturation– Direct rupture of cell membrane by ice crystal– Vascular stasis & microthrombi ischemia & coagulative necrosis

• Complication: – Urinary incontinence (70%), persistent > 1 yr (20%)– Obstructive symptoms (65%)– Impotence (70%)– Severe perieneal pain (8%)– Rectal fistula (2%)– Require surgery for txn asso complication (4%)

• Results: – Good short term PSA response (66%)– 5yr BPFS : 50% overall : low (70%), intermediate (45%) , high (10%)

• HIFU: High intensity Focus USG– Transrectal device– High energy USG deliver heat to prostate causing

coagulative necrosis (Temp > 85degree)– Ablative region: 6x2x2mm cigar shape– GA, day case

• Complication:– Urinary incontinence: (50%)– Require urinary sphincter (10%)– Recto-urethral fistula (7%)

• Result: oncological control rate after 2-yr : 30-40%

Locally Advance CaP T3-4 N0M0• Brachy, Cryo, HIFU: Not recommended• RP:

– Generally discourage for T3– 80% require additional txn– 30% cT3 are organ confined– Cytoreductive surgery may reduce morbidity ,but LND is require for further staging

• EBRT + ADT: – Mainstay of treatment– Consistently show better outcome then EBRT alone [EORTC 22863]– 10yr OS : 15-30%– NICE 2008: neo-adj + concurrent ADT for 3-6m Adj ADT for at least 2yr if GS >8

• Pelvic RT: consider if Risk of N+ > 15 (Roach formula)• Bisphosphonate: NO• ADT alone:

– Options for elderly unwilling to undergo EBRT– Bicalutamide 150mg daily has equvilant efficacy to orchidectomy or LHRHa– Adv: reduce side effect

• WW: options in T3 & elderly asymptomatic men• Other palliative txn: TURP, med for LUTS

Ca Prostate (T1a)• Natural Hx

– Low risk of progression esp if GS< 7– But progression & mortality increase in long term i.e. after 15 yrs– 5% progress after 5 yr, but 50% progress after 10 yr (note: most T1b progressed after 5 yr) (Lowe) – 10 yr metastasis for Grade 2 (GS 5-7): 20%– 10 yr CS mortality for Grade 2: 6% (Chodak)– 15 yr CSM 20% ↑ to 40% at 20 yr (<25% of specimen by TNM 1978) (Johansson, Swedish)

• Treatment options: Active surveillance /WW , RP, RT• Watchful waiting

– Inclusion: • Well & mod diff tumors & <10 yr life expectancy• Restaging TRUS Bx & active surveillance if >10 yr LE

– Adv:• Avoid overtreatment in 94% (Chodak)• Avoid Cx of definitive treatments• QOL & normal activities retained

– Disadv:• Risk of progression & mortality in pts with long life expectancy > 10 yrs

– 50% progressed & 40% CSM at 20 yrs, (Johansson)• Psychological burden of untreated cancer

– Supporting Ev:• Only 5% progress after 5 yr• Only 20% metastasize & 6% died of CaP after 10 yrs (Chodak)

T1a• RP

– Inclusion • Young pts with long LE (>15 yrs) esp poorly diff tumours• May consider restage TRUS Bx in young pts with long LE to exclude

more extensive or poorly diff tumours– Adv

• Avoid long term disease progression & mortality• ↓ local progression, metastasis & ↑ CSS in RCT (Holmberg)• Acceptable & treatable Cx, minimal invasive approach a/v• Accurate pathological staging• No psychological burden of untreated cancer

– Disadv• Overtreatment in 50% (Johansson)• Necessary hospitalization & recovery period• Cx of treatment e.g. mortality, ED, incontinence

– Ev• 15 yr CSM 20% ↑ to 40% at 20 yr (Johansson, Swedish)

T1a• RT

– Inclusion• Younger pts with long LE (>10 yr), esp poorly diff tumours

– Adv• Avoid long term disease progression & mortality• Comparable oncological outcome with RP• Avoid Cx of RP e.g. bleeding, anaesthesia, ↓ incontinence, ↑ short

term erectile fx preservation• 3DCRT, IMRT• Avoid psychological burden of untreated cancer

– Disadv• Overtreatment in 50% (Johansson)• Higher Cx risk after TURP

– Short term: 50% temporary bladder or bowel symptoms– Long term: irradiation cystitis/proctitis, ED, secondary malignancy

T1b (>5%)– Significant risk of progression after 5 yr– 33% progression by 5y [Walsh J Urol 1981]

– RP if life expectancy > 10 y– Others: AS, RT, WW

Low risk (PSA<10, GS≤6, cT1c-T2a)• Natural Hx

– 50% progressed at 5 yr & 70% progressed at 15 yrs (Johansson)– 40% died of CaP at 15 yrs (Albertson) – More likely to die of other causes than CaP (Albertson)– <10% LN metastasis (Partin Tables)– 10% Biochemical recurrence after definitive Rx (D’Amico)

• Options: WW, AS, RP, RT• WW

– Inclusion• LE < 10 yrs, comorbidities• Not accept Cx of definitive Rx

– Advantages• Avoid unnecessary treatment in patients with short LE• Avoid Cx of definitive Rx• QOL & normal activities retained

– Disadvantages• Risk of metastasis & 40% CSM in long term• Missed opportunity for cure• S/E of hormonal therapy if progressed

– Ev Only 40% died of CaP at 15 yrs (Albertson)

Low risk (PSA<10, GS≤6, cT1c-T2a)• Active surveillance

– Inclusion• Esp if ≤ 2 cores +ve, ≤ 50% core involved• Fit for radical Rx• Compliant patient

– Trigger pt for intervention• PSADT ≤ 2-4 yrs• Higher grade or more extensive tumour on Bx

– Adv1. Small indolent cancer may not need Rx2. Avoid Cx of definitive Rx e.g. ED3. QOL & normal activities retained4. ↓ initial costs

– Disadv1. May progress or metastasize before Rx2. Missed opportunity for cure3. Rx of a larger, more aggressive cancer may be more intense with more S/E4. Nerve sparing at subsequent surgery may not be feasible5. Frequent medical examination & periodic Bx needed6. Uncertain long term natural Hx of untreated CaP7. Timing & value of periodic imaging studies not determined8. Anxiety of untreated cancer

– Ev• Low progression rate & CS mortality, only minority require delayed radical intervention• Only 30% progressed, 1% metastasis & 1% died of CaP at 8 yrs on AS (300 pts, Klotz)

Low risk (PSA<10, GS≤6, cT1c-T2a)• RP

– Inclusion• LE > 10 yrs who accept Rx related Cx• Active surveillance offered but refused (UK NICE 08)

– Operation• Nerve sparing to be considered (unilateral an option if cT2a)• No LN dissection (<10% LN+, Partin Tables)

– Adv1. Provide pathological staging (30% upstaged)2. The only intervention shown to ↓ local progression & metastasis, ↑ CSS & OS in RCT (Holmberg)3. Surgical Cx e.g. incontinence, ED are acceptable & manageable & can be improved with better

techniques & other measures e.g. AUS4. Easier FU by PSA monitoring due to whole prostate removed5. Salvage RT possible if recurred6. Minimal invasive surgery e.g. lap / Robot available

– Disadv1. Invasive intervention under anaesthesia with potential Cx e.g. bleeding, incontinence, ED2. Hospitalization & recovery period required

– Ev• 15yr BRFS 70%, 15yrCSS 90%, 90% pad free & 70% recovered potency at 1 yr (Walsh) • Of those 30% with biochemical recurrence, 80% recur within 3 yr• Mean time to metastasis after progression: 8 yr [Pound JAMA 1999]• SPCG-4: CSM reduced from 18% (WW) to 13%, Metastasis reduced from 26% (WW) to 20% at FU 11

yrs (695pt, Holmberg)• Limitation of study: Only 5% PSA screening or T1c; high grade excluded; No. of death small; CSS only

improved if age<65; rate of upstage due to +ve margin unknown

Low risk (PSA<10, GS≤6, cT1c-T2a)• RT (EBRT ≥74Gy, brachytherapy)

– Inclusion• LE >10 yr & accept Rx related Cx• Contraindicated for RP

– Contraindications• Prior pelvic RT• Active inflammatory disease of rectum• Severe LUTS

– Brachytherapy for• Prostate vol ≤ 50 ml• IPSS ≤ 12

– Adv (EBRT)1. Avoid Cx of RP e.g. bleeding, anaesthesia2. Comparable oncological outcome in retrospective studies (Kupelian)3. Suitable for elderly with co-morbidities4. 3CRT & IMRT low risk of urinary incontinence, stricture & good short term preservation of erectile function5. Readily available in community practice

– Disadv1. No pathological stage2. No evidence from RCT showing benefit over WW 3. Long Rx course of 8-9 weeks4. Monitoring for recurrence by PSA difficult due to prostate not removed5. Cx of GU toxicity (20%), GI toxicity (20%) & secondary malignancy (2x risk) (Bolla)6. Risk of ED ↑ over time7. Salvage surgery associated with ↑ Cx

– Ev• 5yr BRFS (>72 Gy) 80% (retrospective, Kupelian)• Escalated dose 78Gy ↑ BRFS vs 70Gy (MD Anderson, Pollack)

INTERMEDIATE RISK

• cT2b-T2c or Gleason 7 or PSA 10-20

• Progression is expected: palpable tumor / visible on imaging but still confined to the prostate

• Median time to progression of untreated T2 : 6-10 yr• T2b : 70% progress in 5 yr• RP vs WW: significant ↓ in disease specific mortality in favor of RP in

pt < 65 (Axelson 2008 SPCG-4)– 70% T2 disease– CSS : RP 19.5%vs WW 13.5% (+6%)– Risk of metastasis: RP 20% vs WW 26% but no further increase in benefit >10

yrs• RP should be advocated (LE> 10yr)• eLND should be performed if est. risk of +ve LN > 7% (by Partin’s

tables) [Brignati BJU06]

High risk (PSA>20, GS 8-10, cT2c)• Natural Hx

– 80% progressed at 15 yrs (Johansson)– 70% died of CaP at 15 yrs (Albertson) – More likely to die of CaP than other causes (Albertson)– 15-40% LN metastasis (Partin Tables)– 70% Biochemical recurrence after definitive Rx (D’Amico)

• Assessment before definitive Rx– MRI with endorectal coil– Bone scan

• Options: RT, RP, ADT, WW

• EBRT + adjuvant ADT (3 yr) (Not brachytherapy)– Aim of ADT

• Treating micrometastasis & prevent distant metastasis• ↓ risk of local recurrence as a source of secondary metastasis though effect of

radiation-induced apoptosis – Inclusion

• LE >5-10 yr• Unfit for RP

High risk (PSA>20, GS 8-10, cT2c)• EBRT (escalated dose ≥70Gy) + adjuvant ADT (3 yr)

– Adv 1. Improved 5 yr PFS from 40% (RT alone) to 75% (EORTC, Bolla)2. Avoid Cx of RP e.g. bleeding, anaesthesia3. Suitable for elderly with co-morbidities4. 3CRT & IMRT low risk of urinary incontinence, stricture & good short term preservation

of erectile function5. Readily available in community practice

– Disadv1. No pathological stage2. No evidence from RCT showing benefit over WW 3. Long Rx course of 8-9 weeks4. Monitoring for recurrence by PSA difficult due to prostate not removed5. Cx of GU toxicity (20%), GI toxicity (20%) & secondary malignancy (2x risk) (Bolla)6. Risk of ED ↑ over time

– Ev• 5yr PFS improved from 40% (RT alone) to 75% (RT + 3 yr ADT) (EORTC, Bolla)

– 70Gy RT + 3 yr Goserelin vs RT alone for (T1-2 & WHO G3 ) or (T3-4,N0-1,M0) 415 pts, RCT, multicentred

• Addition of 1 yr adj ADT (goserelin & flutamide) to RT ↓ biochemical failure, metastasis, ↑ CSS (84-> 90%) & OS (30->45%) than neoadj & concomitant ADT & RT (RTOG 9202, Horwitz)

High risk (PSA>20, GS 8-10, cT2c)• RP

– Inclusion• LE >10 yr who accept Rx related Cx & • Selected cT3a pts with low volume disease • Highly selected cT3b pts in context of multimodality Rx• “Only if realistic prospect of long term disease control” (UK NICE 08)

– Adv1. Accurately define extent of disease as 20% can be clinically overstaged 2. Improved local control of primary tumour3. ↑ metastatic free & cancer specific survival4. Allow early recognition of Rx failure, early initiation & improved delivery of adjuvant & salvage

therapy5. Surgical Cx e.g. incontinence, ED are acceptable & manageable & can be improved with better

techniques & other measures e.g. AUS

– Disadv1. High risk of residual disease -> adjuvant therapy needed2. ↑ surgical expertise required3. Invasive with ↑ Surgical Cx esp ED by non-NS surgery & Cx of LN dissection4. Hospitalization & recovery period required

– Ev• LN+ in 15-40%(Partin Tables)• 15yr PFS 70%, CSS 80% in cT3, 27% overstaged (retrosp, 841pt, FU 10 yr, Ward, Mayo clinic)• SPCG-4 (50% ≥pT3): CSM reduced from 18% (WW) to 13%, Metastasis reduced from 26% (WW) to

20% at FU 11 yrs (695pt, Holmberg)

High risk (PSA>20, GS 8-10, cT2c)• RP

• Points to take1. Endorectal MRI2. Bone scan3. Pts must be informed of high risk of residual disease4. Likelihood of multimodal approach e.g. subsequent RT/ ADT5. Likely non nerve sparing surgery6. LN dissection mandatory, extended (bifurcation of CIA)

• LN+ in 15-40%, limited LND miss 50% 7. Early FU to review pathology & PSA nadir for potential adjuvant

therapy• Adj RT ↓ progression & metastasis, ↑ overall survival (50->

60% ) at 12 yr (SWOG, Thompson)• Adj RT if pT3, +ve margin, post-op PSA persistently ↑• Immediate ADT ↑ OS at 12 yr if LN+ (Messing)

High risk (PSA>20, GS 8-10, cT2c)• Ext LN dissection

– ↑ staging accuracy & guide decision for adj therapy– Not sufficient evidence e.g. RCT to support therapeutic

benefit– Removal of LN overlying obturator fossa, ext iliac a & v,

medial & lateral to int iliac a (i.e. bifurcation of CIA) – LN of diff region sent separately to ↑ yield– 20 LN to be representative– Limited LND missed 50% – Cx

• Lymphocele, lymphoedema, DVT, PE• 3x vs limited LND (Briganti)

High risk (PSA>20, GS 8-10, cT2c)

• ADT– Inclusion

• Symptomatic pts, extensive T3-4, high PSA (>25-50), PSADT<1 yr• Unfit pts• Pts refused curative intent intervention eg. RT

– Adv1. Avoid Cx of RP & RT2. Delay local progression, metastasis, ↓ skeletal Cx (2x less) (MRC)3. ↑ overall survival (MRC; EORTC Studer)

– Disadv1. Palliative2. S/E of ADT

– Ev• Immediate ADT delayed local progression, metastasis, ↓skeletal Cx (2x less), ↑

initial CSS & OS than deferred ADT (MRC early result 1997)• Immediate ADT↑ (modest but significant) OS in N0-2 pts (EORTC 30891,

Studer) • Bicalutamide 150mg ↑ PFS in locally advanced CaP than WW at 10 yr(Iverson)

High risk (PSA>20, GS 8-10, cT2c)• WW / Deferred ADT

– Inclusion• Asymptomatic pts with well or mod diff cancer• Short LE <10 yr• PSA<50 & PSADT>12 mth (EORTC, Studer)• Refused any intervention

– Adv1. Avoid Cx of intervention2. Short term QOL & normal activity retained3. No evidence of compromising long term survival

– Disadv1. More rapid progression, metastasis, skeletal Cx (2x) than immediate ADT (MRC)2. ↓ QOL e.g. BOO, ureteric obstruction, uraemia, bone pain, cord compression3. Closer FU to monitor progression

– Ev• No difference in long term survival b/w immediate & deferred ADT (MRC, Kirk)• Immediate ADT: No difference in CSM or symptom-free survival, & only modest

↑ in OS (EORTC, Studer)

Metastatic CaP• Natural Hx

– 5 yr overall survival 25%– Survival: 10% < 6m, 10% > 10yr– 30% have skeletal Cx– 80% died of CaP, 80% of them have bone metastasis in autopsy– > 70% respond to ADT– Mean time for androgen independent state is 14m– M0 : Median OS > 10 yr– M1: 10 yr survival < 7%

• Asymptomatic M1: Median survival 2-3 yr • Symptomatic M1: Median survival 1 yr

• Rx Objective1. To prevent or delay progression2. To reduce or palliate symptoms & morbidities3. To prolong survival4. To improve QOL5. To minimize Rx S/E

• ADT1. Delay progression2. Prevent potentially catastrophic Cx3. Palliate symptoms4. But not prolong overall survival

Metastasis CaP• Common complication of mCaP:

– Spinal cord compression– Ureteric obstruction/ renal failure– Sepsis– Hypercalcaemia– Anemia– Hepatotoxicity– Skeletal fracture– Urinary retention

• Predictor for poor hormone therapy response:– > 5 metastatic lesion– Raise ALP – Anemia– Poor performance status– Low serum testosterone– Failure of bone pain to improve after 3m of treatment– Failure of PSA to fall < 4ng/ml within 6m of treatment (good long term

response if PSA < 0.1ng/ml)

Basic of Hormonal therapy• Huggin and Hodges 1941: Favorable effect of surgical castration and estrogen administration

on the progression of metastatic Ca prostate• Prostate cells are physiologically dependent on androgens to stimulate growth, function and

proliferation• Testosterone is essential for growth and perpetuation of tumor cell , although not

tumorigenic• If prostate cell deprived of androgenic stimulation apoptosis • Source of Testosterone:

– Testis 95%– Adrenal 5-10%

• Controlled by Hypothalamic- pituitary - gonadal axis– LHRH (hypothalamus) LH & FSH (ant pit) testosterone (Leydig cells of testis) – Within prostate cell: Testosterone Dihydrotestosterone (DHT) by 5-alfa- reductase (10x more

potent) – DHT bind to AR translocation to nucleus activate transcription of androgen response gene

Drive cell cycle and inhibit apoptosis– Circulating testosterone converted to oestrogen -ve feedback to control hypothalamnic LH

secretion• Androgen Deprivation therapy (ADT) Any txn result in suppression of androgen activity • Complete androgen blockade (CAB) :

– Suppress testicular androgen (surgical /medical castration) + – Inhibit action of circulating androgens at level of prostate cell receptor using competing

compounds (Anti-androgens)

Before ADT• Cardiac consultation if hx of CVS disease• Screen for DM (fasting glucose & HbA1c) • Glucose tolerance test in selected case• Refer for endocrine if DM• Modified lifestyle: diet, exercise, smoking cessation • Txn existing conditions: DM, hyperlipidemia, HT• Monitor: fasting glucose, lipids, BP• Go back to the indication of ADT

Metastatic CaP: ADT• Bilateral orchidectomy

– GA/LA– Procedure:

• Midline scrotal incision• Subcapsular , total or epididymal sparing orchidectomy

– Adv1. Quickest to achieve castration level (<50ng/dL) of

testosterone (90% in 24 hrs)2. Can be done under LA3. Compliance not required4. Lower cost, most cost effective5. For Old, pending cord comp, severe symptom

– Disadv1. Irreversible2. Wound Cx (up to 15%) , hematoma3. Psychological impact4. 10% non responder

ADT• LHRHa

– busereline, gosereline (Zoladex), leuproreline (Enantone) and triptoreline (Trelstar)– Depot injection 1- or 3-monthly– MOA:

• Initially stimulating pituitary LHRH receptors induce transient rise in LH & FSH • Induce elevate testosterone “flare-up phenomenon” (start 2-3 days & last 1 week) • Chronic exposure lead to down regulation of LHRH- receptors

– Adv• Comparable efficacy as surgical castration• Avoid surgical Cx• Avoid psychological impact due to surgical castration• Reversible, allow intermittent ADT

– Disadv• Potential flare phenonmen

– High risk: high vol, symptomatic, bone disease– Cord compression, ↑ bone pain, fatal cardiovascular events due to hypercoagulation,

acute BOO, obstructive renal failure• Slower to achieve castration level (3 weeks)• Compliance required for regular injections• Higher cost than surgical castration

– Txn of flare : • Antiandrogen started on same day/1 week before and continue for 2 week• In impending cord compression: BSO or LHRH antagonist

ADT• LHRH antagonist

– Bind immediately & competitively to LHRH receptor at pituitary– ↓ LH concentration 80% within 24 hrs– Adv

1. No flare phenomenon2. Quick to achieve castration level

– Disadv1. Severe allergic reaction in earlier studies2. Shorter injection interval (1 mth)3. Long term efficacy unknown

• Abarelix: phase III RCT – Abarelix vs LHRHa (leuprorelin acetate) [McLeod Urology 2001)– Abarelix vs CAB [Trachtenberg JU 2002]– Metastatic or recurrent CaP– No difference in maintaining castration level and PSA reduction– No flare up phenomenon in abarelix arm– Overall adverse incidence :similar– NO data on survival end-points & long-term safety– FDA 2003: only in metastatic and symnptomatic CaP with no other treatment options available

• Degarelix: phase II RCT [Van Poppel EU 2008]– Monthly SC formulation– Standard dosing: 1st month 240mg, then 80mg monthly– Castration achieved in day 3: 95%– No allergic reaction observed– SE: painful injection 40% , after 1st injection

Antiandrogen• Compete with testosterone & DHT at receptor level in

prostate cell• Oral compound , classified according to chemical structure• Steroidal AA have progestational properties central

inhibition of pituitary gland lower testosterone• Non-steroidal AA dose not testosterone normal or

elevated [purely as competitors of androgen at receptor level]

• Steroidal Anti-androgens1. Cyproterone acetate (CPA) [Androcur] 100mg BD/TDS ,

inferior to LHRHa ,SE: CVS & hepatotoxicity2. Megestrol acetate and Medroxyprogesterone acetate (poor

efficacy not use)

• Non-steroidal anti-androgens1. Nilutamide 100mg TDS : as 2nd line in HRPC SE: interstitial penumonitis2. Flutamide 250mg TDS PO: for CAB, poor as mono in PSA> 100

SE: diarrhoea & hepatotoxicity1. Bicalutamide 50mg /150mg QD PO (Adv: less GI SE)– No suppression of testosterone preserved libido , overall physical

performance & bone mineral density– Pharmacological SE: similar for all 3 drug

• Gynaecomastia [80%]– imbalance in androgen:oestrogen ratio in breast tissue– Peripheral aromatisation of testosterone to oestradiol– Prevention: 8-10Gy RT to each breast– Txn: Tamoxifen 20mg QD/ bilateral mastectomy

• Breast pain [50%]• Hot flushes [Txn with 50mg BD CPA]

– Non pharmacological SE : Bicalutamide has more safety and tolerability profile than nilutamide & flutamide

– All 3 has liver toxicity : liver enzymes must monitor regularly

Bicalutamide• As monotherapy

– Same efficacy as medical / surgical castration in LA(M0) disease[Tyrrel EU1998]– As an alternative to castration in locally advance disease (M0) or M1 with low PSA if PFS

is target (EAU 2010)– Inferior OS vs medical/surgical castration in M1 disease– Avoid in localized disease

• As Adj to RT in LA disease : Cannot be conclude from the EPCP trial that it is of comparable effect as LHRHa as in the EORTC 22863 trial [EAU 2010]

• Adv1. 150mg daily equal efficacy as castration (Iverson)2. Better QOL in terms of libido & physical capacity (good if want to preserve sex life)3. No bone loss (vs LHRHa)4. Pharmacokinetics not affected by age, renal insufficiency & mod liver impairment

• Disadv1. 50mg daily inferior to castration in survival2. Gynaecomastia & breast pain (70%)3. Worsened survival in localized disease [EPC trail]

ADT• Side effects

1. Loss of libido & ED2. Osteoporosis & fractures (can occur after 1 yr, 50% 10yr)3. Obesity, loss of muscle mass & fatigue4. Hyperlipidaemia & Metabolic syndrome

• Associated with DM & cardiovascular disease (20% ↑ after 1 yr)• ↑ waist circumference, TG, BP, glucose & ↓ HDL cholesterol

5. Gynaecomastia• 70% in bicalutamide• Prevention: RT. Rx: Tamoxifen, mastectomy

6. Hot flushes (60%) 7. Anaemia8. Cognitive decline

ADT: S/E• Osteoporosis & fractures

– Duration dependent (20% risk of # 5yr after ADT [SEER])– ADT ↑ bone turnover & ↓ BMD (3% per yr)– ADT also increase body fat mass (10%) & decrease lean

tissue mass (3%) increase risk of #– 50% ↑ risk of fracture -> ↑ mortality– Pre-ADT DEXA (T score > 2.5 increase risk) – Txn:

• Stop smoking, Vit D, Calcium• weight-bearing exercise• Bisphosphonate: Zoledronic acid ↑ BMD of hip (4%), spine

(7%) (Smith)• Monoclonal Ab: Denosumab

Immediate vs delayed ADT in advance CaP• Immediate ADT [Preferred]

– Inclusion• Symptomatic M1• Optional in asymptomatic M1

– Adv1.Reduce & delay disease progression, their Cx & hence QOL (MRC 97)

– Bone pain, cord compression, Pathological #, ureteric obstruction, TURP (2x less)

2.Improve cancer specific survival (MRC & update by Kirk 04 (15 yr data) (slight adv in M0 disease)

3.If complication arised severe consequence – Disadv

1.No significant improvement in Overall survival (Kirk)– Although initial results showed significant ↑ OS in M0 (MRC)

• Cx of ADT (surgical & medical castration) which ↓ QOL & are potentially fatal

• Cost, & not cost-effective if asymptomatic

What is the role of ADT in CaP?• In localized disease : NO

– Higher mortality in men treated with bicalutamide 150mg vs Placebo [EPC McLeod JU 2004]

– Population observation study: did not improve survival in men with localized CaP, but instead result in worse outcome compare to observation [Wong EU2009]

• In locally advance CaP (T3-4): Immediate or deferred?– Immediate: YES

• Increase OS , but not CSS or symptom free survival [Studer EORTC 30891 2006]

• Less progression , metastasis pain and related event [MRC 1997]• Better PFS & improve OS in RT subgrp with early treatment [EPC Iverson

2006]

Immediate vs delayed ADT• Delayed ADT

– Inclusion• Asymptomatic M1

– Adv1.Avoid Cx of ADT e.g. libido, erectile function preserved2.No significance difference in overall survival (MRC update by

Kirk, VACAUG 1)3.↓ Cost

– Disadv• More no. (2x) & more rapid progression, its Cx & hence ↓ QOL

(MRC) if complication happen it will be worse• Reduce cancer specific survival (MRC & Kirk)

Immediate vs delayed ADT• MRC trial PR03

– RCT, BJU 1997– 934 pts with locally advanced or asymptomatic metastatic CaP– Started in 1985 – Immediate (BSO/ LHRHa) vs delayed ADT– Annual information enquiry on progression, Cx & death

• Limitation1. 6% (29 of 465) in delayed ADT received no ADT before death

(delayed not same as no ADT)2. Staging of any metastasis unknown in 173 pts

• May affect outcome

3. ADT started only when cord compression or pathological # in 10% of delayed ADT gp

4. Lack of standardized FU protocol

Immediate vs delay: Conclusion• There is no question that early ADT delays biochemical and clinical

disease progression, but the effects of early ADT on survival remain unclear

• there is no question that ADT is indicated in symptomatic, metastatic disease

• Against immediate: – Course of CaP:

• biochemical recurrence after radical prostatectomy, the median time from recurrence to metastasis was 8 years and from metastasis to death, 5 years ( Pound et al, 1999 ).

– despite dramatic clinical responses, men undergoing ADT either will die of a non–prostate cancer cause (estimated at 20% on the basis of the CAB meta-analysis) or will eventually demonstrate evidence of hormone-refractory disease and die of prostate cancer.

– ADT has associated SE– lack of a survival benefit in men treated early [VA study, Byar, 1973]

FU after HT• When to FU?

– FU at 3 & 6 months after initiation of hormonal treatment– Good treatment response:

• symptomatic improvement • good psychological coping• good treatment compliance• PSA< 4ng/ml

– Stage M0: every 6m in good response, Stage M1: every 3-6m in good response– Castration-refractory CaP: individualized FU scheme– Pt must be informed on clinical symptoms of spinal cord compression , anemia and etc – Clinical progression occur after median of 12-18months in M1 disease

• How to FU?– PSA PSA <0.2ng/ml has best survival compare with those of 0.2-4ng/ml or > 4ng/ml– Bld test: Cr (upper tract obstruction), Hb (Aneamia in 20%), LFT, Bone Sp ALP– Testosterone monitoring

• 1m after LHRHa: check nadir testosterone level • 6m : evaluated effectiveness of txn and to ensure castration level is maintained• In pt with rising PSA/ clinical progression: to confirmed castrate-resistant state

– Bone scan: not indicated in normal PSA and asymptomatic– USG and CXR: suspected progression– Monitor of metabolic complications: Bone mineral density (DEXA), DM , metabolic syndrome– MAB if 2 consecutive rise of PSA after ADT

MAB or Monotherapy?• Adv of MAB

1. Suppression of all androgen produced by testes & also adrenal gland 2. a small survival advantage (< 5%) versus monotherapy3. ↑ progression-free survival & OS in a few RCT (Crawford), but..

• Disadv1. Gastrointestinal, ophthalmological, and haematological side-effects are worse with CAB.2. No benefit in OS in other RCTs (Eisenberger) 3. Only small absolute (interms of months)↑ (3%) OS after 5 yr in meta-analysis (PCTCG, Cochrane)4. Improvement in OS appears only after 5 yr5. Survival benefit limited to CAB with non steroidal anti-androgen (PCTCG)6. More S/E of ADT: GI pain, diarrhoea-> ↓ compliance (Cochrane)7. ↑ Cost

• Conclusion [Campell]: On the basis of a large meta-analysis of many clinical trials, combined androgen blockade with nonsteroidal antiandrogens provides about a 3% survival benefit at 5 years compared with standard ADT [PCTCG]

• Ev1. 3 meta-analysis

1. Prostate cancer Trialists’ Collaborative gp: Lancet 2000. 8275pts, 27 RCT2. Cochrane, 3. Blue Cross & Blue Shield Association

Intermittent vs Continuous ADT• IHT (Intermittent hormonal therapy)

– MOA• Long-term CAB failed to eliminate the entire malignant cell population• Tumor inevitable relapses after average 24 months (12-18) androgen- independent state• Androgen- independent state coincide with cessation of androgen-induced differentiation of stem cells• Postulation: Stopping androgen deprivation prior to progression to AI cells subsequent tumor growth

should still be androgen depend susceptible to once again androgen withdrawal• Thus: intermittency androgen blockade (IAD) would delay the emergence of androgen- independent clone

– Inclusion• Locally advanced or metastatic CaP• Clear PSA response after ADT: PSA<4 in metastatic; <0.5 in relapsed (not clearly defined)• Well informed & compliant

– Regime: Not clear• MAB with 3-9 mth induction• Stop if PSA<4 in metastatic; <0.5 if relapsed• Resume if PSA ≥ 10 or 20 (Abrhamsson) , same txn for 3-6m• Resume cycle until first sign of HR status

– Adv• Comparable efficacy on biochemical progression, PFS & OS (Abrahamsson EU2010) • Better tolerability with ↓ S/E of ADT esp sexual function-> potentially ↑ QOL in off-Rx period (Calais da

Silva EU2009)• ↓ Cost• Delay (3x) progression to androgen independence shown in animal studies• Long term benefit: bone protection , cognitive and mood change, protect against metabolic

syndrome• Testosterone recovery seen in most studies

Intermittent vs Continuous ADT• IHT

– Disadv1. Strict FU with close monitoring in off-Rx period Q3-6mth2. No evidence so far to suggest delay in development of Castration-

resistant state, OS improvement3. S/E may be slow to resolve after stopping ADT because testosterone can

take up to 9 mth to recover

– Ev• Meta-analysis: IHT equally effective in terms of biochemical progression,

PFS & OS, ↑ sexual function (Abrahamsson EU2010)• IHT equally effective in survival, ↑ sexual function, ↓ cost, no clinical

significant ↓ QOL (Calais Da Silva EU2009)– South European Uro-oncological gp (SEUG)– 766pts, largest RCT: IAD: LHRHa + cyproterone, FU 4 yr – Stop if PSA<4 or ↓ ≥80% baseline– Resume if PSA≥10 (symptomatic), ≥ 20 (asymptomatic)– Median time off-Rx: 1 yr

Relapse after definitive Rx

• After RP– Def: 2 consecutive PSA≥0.2 ng/ml– TRUS Bx of VU anastomosis low sn & low predictive accuracy– CT & bone scan no value unless PSA>20 or PSAV>2ng/ml/yr

• After RT– Def: PSA rise 2ng/ml above nadir (Phoenix 06)– Confirmed by Bx if salvage therapy planned

Post RP Local Distant

Onset of ↑ PSA >2 yr <2 yr

PSADT >1 yr <6 mth

PSA velocity <0.75 >0.75

P-stage

Gleason score

Castration resistant CaP• Definition

1. Serum castration level of testosterone (<50ng/dL or <1.7nmol/L)2. 3 consecutive ↑ of PSA, 1 week apart, with two 50% increase above nadir,

with a PSA>2 ng/mL3. Anti-androgen withdrawal for ≥ 4 weeks; or One secondary hormonal

manipulation4. PSA progression, despite consecutive hormonal manipulations5. Progression of osseous lesions

• (progression or appearance of ≥2 lesions on bone scan or soft tissue lesions using RECIST & LN≥2cm)

• Mechanisms1. Androgen-receptor (AR) dependent mechanism

• AR amplification, mutation & overexpression• Ligand independent activation of AR by growth factors & cytokines e.g. epidermal

growth factor, VEGF2. Androgen-receptor independent mechanism that bypass AR

• Associated with inhibition of apoptosis due to overexpression of oncogenes e.g. bcl-2 & mutation of tumour suppressor gene p53

• Proliferation of androgen-independent clones

• Castration resistant: – Resistant to castration but still hormonal sensitive (e.g MDV3100,

CYP17 inhibitor)• Hormonal resistant:

– Resistant to all hormonal measures• Assessment of Txn outcome in CRPC

– Evaluation of treatment response in solid tumors : RECIST Group (but 80% no measureable disease)

– To monitor bone metastasis– PSA level:> 50% of PSA decline from pre-treatment PSA signify

survival advantage– OS as a more valid end point– Pain reduction– Other marker: circulating tumor cell count , RT-PCR

Should we continue ADT in CRPC?

• Continue androgen supression in CRPC has minimal overall effect

• Yes: Lower survival rate in pt without CAB [Manni JCO 1988]

• No: Marginal benefit for pt remaining on LHRHa during 2nd or 3rd line therapies [Hussain JCO 1994]

• Conclusion: ADT should be continued indefinitely in CRPC patients

Castration resistant CaP• Natural Hx

– Minimal metastases: 1.5 yr (both asymp & symptomatic)– Extensive metastases: within 1 yr

Adrenal androgen blockers• Adrenal glands secrete 5-10% of androgen• Further decrease in androgen by bilateral adrenalectomy/ drug inhibiting

adrenal steroidogenesis• Aminoglutetamide

– Blocks conversion of cholesterol pregenolone– Inhibits: testicular & adrenal androgen , aldostreone, cortisol and estrogen– Replacement glucosteroid must be given to avoid cortisol insufficiency– Overall response rate: 10%– Side effect: fatigue , rash , drowsiness, orthostatic HT & ataxia

• Ketoconazole: – Synthetic compound that effect the C17-20 lyase biosynthesis in adrenal– Suppress both adrenal and testicular androgen production– Response rate: 15% – In pt with progression despite androgen withdrawal : response rate 75%– Side effect: fatigue & nausea

• Low dose corticosteroid (prednisone): – Inhibit hypothalamic secretion of ACTH by –ve feedback mechanism– Result in diminish adrenal androgen production– PSA response: 20%

• With additional of ketoconazole to anti-androgen withdrawal: increase PSA response (32% vs 11%)

Castration resistant CaP: Management• Aim

– Palliative: Counseling & QOL important– Multidisciplinary approach

• Oncologists, urologists, nurses, psychologists, social workers– Prevent & treat Cx

• Obstructive uropathy• Spinal cord compression/ pathological #

– Bisphosphonates– Bone targeting agent: Denosumab

• Monoclonal Ab inhibit osteoclast activity-> ↑ BMD, ↓ # (RCT, Smith)

– Palliate symptoms• Bone pain

– ↑ survival• Chemo, Sipuleucel-T

Castration resistant CaP: Management• Management

1. Continue androgen suppression with LHRHa (improve survival, RCT, Manni)2. 2nd & then 3rd line hormonal therapy

• Addition / replacement of anti-androgen : Casodex 150mg 20% PSA response • Switching to alternative anti-Andrgen : flutamide to casodex or VV : 35% PSA

response• Anti-androgen withdrawal: 30% PSA response for 3 mth• Adrenolytic agents e.g. ketoconazole & steroids: 25% PSA response for 4 mth• Oestrogens e.g. Diethylstilboestrol• Novel anti-androgen: MDV3100: block AR transfer to nucleus, 50% respond if chemo-

refractory• Abiraterone acetate: improve OS after docetaxel [NEJM 2011]

3. Cytotoxic chemotherapy• Inclusion: Symptomatic metastatic CRPC• Contraindications: Poor performance status, renal failure or haematological

abnormalities (correct first)• Docetaxel-based chemo ↓ pain & ↑ OS by 2 mth vs mitoxantrone + prednisolone

(Tannock, TAX327 NEJM2004 )4. Non-cytotoxic drugs

• Immunotherapy: Sipuleucel-T (Provenge)1. A dendritic cell-base therapeutic vaccine to stimulate T cell immunity against prostatic acid

phosphatase2. Antigen presenting cells isolated from pts plasma, activated & cause T cell immunity against PAP3. Well tolerable & ↑ OS by 4 mth vs placebo (IMPACT, Kantoff)

Cytotoxic Agent

TAX327 NEJM2004

Cytotoxic agents• Significant improvement in median survival of about 2 months seen in docetaxel-

base chemotherapy (with pred or EMP) vs mitoxantrone + prednisolone • Pain relief was similar but side effects of Gd 3-4 neutropenic fever, nausea ,

vomiting , CVS events more often with docetaxel • Base on 2 study in NEJM 2004: TAX 327 & SWOG 99-16

Timing of chemo in metastatic HRPC

• Start immeditately in symptomatic patient• Doxetaxel based chemo• 3 weekly (improve OS) or 1weekly (in pt cannot tolerated) as it is more effective

than best supportive care [EU 2007]• Asymptomatic patient: controversial • Poor prognostic factors: base on ASCO 2007 & TAX 327 trial

– PSA > 114ng/ml– PSA DT < 55 days– Presence of visceral metastases – Anemia – Bone scan progression – Prior estramustine before docetaxel

• Good risk (0-1 factor) , intermediate (2 factors) , high risk (3-4 factors)• Median OS: 25 % , 18 % & 13% respectively• Also improved survival if CRP level < 8mg/L • Conclusion: current indication for Chemotherapy in HRPC non-metastatic patient is

inside clinical trials

Side effect of Doxetaxel

• Frequent– Neutropenia– Fatigue– Diarrhoea

• Less common– Anemia & thrombocytopenia– Infection– Hypersensitivity – Fluid retention– With prednisolone: immunosuppression , glucose intolerance

& adrenal suppression

Combination therapy• Docetaxel vs docetaxel + thalidomide

– Chemo-naïve HRPC, 30mg/m2 for 5 of every 6 weeks– Thalidomide 200mg PO daily– No significant difference in PSA response, PFS or OS– Considerable SE : thromboembolic events

• Docetaxel + bevacizumab/ aflibercept / sunitinib or dasatinib

Mitoxatrone + corticosteroid• CALGB 9182 study: [Kanthoff JCO 1999]

– 244 pt with symptomatic metastatic HRPC – Mitoxantrone + hydrocotisone vs hydrocortisone alone– No difference in PSA response , PFS, OS– QoL significantly improved in combination arm

• QoL was improved due to pain reduction

Estramustine combination• Estramustine target microtubule action• Estramustine + vinblastine:

– Significant PSA & measureable response– Higher PSA response & time to progression– NO benefit in median survival

• Meta-analysis: Meta-analysis of Estramustine in Prostate Cancer (MECaP) Trialists [Lancet oncology 2007]: increase time to PSA progression and OS

• SE: thromboembolic (7%)

What can we give after doxetaxal ?• Cabazitaxel + prednisone

– Cabazitaxel arm : increase OS, PFS, PSA response rate– 30% reduction in risk of death– More hematological toxicities: grade 3–4 neutropenia was 22% in

the TAX327 study compared with 58% in TROPIC– TROPIC trial: [Bono 2010 Lancet]

• MDV3100: – MOA: blocks AR transfer to the nucleus, no agoinst-like activity– ASCO 2009, phase I/II trial: [Scher JCO 2009]

• 140 CRPC pt• PSA response : 57% chemo-navie, 45% chemo-refractory pt

– Current Phase III trial: pending• Abiraterone:

– Better PSA response rate, PFS, OS (5m)– COU-AA-301 [Bono NEJM 2011]

• COU-AA-301 [Bono NEJM 2011]• Abiraterone Acetate (AA): Inhibitor of androgen biosynthesis• To evaluated whether AA prolongs OS in CRPC + post chemotherapy patient• 1195pt, previous docetaxel recipient• Abiraterone acetate (1000mg) + prednisone 5mg vs placebo + prednisone 5mg• FU: median 12.8m• Result: AA able to achieved longer

– OS (15m vs 10m)– Time to PSA progression (10m vs 6.6m)– Progressive free survival (5m vs 3m) – PSA response rate (29% vs 6%)

• SE: fluid retention , HT, hypo K were more in AA gp as well

Tumor vaccines: Spiuleucel- T• Sipuleucel-T (Provenge) [APC 8015 : JCO 2006]

– 127 CRPC pt– Provenge vs placebo– Significant difference in OS

• Autologous peripheral mononuclear blood cell (PMBCs), including APC

• Culture ex-vivo and activated by exposure to remobinant antigen PA2024

• PA2024: 2 part– Prostatic acid phosphatase (attach to CaP)– Granulocyte-macrophage colony-stimulating factor that active the immune

cell • Administration: IV infusion every 2 week for 3x• Result: patient treated with Spiulecucel-T vs Placebo

– 22.5% reduction in risk of death– 4 month improvement in median survival (25m vs21)

• Common side effect: – Chills , pyrexia– Headache and myalgia

Metastatic bone pain• Management

1. Analgesics e.g. NSAID, opiate2. EBRT when pain is localized3. Radionucleide therapy

• Strontium 89 for widespread disease -> emit high energy radiation which deposit in bone

4. Bisphosphonate5. Steroids

Bisphosphonate• Drug: Pamidronate, alendronate , zoledronic acid (3rd gen) (4 mg IV/month) • MOA:

– Inhibit osteoclast mediated bone resorption – increase BMD in hip and spine (7% in 1yr)– Prevent bone loss asso with normal ageing process

• Inclusion:– NCCN: recommend for ADT-related bone loss & bone met in CaP, – Initial BMD guide choice of regimen: e.g 3monthly injection in osteoporotic pt– 3 weekly injection (more common) vs annual injection (inconsistent result)

• CI: – Renal impairment – Hypocalcaemia

• Monitor: periodic bone densitometry to assess BMD• Results: Zoledronic acid for 15m vs placebo [Saad JNCI 2004]

1. Prevent skeletal related events (33% vs 44%): spinal cord compression, need of surgery and palliative RT2. Increase BMD & Reduce pathological fracture (13% vs 22%)3. Prolong time to skeletal event 4. Decrease bone pain in 80%5. Increase QOL – On-going trail ZEUS trial [Effectiveness of Zometa® treatment for the prevention of bone metastases in

high risk prostate cancer patients ] (Zomaril Efficacy/Utility & Safety Trial)• Side effects:

– Pamidronate: Arthralgia & fever (actue phase rxn)– Zoledronic acid: Renal impairment – Jaw necrosis: Risk factors: Dental pathology, surgery & infection, trauma, dentures, long term iv

bisphosphonate

Smith NEJM 2009• Denosumab : Fully human monoclonal antibody against RANKL • Mediator for osteoclast fxn, activation and survival• 1468 men, non-met CaP with ADT• Denosumab 60mg SC Q6m vs Placebo• Result: Denosumab is asso with

– Increase BMD in lumbar (5.6%vs 1 %)– Increase BMD also in hip, FN & distal radius– Less vertebral fracture: 1.5% vs 3.9% p=0.006– Benefit shown irrespective of : age, duration of ADT, initial BMD, BMI– NO significant different in toxicity (no jaw necrosis /delay healing of vertebral

fractures)