Ahmed Zeeneldin
¨ Cancer: An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
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AnatomyAnatomy1. Position
2. 5 Lobes: • Ant,
• Post : cancer
• Median: BPH
• 2 Laterals
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A: normal B: BPHC: intraepitjrlial neoplasia D: Prostatic Adeno CANB: IHC of p501s
Tumor Grade Gleason’s GradeG1: Well differentiated (slight anaplasia) 2-4G2: Moderately differentiated (moderate anaplasia) 5-6G3: Poorly differentiated (severe anaplasia) 7-8G4: undifferentiated (marked anaplasia) 9-10
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¨ The sum of first and second most common tumor pattern
¨ G pattern of 1st + G pattern of 2nd
¨ Min: 2 Max: 10
¨ Prognostication, the higher the worse
¨ GS=7: 3+4 > 4+3
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1 2 3 4 51 223 74 75 10
Pattern 1
Pattern 2
T1 T2 T3 T4 N1 M1
Clinically inapparent
T1A: incidental <=5% of TURP
T1B: incidental >5% of TURP
T1C: +ve FNA due to + PSA
Confined to prostate(clinical, imaging)
T2A: <=½ of one lobe
T2B: >½ of one lobe
T2C: both lobes
Extends through the
prostatic capsule
T3A: capsule only
T3B: seminal vesicle
Fixed or invades adjacent
structures
organs, muscles, bones
Regional LN
M1a: non-regional LN
M1B: bone
M1C: others
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T1a T1b,c T2 T3 T4N0M0 G1: I
G2-4: IIII II III IV
N1 and /or M1 IV IV IV IV IV
¨ Clinically Localized: T1-3a, N0M0¡ Low: ALLú Very low: as Low + T1a + PSA desity: <0.15 ng/mL/g + Fewer than 3 biopsy cores
positive, 50% cancer in each core¡ intermediate: One*¡ high-risk: One*¡ If more than one move to the next higher category
¨ Locally advanced : T3b-4, N0M0 ¡ very high-risk
¨ Metastatic: any T, N1 and or M1
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LOCALIZED Locally advanced
Metastatic
Risk Low Intermediate High Very high Extremely high
N/M N0M0 N0M0 N0M0 N0M0 N1/M1
T 1-2a AND 2b,2c OR 3a OR 3b-4
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA (ng/mL) <10 AND 10-20 OR >20 OR
¨ PSA¨ DRE
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¨ In 2008:¡ 25% of Men cancer
¡ 29,000 deaths
¨ PSA screening:¡ Detect early stage
(asymptomatic, localized)
¡ and low-risk disease
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¨ Options¡ Active surveillance
¡ Surgery
¡ Radiotherapy (RT)
¡ Systemic therapy
¨ Treatment depends on:¡ Life expectancy
¡ Stage
¡ PSA
¡ Gleason’s score
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¨ Possible for groups & challenging for individuals
¨ Social Security Administration tables¡ http://www.ssa.gov/OACT/STATS/table4c6.html
¨ Adjusted to the health status 66+16 =92¡ Best quartile of health - add 50% 66+16+6=98
¡ Worst quartile of health - subtract 50% 66+16-6=88
¡ Middle two quartiles of health - no adjustment 66+16 =92
¨ LE: < 5y: no treatment unless symptomatic or high-risk
¨ LE:<10y no surgery LE>10y: best therapy
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¨ Clinically Localized: T1-3a, N0M0¡ Low: ALLú Very low: as Low + T1a + PSA desity: <0.15 ng/mL/g + Fewer than 3 biopsy cores
positive, 50% cancer in each core¡ intermediate: One*¡ high-risk: One*¡ If more than one move to the next higher category
¨ Locally advanced : T3b-4, N0M0 ¡ very high-risk
¨ Metastatic: any T, N1 and or M1
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LOCALIZED Locally advanced
Metastatic
Risk Low Intermediate High Very high Extremely high
N/M N0M0 N0M0 N0M0 N0M0 N1/M1
T 1-2a AND 2b,2c OR 3a OR 3b-4
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA (ng/mL) <10 10-20 >20
Treatment PR or RT RP or RT RT+ ADT RT+ADT ADT+/-RT
¨ Surgery: radical prostatectomy¨ RT: EBRT and Brachytherapy¨ Systemic therapy:
hormonal therapy or chemotherapy¡ Hormonal therapy: ú Orchiectomy, LHRLú Ani-androgensú Fenasterideú Combinations ADT: two or three
¡ Chemotherapy:ú Mitoxantrone & steroidsú paclitaxel
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¨ Prostate and seminal vesicles are removed
¨ Pelvic LNs can also removed.
¨ The urethra is joined to the bladder.
¨ Impotence: cavernous N¨ No ejaculation¨ Indications: localized
LR, IR (T1-T2) with life expectancy > 10years
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¨ EBRT (3D, IMRT):¡ 70-79 GY (8-9 w)¡ Localized (LR, IR, HR) &
locally advanced¨ Brachytherapy:
¡ 125-145 GY (once)¡ LLR
¨ Combined (EB->BR):¡ LIR
¨ PALLIATIVE RT:¡ Prostate¡ bone
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Surgery RT
Radical prostatectomy
EBRT (3D, IMRT: 70-80Gy)
Bleeding andtransfusion-related effects
Possible No
Anesthesia ( myocardial infarction and pulmonary embolus
Possible No
urinary incontinence and stricture (Urethera) More Very low
preservation of erectile functionCavernous ns
Less More
RT complications:Bladder or bowel symptoms
No Yes 8-9 weeks course
Indication T2, Life expect> 10y
Any TAny Life expect
Salvage RT Surgery (difficult)
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¨ Castration:¡ Surgical: orchiectomy¡ Medical: LHRH
¨ Combined androgen blockage (AB):¡ Castration+antiandrogen
¨ Triple AB¡ Castration+antiandrogen
+5aReductase inhibitor
¨ NB: LHRH cause initial flare, premedicate with anti-androgen for 7 days
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¨ Suppress testosterone levels to castrate level (< 50 ng/mL)¡ With surgical castration this can take few weeks¡ With medical castration (LHRH) this takes longer (several
weeks)¡ If this not achieved, we add antiandrogens, estrogens or
steroids ¨ With LHRH: there is initial surge in FSH and LH by
pituitarty (LHRH is agonist/antagonist) leading to surge in testosterone that can lead to tumor flare (clinically (pain, obstruction) and radiologically). This flare can last for a week¡ To avoid flare use androgen receptor blocker for a week before
and few weeks during LHRH (Bicalutamide 150 mg)¨ Rapid fall and undetectable PSA is of good prognosis
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¨ Combined or triple androgen blockage provides no proven benefit over castration alone¡ Meta-analysis showed:ú No OS benefit at 2 yearsú 2-3% increase in OS at 5 yearsú Combinations are better reserved for resistance
¨ Antiandrogen monotherapy appears to be less effective than castration, with the possible exception of patients without overt metastases (M0).
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¨ Primary for metastatic disease: immediate therapy
¨ With Definitive RT:¡ Localized high-risk¡ Locally advanced¡ Timing:ú Before RT: neo-adjuvantú During: concomitantú After: adjuvant
¨ Aim: early ADT delays mets and symptoms
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¨ Localized disease (T1-3a, N0M0):¡ VLR: LE< 20 Y à active surveillance (PSA q 6m, DRE q 12 m): 2010 update¡ LR: RT (EB=BT) or Surgery¡ IR: RT (+/- ADT NCA x 4-6 months) or Surgery¡ HR: RT + ADT (Neoadj/conccurrent/adjuvant =NCA) x 2-3 years
¨ Locally advanced disease (T3b-T4, N0M0):¡ RT + ADT (NCA) x 2-3 yearsú N=2m C=2m A=rest
¨ Metastatic disease (any T, N1/M1):¡ Local therapy; RT¡ Systemic therapy: ú hormonal àchemo
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LOCALIZED Locally advanced
Metastatic
Risk Low Intermediate High Very high Extremely high
N/M N0M0 N0M0 N0M0 N0M0 N1/M1
T 1-2a AND 2b,2c OR 3a OR 3b-4
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA (ng/mL) <=10 <=20 >20
Treatment PR or RT RP or RT+/-ADT 6m RT+ ADT 2-3y
RT+ADT 2-3y
ADT+/-RT
Surgery (RP) RT
N 2254 381Low-Risk 88% 78% (S)
Intermediate-Risk e low tumor volume
79% 65% (S)
Intermediate-Risk e high tumor volume
36% 35% (NS)
High-Risk 33% 40% (S)
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Anthony et al, Cancer. 2002 ;95(2):281-6.RetrospectivePrimary endpoint: 8-y PSA free survival
LOCALIZED
Risk Low Intermediate High
N/M N0M0 N0M0 N0M0
T 1-2a AND 2b,2c OR 3a OR
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA (ng/mL) <=10 <=20 >20
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Low risk and intermediate risk with low biopsy tumor volume
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intermediate risk with high biopsy tumor volume and high-risk
Surgery (RP)
RT Brachytherapy
N 746 340 733
7-y FFBR (NS) 79% 77% 74% (NS)
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Potters et al, Oncol. 2004;71:29-33.Prospective, T1-T2Primary endpoint: (failure from Biochemical Recurrence FFBR)Mono-therapy with no adjuvant ADT
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¨ Survival Following Primary Androgen Deprivation Therapy Among Men With Localized Prostate Cancer
¨ Lu-Yao et al, JAMA. 2008;300:173-181.¨ Age 66 y and T1, T2¨ Orchiectomy or LHRH
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PADT Survillance
N 7867 11,404ALL: 10-y prostate CA specific survival 80% 83% (NS)
ALL: 10-y OS 30% 30% (NS)
Poorly differentiated tumors 10-y PCSS 60% 54% (S)
Poorly differentiated tumors 10-y OS 17% 15% (NS)
¨ McLeod et al, J Urol. 2006;176:75-80.¨ Standard of care (RT, RP (Adj)) -> then¨ Randomization to bicalutamide 150 mg x 2y vs
placebo¨ Localized or locally advanced (adj)¨ N+ not allawed No survillance
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bicalutamide placebo N 1,647 1,645HR PFS = 1 (NS) 15% 15%
HR OS = 1 (NS) 13% 12%
HR PSA progression= 0.84 (S) 32% 38%
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¨ Adverse Effects of ADT:¡ Osteoporosis, sarcopenia ( - mucsle) & - lean BMú Greater incidence of clinical fractures,
¡ Alterations in lipids (+Chol & TG), Obesity, insulin resistance, ú Greater risk for diabetes (+40%) and cardiovascular disease
(coronary +15% and MI + 10%).¡ Screen, prevent and early treat
¨ Side effects are proportional to ADT duration¨ Intermittent ADT
¡ Reduce side effects¡ Same survival effect¡ Unproven long term efficacy
¨ May be considered for those with stable or undetectable PSA
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¨ Options: ¡ Early ADT: may be better¡ Late ADT: acceptable, upon progression
¨ Criteria for early ADT¡ High PSA >50¡ Shorter PSA doubling time (rapid velocity¡ Long life expectancy)
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¨ Messing et al, Lancet Oncol. 2006;7:472-479. ¨ Following RP and Pelvic LND¨ +ve LN¨ Immediate vs delayed ADT
¡ LHRH: goserlin or Orchiectomy (patient choice)
¨ FU 12 years
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Early ADT Delayed ADTN 47 51Improved OS HR = 1.8 (S) 1.8 1
Improved PCSS HR = 4 (S) 4 1
Improved PFS HR = 3 (S) 3 1
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¨ Life expectancy:¡ <5 Y:ú Not high-risk for mets or hydronephrosis AND asymptomatic: Observe till symptoms develop
ú High-risk for mets or hydronephrosis OR symptomatic: ADT or RT
¡ >5Y OR symptomatic:¡ BS and pelvic CT/MRI:ú T3-4: all casesú T1-2: if PSA >20 or GS =>8
¨ Recurrence risk
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LOCALIZED Locally advanced
Metastatic
Risk Low Intermediate High Very high Extremely high
N/M N0M0 N0M0 N0M0 N0M0 N1/M1
T 1-2a AND 2b,2c OR 3a OR 3b-4
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA (ng/mL) 1-2a AND 2b,2c OR 3a OR
¨ LE<10y¡ Active surveillance¡ RT
¨ LE=>10y¡ As above +¡ RP+/- pelvic LND:ú + SM: observe/RTú +LN: observe/ADT
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LOCALIZED Locally advanced
Risk Low Intermediate
High Very high
T 1-2a AND 2b,2c OR 3a OR 3b-4
GS 2-6 AND 7 OR 8-10 OR
PSA <10 10-20 >20
T1 T2 T3 T4
Clinically inapparent
T1A: incidental <=5% of TURP
T1B: incidental >5% of TURP
T1C: +ve FNA due to + PSA
Confined to prostate(clinical, imaging)
T2A: <=½ of one lobe
T2B: >½ of one lobe
T2C: both lobes
Extends through the
prostatic capsule
T3A: capsule only
T3B: seminal vesicle
Fixed or invades adjacent
structures
organs, muscles, bones
¨ Johansson et al, AMA. 2004;291:2713-2719.¨ Prospective, FU 21 years¨ 233 patients, T0-T2 NX M0¨ Untreated and followed up till progression where orchiectomy or estrogens were
given
¨ Most cancers had an indolent course during first 10 to 15 years.¨ The mortality rate was significantly higher (approximately 6-fold)
after 15 years of follow-up when compared with the first 5 years.¨ These findings would support early radical treatment, notably
among patients with an estimated LE>15 years.
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0-15y >15YN 233 49PFS 45% 35%
Prostate cancer specific survival 80% 55%
¨ Bill-Axelson et al, J Natl Cancer Inst. 2008;100:1144-1154.¨ Prospective, RCT, FU 10 years¨ ~700 patients, T0-T2 NX M0
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RP WWN 347 34810 y mortality (due to PC) 137 (47) 156 (68) (NS)
12 y PC mortality (HR = 0.65) 13% 18% (S)
12 y mets (HR = 0.65) 19% 26% (S)
¨ LE<10y¡ Active surveillance¡ RT +/- short term
ADT 4-6 mú Neoadjú Concurrentú adjuvant
¡ RP+/- pelvic LND:ú + SM: observe/RTú +LN: observe/ADT
¨ LE=>10y¡ As above without ¡ Active surveillance
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LOCALIZED Locally advanced
Risk Low Intermediate
High Very high
T 1-2a AND 2b,2c OR 3a OR 3b-4
GS 2-6 AND 7 OR 8-10 OR
PSA <10 10-20 >20
T1 T2 T3 T4
Clinically inapparent
T1A: incidental <=5% of TURP
T1B: incidental >5% of TURP
T1C: +ve FNA due to + PSA
Confined to prostate(clinical, imaging)
T2A: <=½ of one lobe
T2B: >½ of one lobe
T2C: both lobes
Extends through the
prostatic capsule
T3A: capsule only
T3B: seminal vesicle
Fixed or invades adjacent
structures
organs, muscles, bones
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DFCI EBRT EBRT+ 6M ADTUnfavourable localized
All cause Mortality (HR) (S) 1.8 1
RTOG 9610 EBRT EBRT+3MADT
EBRT+6MADT
(locally advanced)
HR: LF/BFFS/DFS (S) 1 .56/.7/.65 .42/.58/.56
HR: DF/PCSS (S) 1 NS .67/.56
RTOG 8610 EBRT EBRT+ 4mADT
(bulky T2-4 [5cm]/ LN + or -)
10 y OS (Median OS) 34% (8y) NS 43% (9y)
10y DFS 3% (S) 11%
10y D Sp Mortality/mets/BF 36/47/80% (S) 23/35/65%
Goserlin (3.6 mg SC M)+ flutamide (250 x3xd PO)
1. Clin Oncol. 2008;26:585-591.x 2 m before 2m concurrent
2. Lancet Oncol. 2005 ;6(11):841-50.
x 2 m before 1m concurrent
X 5 m before 1m concurrent
3. JAMA.2008;299:289-295.
¨ RT + long term ADT (2-3y) ú Neoadjú Concurrentú adjuvant
¨ RT + short term ADT (4-6m): single HR factor
¨ RP+pelvic LND (if possible):ú + SM: observe/RTú +LN: observe/ADT
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LOCALIZED Locally advanced
Risk Low Intermediate
High Very high
T 1-2a AND 2b,2c OR 3a OR 3b-4
GS 2-6 AND 7 OR 8-10 OR
PSA <10 10-20 >20
T1 T2 T3 T4
Clinically inapparent
T1A: incidental <=5% of TURP
T1B: incidental >5% of TURP
T1C: +ve FNA due to + PSA
Confined to prostate(clinical, imaging)
T2A: <=½ of one lobe
T2B: >½ of one lobe
T2C: both lobes
Extends through the
prostatic capsule
T3A: capsule only
T3B: seminal vesicle
Fixed or invades adjacent
structures
organs, muscles, bones
¨ Bolla et al, N Engl J Med. 1997 Jul 31;337(5):295-300.¨ Prospective, RCT, FU 7 years¨ ~415patients, locally advanced ¨ RT vs RT+ Goserlin x 3y starting with RT¨ cyproterone acetate (150 mg orally per day) during the first month of treatment to
inhibit the transient rise in testosterone
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EBRT EBRT+2y LHRH
5y OS 79% 62% (S)
5yDFS 85% 48% (s)
cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone
¨ long term ADT alone:¡ N1 and M1
¨ RT + short term ADT (4-6m)¡ N1 only not in M1 ¡ Neoadj¡ Concurrent¡ Adjuvant
¨ RP+pelvic LND (if possible):¡ Not in M1¡ + SM: observe/RT¡ +LN:
observe/ADT
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LOCALIZED Locally advanced
Metastatic
Risk
Low Intermediate
High Very high N1/M1
T 1-2a AND
2b,2c OR
3a OR
3b-4
GS 2-6 AND
7 OR
8-10 OR
PSA <10 10-20 >20
T1 T2 T3 T4
Clinically inapparent
T1A: incidental <=5% of TURP
T1B: incidental >5% of TURP
T1C: +ve FNA due to + PSA
Confined to prostate(clinical, imaging)
T2A: <=½ of one lobe
T2B: >½ of one lobe
T2C: both lobes
Extends through the
prostatic capsule
T3A: capsule only
T3B: seminal vesicle
Fixed or invades adjacent
structures
organs, muscles, bones
¨ Used in¡ Low risk regardless of LE¡ Intermediate risk with LE<10y¡ Not undifferentiated tumors even if risk is low or
intermediate¡ Not in high or very high risk or mets
¨ Protocol:¡ PSA: q 3-6m¡ DRE: q6-12m¡ Repeat biopsy q 12 m¡ Less intense if LE<10y
¨ Upon progression:¡ RT or RP
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LOCALIZED
Risk Low Intermediate
High
T 1-2a AND 2b,2c OR 3a OR
GS 2-6 AND 7 OR 8-10 OR
PSA <10 10-20 >20
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