Comprehensive overview of Prostate Cancer: staging, diagnosis, risk stratification and treatment

1. Ahmed Zeeneldin

2. ¨ Cancer: An abnormal growth of cells which tend to
proliferate in an uncontrolled way and, in some
cases, to metastasize (spread).
Ahmed Zeeneldin 2

3. Anatomy
1. Position
2. 5 Lobes:
• Ant,
• Post : cancer
• Median: BPH
• 2 Laterals
Ahmed Zeeneldin 3

4. A: normal B: BPH
C: intraepitjrlial neoplasia D: Prostatic Adeno CA
NB: IHC of p501s
Ahmed Zeeneldin 4

5. Tumor Grade Gleason’s Grade
G1: Well differentiated (slight anaplasia) 2-4
G2: Moderately differentiated (moderate anaplasia) 5-6
G3: Poorly differentiated (severe anaplasia) 7-8
G4: undifferentiated (marked anaplasia) 9-10
Ahmed Zeeneldin 5

6. Ahmed Zeeneldin 6

7. ¨ The sum of first and
second most common
tumor pattern
¨ G pattern of 1st +
G pattern of 2nd
Pattern 1
¨ Min: 2 Max: 10
1 2 3 4 5
¨ Prognostication, the 1 2
higher the worse 2
¨ GS=7: 3+4 > 4+3 3 7
4 7
Pattern 2
5 10
Ahmed Zeeneldin 7

8. T1 T2 T3 T4 N1 M1
Clinically Confined to Extends Fixed or Regional
inapparent prostate through the invades LN
(clinical, prostatic adjacent
imaging) capsule structures
M1a: non-
T1A: incidental
<=5% of TURP T2A: <=½ of T3A: capsule organs, regional LN
one lobe only muscles, bones
T1B: incidental M1B: bone
>5% of TURP T2B: >½ of one
lobe T3B: seminal M1C: others
T1C: +ve FNA vesicle
due to + PSA T2C: both
lobes
Ahmed Zeeneldin 8

9. T1a T1b,c T2 T3 T4
N0M0 G1: I II II III IV
G2-4: II
N1 and /or M1 IV IV IV IV IV
Ahmed Zeeneldin 9

10. ¨ Clinically Localized: T1-3a, N0M0
¡ Low: ALL
ú 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
LOCALIZED Locally Metastatic
advanced
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
Ahmed Zeeneldin 10

11. ¨ PSA
¨ DRE
Ahmed Zeeneldin 11

12. ¨ In 2008:
¡ 25% of Men cancer
¡ 29,000 deaths
¨ PSA screening:
¡ Detect early stage
(asymptomatic, localized)
¡ and low-risk disease
Ahmed Zeeneldin 12

13. ¨ Options
¡ Active surveillance
¡ Surgery
¡ Radiotherapy (RT)
¡ Systemic therapy
¨ Treatment depends on:
¡ Life expectancy
¡ Stage
¡ PSA
¡ Gleason’s score
Ahmed Zeeneldin 13

14. ¨ 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
Ahmed Zeeneldin 14

15. ¨ Clinically Localized: T1-3a, N0M0
¡ Low: ALL
ú 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
LOCALIZED Locally Metastatic
advanced
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
Ahmed Zeeneldin 15

16. ¨ Surgery: radical prostatectomy
¨ RT: EBRT and Brachytherapy
¨ Systemic therapy:
hormonal therapy or chemotherapy
¡ Hormonal therapy:
ú Orchiectomy, LHRL
ú Ani-androgens
ú Fenasteride
ú Combinations ADT: two or three
¡ Chemotherapy:
ú Mitoxantrone & steroids
ú paclitaxel
Ahmed Zeeneldin 16

17. ¨ 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
Ahmed Zeeneldin 17

18. ¨ 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
Ahmed Zeeneldin 18

19. Surgery RT
Radical EBRT (3D, IMRT:
prostatectomy 70-80Gy)
Bleeding and Possible No
transfusion-related effects
Anesthesia ( myocardial infarction and Possible No
pulmonary embolus
urinary incontinence and stricture (Urethera) More Very low
preservation of erectile function Less More
Cavernous ns
RT complications: No Yes
Bladder or bowel symptoms 8-9 weeks course
Indication T2, Any T
Life expect> Any Life expect
10y
Salvage RT Surgery (difficult)
Ahmed Zeeneldin 19

20. ¨ 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
Ahmed Zeeneldin 20

21. Ahmed Zeeneldin 21

22. ¨ 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
Ahmed Zeeneldin 22

23. ¨ Combined or triple androgen blockage
provides no proven benefit over castration
alone
¡ Meta-analysis showed:
ú No OS benefit at 2 years
ú 2-3% increase in OS at 5 years
ú 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).
Ahmed Zeeneldin 23

24. ¨ Primary for metastatic disease: immediate
therapy
¨ With Definitive RT:
¡ Localized high-risk
¡ Locally advanced
¡ Timing:
ú Before RT: neo-adjuvant
ú During: concomitant
ú After: adjuvant
¨ Aim: early ADT delays mets and symptoms
Ahmed Zeeneldin 24

25. ¨ 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 years
ú N=2m C=2m A=rest
¨ Metastatic disease (any T, N1/M1):
¡ Local therapy; RT
¡ Systemic therapy:
ú hormonal àchemo
LOCALIZED Locally Metastatic
advanced
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 RT+ADT 2- ADT+/-RT
2-3y 3y
Ahmed Zeeneldin 25

26. Anthony et al, Cancer. LOCALIZED
2002 ;95(2):281-6. Risk Low Intermediate High
Retrospective N/M N0M0 N0M0 N0M0
T 1-2a AND 2b,2c OR 3a OR
Primary endpoint: 8-y
Gleason’s Score 2-6 AND 7 OR 8-10 OR
PSA free survival PSA (ng/mL) <=10 <=20 >20
Surgery (RP) RT
N 2254 381
Low-Risk 88% 78% (S)
Intermediate-Risk e low tumor 79% 65% (S)
volume
Intermediate-Risk e high tumor 36% 35% (NS)
volume
High-Risk 33% 40% (S)
Ahmed Zeeneldin 26

27. Low risk and intermediate risk with low biopsy tumor volume
Ahmed Zeeneldin 27

28. intermediate risk with high biopsy tumor volume and high-risk
Ahmed Zeeneldin 28

29. Potters et al, Oncol. 2004;71:29-33.
Prospective, T1-T2
Primary endpoint: (failure from Biochemical Recurrence
FFBR)
Mono-therapy with no adjuvant ADT
Surgery RT Brachytherapy
(RP)
N 746 340 733
7-y FFBR (NS) 79% 77% 74% (NS)
Ahmed Zeeneldin 29

30. Ahmed Zeeneldin 30

31. ¨ 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 PADT Survillance
N 7867 11,404
ALL: 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)
Ahmed Zeeneldin 31

32. ¨ 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
bicalutamide placebo
N 1,647 1,645
HR PFS = 1 (NS) 15% 15%
HR OS = 1 (NS) 13% 12%
HR PSA progression= 0.84 (S) 32% 38%
Ahmed Zeeneldin 32

33. Ahmed Zeeneldin 33

34. ¨ Adverse Effects of ADT:
¡ Osteoporosis, sarcopenia ( - mucsle) & - lean BM
ú 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
Ahmed Zeeneldin 34

35. ¨ 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)
Ahmed Zeeneldin 35

36. ¨ 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
Early ADT Delayed ADT
N 47 51
Improved OS HR = 1.8 (S) 1.8 1
Improved PCSS HR = 4 (S) 4 1
Improved PFS HR = 3 (S) 3 1
Ahmed Zeeneldin 36

37. Ahmed Zeeneldin 37

38. ¨ 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 cases
ú T1-2: if PSA >20 or GS =>8
¨ Recurrence risk
LOCALIZED Locally Metastatic
advanced
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
Ahmed Zeeneldin 38

39. T1 T2 T3 T4
¨ LE<10y
¡ Active surveillance Clinically
inapparent
Confined to
prostate
Extends
through the
Fixed or
invades
(clinical, prostatic adjacent
¡ RT T1A: incidental
imaging)
T2A: <=½ of
capsule
T3A: capsule
structures
<=5% of TURP one lobe only
T1B: incidental T2B: >½ of one organs,
LE=>10y
>5% of TURP lobe T3B: seminal muscles, bones
¨ vesicle
T1C: +ve FNA T2C: both lobes
¡ As above + due to + PSA
¡ RP+/- pelvic LND: LOCALIZED Locally
advanced
ú + SM: observe/RT
ú +LN: observe/ADT Risk Low Interm High Very high
ediate
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
Ahmed Zeeneldin 39

40. ¨ 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.
0-15y >15Y
N 233 49
PFS 45% 35%
Prostate cancer specific survival 80% 55%
Ahmed Zeeneldin 40

41. ¨ Bill-Axelson et al, J Natl Cancer Inst. 2008;100:1144-1154.
¨ Prospective, RCT, FU 10 years
¨ ~700 patients, T0-T2 NX M0
RP WW
N 347 348
10 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)
Ahmed Zeeneldin 41

42. T1 T2 T3 T4
¨ LE<10y
¡ Active surveillance Clinically
inapparent
Confined to
prostate
Extends
through the
Fixed or
invades
(clinical, prostatic adjacent
¡ RT +/- short term T1A: incidental
imaging)
T2A: <=½ of
capsule
T3A: capsule
structures
ADT 4-6 m <=5% of TURP one lobe only
ú Neoadj
T1B: incidental T2B: >½ of one organs,
>5% of TURP lobe T3B: seminal muscles, bones
vesicle
ú Concurrent T1C: +ve FNA T2C: both lobes
due to + PSA
ú adjuvant
¡ RP+/- pelvic LND: LOCALIZED Locally
advanced
ú + SM: observe/RT
ú +LN: observe/ADT Risk Low Interm
ediate
High Very high
¨ LE=>10y T 1-2a AND 2b,2c OR 3a OR 3b-4
¡ As above without GS 2-6 AND 7 OR 8-10 OR
¡ Active surveillance PSA <10 10-20 >20
Ahmed Zeeneldin 42

43. Goserlin (3.6 mg RTOG 8610 EBRT EBRT+ 4mADT
SC M)+ (bulky T2-4 [5cm]/ LN + or -)
flutamide (250
10 y OS (Median OS) 34% (8y) NS 43% (9y)
x3xd PO)
1. Clin Oncol. 10y DFS 3% (S) 11%
2008;26:585- 10y D Sp Mortality/mets/BF 36/47/80% (S) 23/35/65%
591.
x 2 m before RTOG 9610 EBRT EBRT+ EBRT+
2m concurrent 3MADT 6MADT
2. Lancet Oncol. (locally advanced)
2005 ;6(11):841-
50. HR: LF/BFFS/DFS (S) 1 .56/.7/.65 .42/.58/.56
x 2 m before 1m HR: DF/PCSS (S) 1 NS .67/.56
concurrent
X 5 m before 1m DFCI EBRT EBRT+ 6M ADT
concurrent
3. JAMA. Unfavourable localized
2008;299:289- All cause Mortality (HR) (S) 1.8 1
295.
Ahmed Zeeneldin 43

44. T1 T2 T3 T4
¨ RT + long term ADT
(2-3y) Clinically
inapparent
Confined to
prostate
Extends
through the
Fixed or
invades
ú Neoadj
(clinical, prostatic adjacent
imaging) capsule structures
T1A: incidental T2A: <=½ of T3A: capsule
ú Concurrent <=5% of TURP one lobe only
ú adjuvant T1B: incidental T2B: >½ of one organs,
>5% of TURP lobe T3B: seminal muscles, bones
¨ RT + short term ADT T1C: +ve FNA T2C: both lobes
vesicle
(4-6m): single HR
due to + PSA
factor LOCALIZED Locally
advanced
¨ RP+pelvic LND (if
Risk Low Interm High Very high
possible): ediate
ú + SM: observe/RT T 1-2a AND 2b,2c OR 3a OR 3b-4
ú +LN: observe/ADT GS 2-6 AND 7 OR 8-10 OR
PSA <10 10-20 >20
Ahmed Zeeneldin 44

45. ¨ 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 acetate (150 mg orally per month of treatment to
cyproterone orally per day) during the first
inhibit the transient during the first month of treatment to
day) rise in testosterone
inhibit the transient rise in testosterone
EBRT EBRT+2y LHRH
5y OS 79% 62% (S)
5yDFS 85% 48% (s)
Ahmed Zeeneldin 45

46. T1 T2 T3 T4
¨ long term ADT
alone: Clinically Confined to Extends Fixed or
¡ N1 and M1 inapparent prostate
(clinical,
through the
prostatic
invades
adjacent
¨ RT + short term T1A: incidental
imaging)
T2A: <=½ of
capsule
T3A: capsule
structures
ADT (4-6m) <=5% of TURP one lobe only
¡ N1 only not in M1 T1B: incidental
>5% of TURP
T2B: >½ of one
lobe T3B: seminal
organs,
muscles, bones
¡ Neoadj T1C: +ve FNA T2C: both lobes
vesicle
¡ Concurrent due to + PSA
¡ Adjuvant
LOCALIZED Locally Meta
¨ RP+pelvic LND (if advanced static
possible):
¡ Not in M1 Ris Low Interm High Very high N1/M1
k ediate
¡ + SM: observe/RT
T 1-2a 2b,2c 3a 3b-4
¡ +LN: AND OR OR
observe/ADT GS 2-6 7 8-10
AND OR OR
PSA <10 10-20 >20
Ahmed Zeeneldin 46

47. ¨ 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: LOCALIZED
¡ PSA: q 3-6m
¡ DRE: q6-12m Risk Low Interm High
¡ Repeat biopsy q 12 m ediate
¡ Less intense if LE<10y T 1-2a AND 2b,2c OR 3a OR
¨ Upon progression: GS 2-6 AND 7 OR 8-10 OR
¡ RT or RP PSA <10 10-20 >20
Ahmed Zeeneldin 47