prostate cancer update 1_2010

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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http://www.ssa.gov/OACT/STATS/table4c6.html

¨ 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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Metastatic





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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Metastatic





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


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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Metastatic





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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Risk Low Intermediate

High Very high


GS 2-6 AND 7 OR 8-10 OR

PSA <10 10-20 >20

T1 T2 T3 T4








T2C: both lobes

Extends through the

prostatic capsule

T3A: capsule only



structures


¨ 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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High Very high


GS 2-6 AND 7 OR 8-10 OR

PSA <10 10-20 >20

T1 T2 T3 T4








T2C: both lobes

Extends through the

prostatic capsule

T3A: capsule only



structures


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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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High Very high


GS 2-6 AND 7 OR 8-10 OR

PSA <10 10-20 >20

T1 T2 T3 T4








T2C: both lobes

Extends through the

prostatic capsule

T3A: capsule only



structures


¨ 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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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








T2C: both lobes

Extends through the

prostatic capsule

T3A: capsule only



structures


¨ 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


High

T 1-2a AND 2b,2c OR 3a OR

GS 2-6 AND 7 OR 8-10 OR

PSA <10 10-20 >20

prostate cancer update 1_2010

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