DR:-OMAR HASHIM

PROSTATE CANCER

Anatomy of the prostateProstate is a fibro-muscular gland. It lie between the base of Bladder and deep transverse perineal muscles.behindThe pubic symphysis and front of the rectum .prostate isPerforated by the prostatic part of the urethra and by theTwo ejaculatory ducts.the prostate is divide into fiveLobes .anterior lobe in front of the urethra. middle lobeIs situated between the urethra and ejaculatory ducts. theUpper surface is related to the trigone.the posterior lobeIs situated behind the urethra and below the ejaculatoryDucts .the right and lift lateral lobe lie on either side ofUrethra .

The 1ry lymphatic derange of the prostate is to the regionalLN s the distant LNs .75% of the cancer is orRegional LN s:-Internal iliac (hypo-gastric) .ObturatorPersacral PerivesicalExternal iliac.Distant LNs:-Deep and superficial inguinal .Common iliacRetroperitonealSupraclavicularCervicalscalene

EPIDEMIOLOGY & ETIOLOGY

Prostate cancer is the most commonly diagnosed cancer .New case in the 2010 an estimated 217,730 .these is

wide Geographical variation .Risk factors for ca prostate ;-a) ↑ life expectancy .b) Routine adoption of PSA .c) Ethnicity .d) Family history .Less common risk factors ;- genetic /hormonal /obesity

/dietary habits /prostate inflammation/infection

Screening for prostate cancer ;-PSA screening is impact in the incidence and

mortality of ca prostate .In USA as example ;-The percentage of low risk disease is ↑ and the Age-adjusted death rate is↓ .* ERSPC trial is demonstrated that PSA

screening in the general population show 20% ↓in the prostate cancer with the screening .

Pathology of ca cancer

the most common histological type of the cancer is adenocarcinoma .the International Society of Urological

Pathology Consensus Statement divide the histological

type into Gleason scoring system that show 5 basic

Tissue pattern referred as tumor grade. The classification

Is depend on the loss of normal glandular structure

DIAGNOSIS OF CA PROSTATE most of the ca prostate is diagnosis due to the screeningOf the PSA with out symptoms .but advanced tumors May invade the adjacent structure or regional lymph nodesSuch case may presented by bladder out let obstructionSymptoms which include (heamaturia, hematospermia,Erectile dysfunction, change in bowel function or bone painExamination :- be side BR examination include LNs,Examination of the skeleton . and neurological examinationFor sign of metastasis.

Deferential diagnosis for enlarged prostate:-Acute prostatitia .Chronic granulomatous prostate.Nodular hyperplasia

Physical examination

1) Digital rectal examination noting rectal tone /presence of

Hemorrhiod or anorectal mass ,prostate size presence of nodules

Involvement of lateral sulci and seminal vesicles.DRE is cornestone for staging although unsensitive for

extracapsularExtension .

TRUS- guaded biopsy

the procedure can miss

SerumPSA

1) PSA screening is leading the majority of prostate cancer diagnosis

2) PSA is sensitive but not specific these false +ve .3) PSA is↑ with age .4) PSA of ≥ 4 ng/ml(atypical clinical threshold ) range 31—

54%Specificity ↑ with age and DRE is considered .5)Another laboratory value include (free PSA/PSA

density/PSAvel-Ocity) .6) Persistent ↑PSA and presence of palpable prostate

indicationTo transrectal U/S guide needle biopsy (TRUS)

Prostate cancer suspected (↑pSA) .

Complete history &exam (DRE) .

Trans-rectal U/S guided prostate biopsy .

If life expectancy >5yrs or symptomatic treatment is recommend . If life expect-

Ancy <5yrs and asymptomatic no further treatment .

Risk classification based on PSA,DRE&Gleason .

Work up depend on risk classification . Bone scan;-1)T1,T2 and PSA >20ng/ml

2)Gleason score≥8 3)T3/T4 4)sypmtomic..Abdominal pelvic CT/MRI ;- 1)T3/T4 .

2)T1-T2 &nomogram probability of Lns involvement Multidisciplinary treatment based on

risk classification

Algorithm for Diagnosis and stag-Ing of prostate cancer

Tumor node .and metastasis (TNM) staging system of Amer-Ican Joint Committee on Cancer (AJCC) is presented in the Table blew ;- Stage Description

TX Primary tumor can not assessed

T0 No evidence of primary tumor .

T1a tumor finding in 5% or less of tissue resected

T1b Tumor finding in more than 5% of tissue resected

T1c tumor is find by needle biopsy because of elevated PSA .

T2a/pT2a Unilateral ,one half of one side or less

T2b/pT2b Unilateral involving more than one half of side but not both sides .

T2c/pT2c tumor involve both side

T3a/pT3a Extra prostatic extension or microscopic invasion /microscopic bladder neck invasion

T3b/pT3b Tumor invade the seminal vesicle

T4/pT4 Tumor invade structure other than seminal vesicle (rectum /external sphincter levator muscle

Primary tumor;-

-Regional lymph nodes ;- NX Regional lymph nodes cannot be assessed

N0 No regional lymph nodes metastasis

N1 Regional lymph nodes metastasis

Distant metastasis ;-

MX Distant metastasis can not be assessed .

M0 No distant metastasis

M1a distant metastasis to non regional L Ns

M1b Distant metastasis to the skeletal system

M1c Distant metastasis to the additional sites with or without skeletalmetastasis

T N M PSA Gleasonscore

T1a-c 0 0 < 10

≤ 6

T2a 0 0 <10 ≤ 6

T1-2a 0 0 -- --

T1a-c 0 0 <20

7

T1a-c 0 0 10--20

≤6

T2a 0 0 <20

< 7

T2b 0 0 -- --

T2c 0 0 any

any

T1-2 0 0 ≥20 any

T1-2 0 0

any ≥8

T3a-b 0 0 any any

T4 N1

M1

any any

1

11A

11B

111

1V

prognosis

Factors affecting the prognosis of ca prostate ;-

A. Gleason score .B. Pretreatment serum PSA .C. Stage at diagnosisD. Additional pathological factors include

percent +ve biopsy cores,PSA density,and Velocity length of core involvement and

presentOf per neural invasion / age

TREATMENTTreatment of localized prostate cancer ;-The treatment option for localized disease include Surveillance versus active treatment with

radiotherapy,Surgical, and systemic modalities of treatment .A) Active surveillance ;- indicated in patients with very

lowDisease if life expectancy <20 yrs or low risk disease(if life expectancy <10yrs) .Active surveillance include PSA, DRE,and repeatNeedle biopsy .Definitive treatment recommended if clinical PSA↑,Or pathological (higher Gleason score,↑number of

Advantage of active surveillance include avoidance

Of unnecessary treatment and potential side effects .

Disadvantages of surveillance include tumor prog-

Gression and need for more aggressive treatment .

Radical prostatectomy ;- indicated for patients with

Clinically localized prostate cancer with life expectancy exceeds 10 yrs . PR is considered as the standard

surgical treatment .The only local treatment that reduce mortality

(RR=0.56)Local progression (RR=0.33),metastasis

(RR=0.6) over

The procedure is done by perineal to retro pubic,Retroubic nerve sparing, laparoscopic, and robot Assisted approaches .Side effects include ;- intra-operative bleeding,urinaryIncontinence and erectile dysfunction .Overall prostate-cancer-specific mortality of 12%

(range5—38) at 15 yrs after surgeryExternal beam radiation therapy (EBRT) ;-As monotherapy for low-risk and selected

intermediateRisk patients

In concurrent for low-risk and selected intermediateRisk patients .Adjuvant post prostatectomy treatment for high-riskPatients .Palliative treatment to primary or metastatic foci .Intensity modulated radiation therapy (IMRT) .Represents the current standard of care of EBRT .If the dose>72 GY IMRT is similar in disease controlTo prostatectomy and seed implant .

Interstitial brachytherapy ;- Is used to curative treatment of localized

prostate Cancer . Advantage ;-Highly conformal dosimetry Moderate invasiveness ,out patient nature .Minimal number of treatment visits

Androgen ablation ;- Short term ADT in intermediate-risk prostate cancer . Long term and adjuvant ADT in high to very high-riskProstate cancer .Mainstary treatment for palliative therapy in metastaticDisease .Unproven role as a component of salvage therapy Although it is utilized empirically in selected high risk-Patients .Orchiectomy or LHRH agonists (90-95% of testosterone)

TAB utilized orchiectomy or LHRH agonist +anti-andro-

Gen for complete testosterone blockade .Estrogen as a second-line hormonal therapy

Diagnosis of prostate cancer

Risk classification

Low risk/t1-2aOr PSA<10

Interm.risk/T2d-c

G=7, or PSA 10-20

High risk/Tt3a.G=

8-10 or PSA>20

Very high riskT3b-t4n0 m0

Active surveillanc

e/IG-IMRTor BT

IG-IMRT±BT

Boost/±short

Term ADT4-6months

IG-IMRT±BT

Boost/±long

Term ADT2—3YRS

Definitive treatment

as high risk or

palliative ADT

Radical prostatectomy

Active follow upc

Radical prostatectomy +PLND±adjRT

or

oror

EBRT(dose escalation&treatment outcomeEBRT IS one of the most important definitive

treat-Ment modality for localized prostate cancer of

allStages .IMRT is represent the current standard

of careFor prostate EBRT .The study show that 3D and IMRT improve the

biochemical control and reduce toxicity rate as

Compared to the 2D .

studies description

hanks number of patients 232. with prostate cancer treated using 3D-CRTFor out come of radiation dose escalation.The dose response was observed for patients with pretreatment PSA = >10 ng/ml based on 5yrs BNED results .5 yrs bbNED rate of 35% at 70 GY and 75% at 76 GY (p=0.0049) .No response was observed for patients with pretreatment PSA<10 ng/ml . dose response was observed for FL-LENT grade 2 and grade3,4 GI sequelae and LENT grade 2GU sequelae .The improvement in 5 yrs bNED for patients with PSA =>10 ng/ml suggested benefit of radiation dose escalation

studies description

RTOG 9406

phase 1/11 study for radiation dose escalation in treatment of stage T1 and T2 prostate adenocarcinoma .Patients number=225 . Treated to 78 GY to prostate alone if probability of seminal vesicles involvement < 15% or 78 GY toProstate and 54GY to seminal vesicle lf the involvement ofSV probability more than 15%Acute toxicity at dose of 78GY was low grade3 acute effectsIn 4% of patients to prostate alone and 2% of patients treatedTo both prostate and SV .NO grade 4 or 5 acute toxicityreported

Randomizedtrial

description

DearnaleyEt al

Pts number =225 . Clinical trial compared 3D-CRT versus conventionalRT to 64GY . The primary end point was the development of late radiationComplication (>3 months after treatment) .Reduced grade 1-2 late radiation proctitis in patients received 3D-CRT comp-Ared with conventional treatment

Koper al (dutch rand-Omized trial)

randomized clinical trial reported anorectal morbidity with the use of 3D-CRT versus conventional RT to 66GY . Number of patients 266 withT1—4N0M0 prostate cancer .Reduction in the GIT toxicity was observed in the arm of 3D-CRT(32and19% p=0.02) mostly due to the reduced grade 2 rectum,sigmoid and analToxicity .No difference in urological toxicity was observed

Randomized trial

description

MD Anderson Comparing clinical trial 78GY versus 70 GY of the EBRT using3D-CRT .number of patient s=301 stage T1b to T3 ca prostate .Significant 8 yrs biochemical DFS improvement in patients Received 78GY (78 versus 59% p=0.004) .The largest benefit amonge patients with pretreatment PSA>10ng/ml .No different in GIT or GU toxicity was observed

Dutch mutlicenterRandomizes trial

Randomized trial compared 78GY versus 68GY using 3D-CRTFor prostate cancer . Pts number =669 with T1B—T4 .The primary end point freedom from failure (FFF) .other end Point were freedom from clinical failure (FFCF) ,overall survival(OS), and toxicity .with follow up of 51 months ,5 yrs FFF wasSignificantly better after 78 GY3D-CRT (64 versus 54%) .No significant difference in FFCF or OS .No difference in late GU or GI toxicity .

PROG/ACR 95--09

Randomized trial compared 70.2 GY conventional or 70.2 GY protonIn the early stage prostate cancer .Number of patients =393 with T1b—T2b and PSA <5 with out Androgen suppression .End point include local failure (LF) biochemical failure .Proton beam therapy reduced LF with HR of 0.57 .The 10 yrs ASTRO BF rate were 32.4 versus 16.7% favored high dose (p=0.0001) .The difference was due to largely to difference in the lowAnd probably intermediate- risk disease .There was strong trend in the same direction for inter-Mediate –risk disease (n=144,37% of total 42 versus30.4%P=0.06) .11 versus 6% of patients required ADT for recurrence After conventional –versus high dose RT ( p=0.047) .No difference in OS (78.4 versus 83.4% . P=0.41)Toxicity rate (1—3% of grade 3—4) between tow arm .

mo

Hormonal therapy for local advanced ca prostate ;-Androgen deprivation therapy ;-Consisting of a combination of luteinizing-hormone-releasing hormone (LHRH) suppression and anti-Androgen . Used as adjuvant therapy to EBRT toImprove outcome in intermediate and high risk Patients .the supportive trial show significant Improvement in local control and disease freeSurvival with inconsistent improvement in overall

survival

Adjuvant radiation therapy ;- prostatectomy provide

Good control when the cancer is confined to the

Prostate while failure rate is high when cancer exten-

Sion beyond the capsule specially in patients with

High Gleason grade and +ve margin.Study show that strong benefit of EBRT of

patientsWith pathological high-risk disease (T3N0

and /or+veMargin)

Metastatic prostate cancer ;-Advanced prostate cancer include those of

distant Metastasis or non regional LNs

metastasis(1vb-1vc )Pts usually required ADT and palliative

radiation Therapy for symptomatic foci

Radiation therapy techniques ;-

IMRT ;-represent the current standard of care for

Prostatic EBRT .PTs set up and planning for prostate cancer

IMRT ;-1) PTs preparation ;-Pts should instructed to present with empty

rectumAnd full bladder .

Randomized trial

description

D’Amino et alIntermediaterisk

Phase 111 clinical trial to compare RT with or with out 6months ofADT . 80% of randomized patients had intermediate –risk caProstate .Conformal dose 79.35 in 36 fr to prostate and seminal vesicles withAcone –down boost to the prostate .Median follow upof 4.5 yrs revealed statistical improvement in Prostate cancer –specific survival,survival free salvage androgenDeprivation and OS rate .Up dated results after a median follow up of 7.6 yrs all causeMortality was significant greater in the RT alone arm (HR 1.8P=0.01) .Sub group analysis show the significant different in pts with no orMinimal comorbid

Cl inical evidance on combined EBRT with hormonal therapy for intermediateRisk ca prostate .

Randomized trial

description

RTOG 85--31

Randomized trial of 977 patients to adjuvant goserelin versus observation .Eligible patients had advanced tumor characteristics (Ct3,N+ or patholOgical penetration through the capsules to the resection margin or SV involvement .RT→regional lymphatic to an initial 44—46 GY in node +ve patients followed by a prostate boost to 65—70 GY.10 yrs up dated results demonstrated significant improvementIn local failure(23 versus 38%), disease specific mortality(16 Versus 22%) DM ( 24 versus 39%) . NED survival (37 versus23%) and OS (49 versus29%)

RTOG 86—10b

Randomized clinical trial to the effect of the androgenSuppression .1st arm → to neoadjuvant and concurrent goserelin And flutamide for 2 months prior and 2 months During RT treatment versus observation .Selected pts have bulky 1ry tumor (≥5x5 cm) with orWithout LNs involvement .Dose include treatment of the regional lymph nodes(Except in LN-ve) .followed by broatatic boost to65—70 GY .Up date result at 10 yrs demonstrated significantImprovement distant metastasis (35 versus 47%) Disease-specific mortality (23 versus 36%) DFS (11Versus 3%) and biochemical failure .non significantTrend toward improved OS with also observed .Non significant impact on the risk of fatalCardiac events was seen .

Clinical evidence on combined EBRT with hormonal therapy for high-riskProstate cancer ;-

EORTC

Phase 111 study (103) compare EBRT with long term (concurrentAnd adjuvant ) androgen suppression.EBRT targeting initially the prostate and pelvic nodes to 50GY Then boost prostate only to anadditonal 20 GY. Hormonal therapy consisted of monthly goeserelin for 3 yrs fromThe first day of the EBRT and 1month of cyproterone .With median follow up of 66 months→ this result improvement inDFS (40 versus 74%), DSS (79 versus 94%) and OS (62 versus 78%)

Clinical evidence on combined EBRTNwith hormonal therapy for high-risk ca prostate

RTOG dataset analysis

Long-term pelvic toxicity does not appreciably worsen withAddition of androgen suppression .Pts treated with EBRT +short term hormonal therapy have > grade3 GI ,GU and other toxicity as compared to RT .Pts treated with long term hormonal therapy + EBRT had Significant lower probability>grade 3 GU toxicity as compared to RT alone .Demonstrated no ↑ cardiovascular toxicity after hormonaltreatment

Study examined long-term toxicities of androgen suppressionTreatment used with EBRT .

RTOG 92—02b

Analysis for the cardiovascular toxicity after hormonal Therapy for prostate cancer .Demonstrated no↑cardiovascular mortality after Hormonal treatment from 24 versus 4 months

TROG 96.01 of(Australia)

Randomized clinical trial studies the optimal duration of shortCourse hormonal therapy .3arm study compared prostate –only radiation to 66 GY versus3 or 6 months of androgen deprivation before and during radiationFor intermediate –risk patients .Result revealed a significant improvement in prostate cancer Specific mortality with 6(HR=0.56) but not 3 (HR;0.95) months