CARCINOMA PROSTATE AND IT’S MANAGEMENT

Mod: Dr S. Ghoshal 18.09.08

ANATOMY Male accessory reproductive organ Conical fibro-muscular-glandular organ, surrounding the proximal

urethra Situation – shape-dimension- capsules Parts- Apex/ base/ Ant./Post./ 2 Inferolat. & post. surfaces Vascular system-Prostatic venous plexus & Batson plexus Lymphatic drainage- Regional / Distant LNs- pathways: Laterally to the hypogastric and internal iliac nodes (primary) Inferiorly to the pudendal and then subsequently to the obturator fossa (secondary) Superiorly from the top of the prostate over the bladder to the external iliac nodes, a

few centimeters below the bifurcation of the common iliac artery (tertiary) Posteriorly alongside the rectum to the presacral nodes of the promontory

(quaternary)

Lobar & Zonal anatomy (Mc Neal) Peripheral zone : 60- 70% of Ca P origin Transitional zone: 10-20% of Ca P origin Central zone: 5-10% of Ca P origin

Lobes

Zones

EPIDEMIOLOGY

5th most common cancer 33% of all newly diagnosed cancers 2nd most common cancer in men- 29% of all male

cancers 2nd leading cause of cancer death in men in western

world World wide incidence- 25.3 per lakh (Vera Nelson, RRCR, vol. 175,

2007)

Higher incidence – Scandinavia, North America, Australia, western and northern Europe

Low incidence- Asian countries India- 4% of all male cancers

ETIOLOGY Age related , racial-ethnic and geographical variation

suggesting primary environmental and genetic influence RISK FACTORS

Advanced age Diet- Higher fat and zinc/ selenium/ lycopene/ vit.E Higher BMI F/H – hereditary-1st degree relative– 5 to 11 fold risk Genetic- 1q24-25 and familial link with HPC1, 5-α Reductase

Polymorphism (SRD5A2 gene)/Cytochrome P459C17 & Cytochrome P4503A4/Androgen receptor- CAG repeat

Histologic precursors- PIN(35% within10 yr) and AAH Hormonal Race Environmental/ occupational- cadmium, heavy/ rubber

industries ? BHP/ Vasectomy/ STD/ Sexual promiscuity

No a/w cigarette smoking/ alcohol

NATURAL HISTORY LOCAL GROWTH PATTERN

Almost all prostatic carcinomas (>70%) develop in the PZ and BHP (>90%) arises from the TZ (McNeal)

Small tumors tend to occur in the anteromedial gland, adjacent to the fibromuscular stroma, whereas larger, more advanced T stage tumors are often located in the posterior gland near the prostatic capsule

Multifocality is characteristic of prostate cancer -77% (Jewett)

TZ tumors - demonstrate a lower frequency of ECE and may harbor large volumes of disease with relatively high PSA levels but remain confined to the prostate. Despite a high PSA value (>10 ng/mL), considered to have a favorable prognosis

PZ cancers - spread along the capsular surface of the gland, and may extend through the capsule of the gland, invade seminal vesicles and periprostatic tissues, and involve the bladder neck or the rectum.

Clinical stage closely correlates with risk of ECE and disease progression

Incidence of microscopic tumor extension beyond the capsule of the gland (at the time of RP) in patients with clinically organ-confined disease ranges from 8% - 57%

The incidence of SVI also is associated with the level of PSA, the Gleason score, and the clinical stage

Lymphatic spread Obturator node - commonest and earliest / Iliac/ Presacral Common iliac/ inguinal/Paraaortic

Hematogenous distant metastasis Spine/ pelvis/ femora/ lung/ liver / adrenals

CLINICAL MANIFESTATIONS EARLY STAGE

Asymptomatic Cancer is in the peripheral zone

LOCALLY ADVANCED DISEASE Obstructive / irritative voiding Retention of urine Hematuria Renal failure Pelvic pain

METASTATIC DISEASE Bone pain Spinal cord compression symptoms Paraperesis

History- Urinary status/ sexual function/ skeletal symptoms/ co-morbidities

OBTRUCTIVE SYMPTOMS: PROSTATISM Symptom complex- initially

Urinary hesitancy Diminished force of urine stream Intermittancy Sense of incomplete voiding

Loss of bladder detrusor compliance Urgency Frequency Nocturia Incontinence Acute retention may occur

LUTS: constellation of obstructive symptoms often a/w BHP/mechanical or functional disorder of UB

Hematuria- prostatic urethra/ trigone involvement Hematospermia

Extra prostatic spread- often asymptomatic/ extensive dis.

Rectal involvement- Hematochezia Constipation Intermittent diarrhoea Decreased stool caliber Abdomino-pelvic pain

Renal impairment due to prolonged BOO Fluid retention/ electrolyte imbalance

Involvement of neurovascular bundles/ UGD/ corporeal bodies – Impotence/ pelvic pain/ priapism

Advanced disease- metastatic symptoms Bony- pain / pathological fracture/ Spinal tendernesss Spinal cord compression- neurological deficits/ sensory-

motor changes/ bladder-bowel dysfunction Pelvic / Paraaortic LAP- edema of abdominal wall,

genitalia or lower extrimities/ mass abdomen Adrenal/ lung/ skin mets PNS- SIADH/ Cushing syndrome/ Hematologic

PHYSICAL EXAMINATION G/E Systemic examination DRE- cornerstone of the physical examination/ instrumental in

staging Sim’s lateral prone/ Lithotomy/ Knee-chest/ Standing Organ palpation:

Craniocaudal and transverse dimension Consistency/ Sensitivity/ Mobility Any firm/ elevated area and its size Typical finding ca prostate- Hard, nodular, asymmetrical may

or may not be raised above the surface of gland and is surrounded by compressible prostatic tissue Prostatic induration- BHP nodule/ calculi/ infection/

granulomatous prostatitis/ infarction SVI- Firmness extending superior to the prostate gland

Positioning

DRE Specificity- 50% and Sensitivity- 70% Only 25-50% of men with an abnormal DRE have cancer DRE+PSA specificity 87%

DIAGNOSTIC WORK-UP Laboratory

Complete blood cell count, blood biochemistry Serum PSA (total, free, percentage free) Plasma acid phosphatases (prostatic/total)

Radiographic imaging Transrectal ultrasonography (for biopsy guidance) Biopsy/Needle biopsy of prostate (transrectal,

transperineal) Chest radiograph (high risk for metastatic disease) Computed tomography of pelvis Radioisotope bone scan (PSA >20) Magnetic resonance imaging with endorectal coil

LABORATORY INVESTIGATIONS PROSTATE SPECIFIC ANTIGEN

Serine protease glycoprotein secreted by prostatic epithelium Carcinoma specific Normal ~0.4 - 4 ng/ml (upper limit 2.6 ng/ml) t1/2 ~ 2.2±0.8 ― 3.2±0.1 days Mild elevation 4 ― 10 ng/ml Significant elevation >10 ng/ml Sensitivity ― 85% Specificity – 65-70% Estimated rate of cancer detection by PSA screening ― 1.8-

3.3% Clinically localized tumor ― 81-97% and 40% are not

palpable Pathologically localized tumor ― 36-91% Carcinoma with normal PSA ― 25%

Age specific PSA Age PSA Range % 40-50 0-2.5 4-10 25 60-70 0-4.5 >10 60 (localized 50%) 70-80 0-6.5 high suspicion of carcinoma >50 ↑ LN mets/ bone mets disseminated disease

Pretreatment serum PSA is also predictive of EPE and SVI PSA Rate of organ-confined disease 4 -10 ng/ml 53% - 70% 10 -20 ng/ml 31% - 56%

Roach’s Probability of ECE, SVI and LNI: ECE+ = 3/2×PSA +(GS-3)×10 SVI+ = PSA +(GS-6)×10 LNI+ = 2/3×PSA +(GS-6)×10

o Rule out the possibility of ca o Gives idea about intraprostatic volume of diseaseo Decision regarding Bx and treatment o Monitoring response to therapyo Base line for follow up and detecting recurrence after therapyo Detection yield

• DRE+PSA = 4.7-5.8%• PSA+DRE+TRUS = 60%

o Biochemical failure: PSA relapse- rise or persistently detectable serum PSA following definitive treatment (30-40% in localized t/t) o Post op: > 0.2 ng/ml in serum PSAo Post RT:

o ASTRO consensus- 3 consecutive PSA rises with the time of failure backdated to halfway b/w the PSA nadir and the first PSA rise

o Phoenix consensus- PSA rise ≥ 2 ng/ml above the nadir PSA (Standard defn for BCR post RT with or without short term HT)

(Nadir + 2 definition ) Sensitivity-64% Specificity-78% (Mack Roach, IJROBP, 2006)

•DRE+Bx = 22%•PSA+DRE+Bx = 48%

TEMPORAL VARIATION PSAD (PSA Density)

Cancers produce less PSA per cell than nonmalignant prostatic tissues

Calculated by dividing the serum PSA concentration by the volume of the prostate gland measured by TRUS

A higher PSA density is a/w malignancy Important in elderly patients BHP ― 0.3ng/ml/gm Ca prostate― 3.3ng/ml/gm PSA rises @ 3.5ng/ml/gm of intacapsular cancer regardless of

ECE PSAV (PSA Velocity)

Serial PSA measurements and calculate the rate of rise in PSA A rate of rise of >0.75 ng/ml/yr a/w a higher frequency of

cancer Important for young patients

PSA rises after DRE/ ejaculation/ cystoscopy/ message (sampling 1 week later) Biopsy / TURP (sampling 4 week later)

Ratio of free to total PSA(% free PSA) lower for carcinoma(<7%) Complexed-to-total ratio higher and free PSA lower for cancer PROSTATIC ACID PHOSPHATASE (PAP) (N- 0-5.5 u/l)

Sensitivity- 10% Specificity-90% Abnormal PAP correlates with higher tumor stage T3, T4, higher

grade, pretherapy serum PSA Affected by circadian rhythm, prostatic message, Sx manipulation

and BHP ACR & AUA recommendation

Annual DRE+ PSA screening for men>50 yr with life expectancy >10 yrs.

At age of 45 yr in men with african-american origin or with F/H

IMAGING CXR

Pulmonary metastasis Miliary pattern

Axial skeletal survey : Specific sites of bony pain Osteoblastic secondaries

USG abdomen-pelvis: HDUN/ large PVR/ RPLAP/ Liver mets.

TRANRECTAL ULTRASONOGRAPHY(TRUS) TRUS of the prostate, first described by Wantanabe (1968) TRUS-guided systematic sextant biopsy protocol by Hodge Normal adult prostate : Symmetric, triangular, relatively

homogenous structure with an echogenic capsule

The mature average prostate is between 20 and 25 g and remains relatively constant until about age 50, when the gland enlarges in many men ( Griffiths, 1996 )

The paired seminal vesicles are positioned posteriorly at the base of the prostate. They have a smooth, saccular appearance and should be symmetrical. Normal SV measures 4.5 to 5.5 cm(l) and 2 cm (w)

Once gland volume has been obtained, one can calculate derivatives such as the PSA density (PSAD = serum PSA/gland volume)

Predicting a positive cancer diagnosis on repeat biopsy Sensitivity – 75-86% & Specificity- 41-44% ( Djavan et al,

2000 ) All hypoechoic lesions within the PZ should be noted and

included in the biopsy material Hypoechoic-14-39%(~40%) Isoechoic- 14-29% Hyperechoic-1%

TZ BPH nodules are typically hypoechoic but may contain isoechoic or even hyperechoic foci A hypoechoic lesion is malignant in 17% to 57% of cases

(Frauscher et al, 2002 ), highlighting the need to biopsy these lesions but recognizing they are not pathognomonic for cancer as once thought.

Extraprostatic extension Sensitivity-66% Specificity- 46% Accuracy- 58%

Seminal vesicle invasion Echogenic abnormalities Ant. displacement and enlargement of SV

Evaluation of an abnormal DRE and/or abnormal PSA Measurement of prostate volume for treatment planning

and/or monitoring TRUS-directed prostate needle biopsy remains the gold

standard for diagnosis of prostate cancer Guided biopsy of the prostate

Recommendation: TRUS guided Bx in patients with PSA> 4 ng/ml

(ACR & AUA)

To establish the diagnosis To report extent and grade of each core To document presence of Pelvic LN involvement and ECE

Staging of clinically localized prostate cancer Guidance during the seed/interstitial brachytherapy Monitoring prostate cryotherapy Evaluation and aspiration of prostate abscess Monitoring the response to prostate cancer treatment

Other uses Staging of rectal carcinoma and treatment Suspected congenital anomaly of the prostate, rectum,

seminal vesicle or surrounding tissue Diagnosis and/or monitoring of azoospermic or oligospermic

patients with palpable vasa and low ejaculate volumes Evaluation of LUTS (e.g., pelvic pain, prostatitis/prostadynia,

obstructive and irritative voiding symptoms) Experimental, investigational or unproven

Use as a stand-alone screening tool for prostate or rectal ca Transrectal high-intensity focused ultrasound (HIFU)

treatment

PSA DRE TRUS

Sensitivity 96% 87% 84% Specificity 14% 60%

41%-67% PPV 32% 48%

52% NPV 88% 92%

91% (Aarnink, et al.,

1998)

CT SCAN Primary role

Size determination of the gland Assess pelvic LN metastasis Treatment planning in RT EPE:

Loss of periprostatic fat planes Bladder base deformity Obliteration of the normal angle b/w the SV and post. aspect

of UB LN involvement

Abnormality in size Sensitivity 25% Reserved for patients with higher PSA values (>20-25 ng/ml) CT guided FNAC

Limitation of CT Lacks the soft tissue resolution needed to detect intraprotatic

anatomic changes due to primary tumor , capsular extension or SVI because the neoplasm usually has the same attenuation as the normal prostate gland

Can't detect microscopic disease False Positive- Artifact of Bx and plane b/w SV and UB base

may be obscured by rectal distension

MRI Superior to CT in defining prostate apex, NVB and

anterior rectal wall Better delineation of periprostatic fat involvement

T1w- provides high contrast b/w water density structures i.e. Prostate, SV and fat, NVB, perivesical tissue and LNs

T2w fast spine echo- zonal anatomy, architecture of SV Ca Prostate: A focal, peripheral region of decreased

signal intensity surrounded by a normal(high intensity) peripheral zone

BHP: centrally located nodules of similar signal Primary staging sensitivity- 69% Nodal involvement sensitivity increases to 96% with the

use of IOLSPNP Endorectal surface coil MRI- accuracy of 54-72% staging

the primary and detects SVI and ECE

Indications: High likelihood of capsular invasion and LN metastasis Abnormal DRE PSA>20 Poorly differentiated ca

Sensitivity to locate gland tumor- 79% and specificity- 55% LN detection- Low sensitivity but high specificity

MRSI Spectroscopy principle: The electron cloud surrounding

different chemical compounds shields the resonant atoms of interest to varying degrees depending on the specific atomic structure of the compound Glandular Citrate concentrations 240 to 1,300 times greater

than blood plasma concentrations. High levels of citrate -Peripheral zone and lower levels in the transition and central zones.

Choline Tumor: A significant reduction in prostate citrate and a

significant increase in prostate choline levels relative to the normal peripheral zone

Metabolic map of the prostate corresponding to normal and abnormal metabolic activity that can be used to pinpoint the location of prostatic tumors

Improved diagnostic accuracy of MRI both in localizing and staging and risk-stratifying patients

Specificity for tumor location (MRI + MRSI) ~ 91%. Accurate localization of prostate tumors and improved guided

biopsy Combined MRI/MRSI enhances the assessment of both ECE and

SVI and capsular breech Predict tumor aggressiveness Distinguishing b/w tumor and post biopsy hemorrhage Detect residual cancer following t/t and follow-up Development of more focused therapy

99TC BONE SCAN Clinically apparent metastatic disease limited to bone in 80-

85% of patients of metastatic ca prostate A close correlation exists between pretreatment PSA level and

incidence of abnormal bone scan results Osteoblastic secondaries MC sites of metastasis

Vertebral column- 74% Ribs- 70% Pelvis- 60% Femora- 44% Shoulder girdle-41%

Indications: Pretherapy Early stage disease-T1-T2 with

PSA > 20 ng / ml GS≥ 8 Bony pain

T3-T4 –Symptomatic patients High grade tumor Base line: Elderly, patients with h/o arthritis, to document

degenerative changes that may later be interpreted as metastatic osseous disease and to assess t/t effectiveness

ACR recommendation: for pretreatment staging of clinically localized prostate cancer, bone scan can be omitted in case of low-risk patients with PSA of ≤10 ng/mL or GS 2 to 6

Post therapy: Skeletal symptoms in a/w ↑PSA level False +ve

Fractures/ Arthritis / Paget’s disease

PATHOLOGY Normal prostatic histology- composed of PSA, PAP and mucin

secreting secretory cells Primary

Epithelial Stromal Adenocarcinoma (95%) RMS (42%, children <10 yrs) TCC LMS (26%, > 40 yrs) SCC NET- carcinoid Adenoid cystic ca

Secondary- direct invasion from UB, colon/mets from lung, melanoma/ systemic lymphoma

Adenoca arises from acinar epithelium of PZ Premalignant lesion

Atypical adenomatous hyperplasia Duct acinar dysplasia – PIN and CIS

GLEASON SYSTEM Based on the degree of glandular differentiation and overall

pattern of tumor growth Adenocarcinoma- well/ mod./ poorly diff. according to the

cellular characteristics i.e. nuclear content, no. of nuclei, pleomorphism, gland formation and stromal invasion

5 patterns of growth Histologic variation in tumor, so two predominant patterns are

recorded for each case Primary/ predominant pattern (1-5) Secondary / lesser pattern (1-5)

GLEASON SCORE Sum of the 1º and 2º patterns (2-10) >50% ca contain ≥2 patters One of the strongest predictors of biological behaviour,

invasiveness and metastatic potential

GLEASON GRADING

It is important to recognize Gleason pattern 4 tumor because tumors with this pattern have a significantly worse prognosis than those with pure Gleason pattern 3 ( McNeal et al, 1990). Tumors with Gleason score 4 + 3 = 7 have a worse prognosis than those with Gleason score 3 + 4 = 7 ( Chan et al, 2000 )

GS Gleason’s Pattern

Histo.Grade

Differentiation 10 yr Progression

(%)

2, 3, 4 1, 2 I Well <25

5, 6, 7 3 II Mod. 50

8, 9, 10 4, 5 III Poorly 75

TNM STAGING SYSTEM

TNM STAGING SYSTEM PRIMARY TUMOR (T)

TX -Primary tumor cannot be assessed. T0 -No evidence of primary tumor T1 -Clinically inapparent tumor neither palpable nor visible by imaging

 T1a -Tumor incidental histologic findings in ≤5% of tissue resected   T1b -Tumor incidental histologic finding in >5% of tissue resected   T1c -Tumor identified by needle biopsy (e.g., because of elevated

PSA) T2 -Tumor is confined within prostate.  

T2a -Tumor involves one half of a lobe or less  T2b -Tumor involves more than one half of lobe, but not both lobes   T2c -Tumor involves both lobes

T3 Tumor extends through the prostate capsule.   T3a -Unilateral extracapsular extension   T3b -Bilateral extracapsular extension   T3c -Tumor invades seminal vesicle(s)

T4 -Tumor is fixed or invades adjacent structures other than seminal vesicles.  

T4a -Tumor invades bladder neck, external sphincter, or rectum.   T4b -Tumor invades levator muscles or is fixed to pelvic wall, or

both.

NODE (N) NX -Regional lymph nodes cannot be assessed. N0 -No regional node metastasis N1 -Metastasis in single lymph node, ≤2 cm N2 -Metastasis in a single node, >2 cm but ≤5 cm N3 -Metastasis in a node >5 cm

o METASTASIS (M) MX -Presence of metastasis cann’t be assessed

M0 -No distant metastasis

M1 -Distant metastasis  

M1a -Nonregional LNs  

M1b -Metastasis in bone(s)  

M1c -Metastasis in other site(s)

STAGE GROUPING I T1a N0 M0 G1 II T1a N0 M0 G2,3–4

T1b N0 M0 Any G

T1c N0 M0 Any G

T1 N0 M0 Any G

T2 N0 M0 Any G III T3 N0 M0 Any G IV T4 N0 M0 Any G

Any T N1 M0 Any G

Any T Any N M1 Any G

TREATMENT Depends on stage, patient's age and GC EARLY LOCALLY ADVANCED METASTATIC 3 risk group Stage Initial PSA Gleason gr.

LOW RISK T1 –T2a <10 ng/ml ≤ 6

INTERMEDIATE RISK Bulky T2b 10- 20 7

HIGH RISK ≥ T2c >20 8-10

(D'Amico et al)

Localized disease Observation Radical radiotherapy Radical prostatectomy Cryoablation

oLocally advanced disease•Radical radiotherapy•Hormonal therapy

oMetastatic disease•Palliative RT•Hormonal therapy

WATCHFUL WAITING Low risk cases

Life expectancy < 10 yrs Elderly patients Low volume disease (<2.5cc) with PSA <10 and GS 2-6 Probability of progression of disease <2%/yr

An active decision not to seek cure Palliative, not curative As disease progresses supportive measures initiated If a man lives long enough he will die from prostate cancer Disease volume (cc) LN mets (%)

<2.5 <5 2.5-7 25-26 7-13 62

GS 10 yr survival (%) LN mets (%) 2-6 85 <6 7 69 32 8-10 20 76

RADICAL PROSTATECTOMY Selection:

<60 yrs Good GC Life expectancy >10yrs No life threatening ancillary disease

Advantages Curative Removal of entire prostate and seminal vesicle Pelvic lymphadenectomy for staging Preservation of distal sphincter Preservation of cavernosal nerves-to prevent impotence Definitive pathologic information Less chance of biochemical failure

Complications Sexual dysfunction (20-100%) Urinary Incontinence (4-70%) Bleeding

Approaches Retropubic Transperineal Laproscopic (pure,

robot assisted)

• Stricture (0-12%)• Mortality (<1%)

STAGE LOCAL CONTROL at 5 yrs T1a- T2a > 95%

T1b - 2b > 92%

T3a > 82%

Overall biochemical relapse rate 17% PSA relapse free survival rates 84% - 5 yr, 74% -10 yr and 66% for 15

yrs Factors predictive of high chances of local recurrence

Larger volume , ECE Higher grade (GS 8-10) Positive sx margins pT3a or pT3b disease

RADIOTHERAPY Radical Adjuvant Palliative

EBRT- Conventional / Conformal Brachytherapy

RADICAL EBRT Indication:

Age<70 yrs Stage T1b, T2, T3 LN involvement detected by nodal sampling Risk of LN involvement ≥ 15% Documented SVI Gleason score ≥6 PSA ≥ 20 ng/ml

Treatment Volume- Prostate, SV, prostatic urethra and margin of 1-1.5cm for T1-T2 lesion and pelvic LNs to be included if the lesion is T3

Positioning Localization Treatment planning Field selection: Four-field box technique

Field size : 15X15 cm Superior border-L5-S1

Inferior border- 1.5-2 cm distal to junction of prostatic and membranous urethra (lower border of ischial tuberosity)

Lateral border- 1.5-2 cm lateral to bony pelvis Common iliac LN treated by 18X15 cm field

CONVENTIONAL EBRT PORTALS

Anterior margin-0.5 to 1 cm posterior to projected cortex of PS

Posterior margin-S2-3 interspace to include the upper presacral LNs

Prostate+ SV- 12X14 cm Boost field

Superior border extends to the top of the acetabulum - 3-5 cm above pubis

Anterior border-1.5 cm posterior to ant. margin of pubic symphysis

Posterior border- 2 cm behind the rectal marker Inferior border- short of internal anal sphincter or caudal to

ischial tuberosity Laterally to include 2/3 of the obturator foramen

Other methods of boost- Rotational arc- bilateral 120º arc Six field techniques- opposed lateral fields and two sets of

opposed oblique fields angled ±45º Noncoplanar multiple fields- lateral fields and two ant. inf.

oblique fields

Verification

Dose- 70-72.4 Gy/7wk@ 1.8-2 Gy/# 45-50 Gy/5wk to whole pelvis followed by a boost of 20 Gy

to the prostate

Advantages of pelvic EBRT: Primary lesion along with periprotatic tissue and pelvic

LNs are homogenously irradiated Surgical complication avoided Good local control

Based on stage T1a – 66-70 Gy

T1b, c T2b – 70-72 Gy

T2c – 74 Gy

CONFORMAL RT - 3DCRT Three dimensional imaging and treatment planning CT-based images referenced to a reproducible patient position are

used to localize the prostate and normal organs and to generate high-resolution 3D reconstructions of the patient

Treatment field directions are selected using BEV techniques and the fields are shaped to conform to the patient's CT-defined target volume, thereby minimizing the volume of normal tissue irradiated

Dose information for entire target volume and normal tissue Ability to increase total radiation dose Steps

Immobilization, Simulation, and CT Scanning Isocenter placed according to anatomic landmarks near the

center of the prostate gland: midline, at the caudal aspect, and ~ 5 cm posterior to the symphysis pubis

Target and Normal Tissue Contouring CTV = Prostate + SV PTV = CTV +a margin to account for physical uncertainties

including setup reproducibility, inter- and intrafractional organ motion (1-cm margin added to the CTV to form the PTV in all directions except posteriorly at the interface with the rectum, where the margin is reduced to 0.6 cm)

Beam Selection and Planning Standard 3D conformal beam arrangement- six coplanar

fields, including two lateral, two anterior and two oblique beams

Conformal apertures drawn around the PTV adding a margin of ~5 to 6 mm in the axial directions to account for beam penumbra

Beam shaping, MLCs used Dose distribution calculated for a few representative planes,

typically transverse, coronal, and sagittal planes through the isocenter

DVH generated for the PTV, femoral heads, and rectum, bladder and bowel

6-field plan, the two lateral beams typically deliver ~1/2 of the dose to the isocenter with the four oblique beams contributing the rest. The beam weights of the anterior oblique and posterior oblique beams adjusted to obtain a uniform dose within the PTV and to place the hot spots away from the rectum

The plan normalized so that the prescription isodose (100%) covers the PTV

Normal tissue dose limits- Rectal wall volume not ≥ 30% receiving ≥ 75.6 Gy Femurs to ≤68 Gy (90%) Large bowel maximum dose ≤ 60 Gy (79%) Small bowel ≤ 50 Gy (66%)

Careful about: Immobilization/ precise target volume definition / Tumoricidal dose to the tumor while minimizing dose to the normal tissue

GTV = Prostate CTV= GTV+0.5-0.8 cm margin PTV= CTV+0.8-1 cm margin

GTV= Prostate+SV in case of intermediate and high risk cases

Expected movement with respiration Craniocaudal – 1-7 cm A-P - 0.5 cm Lateral- 0.7cm

GTV+SV

GTV+ SV, PTV, CTV LNGTV P+SV, CTV P+SV

CTV P+SV

3DCRT FIELDS ARRANGEMENTS

AP LATERAL

IMRT Radiation beam intensity or ‘Fluence’ varies across the

fields Delivery of an IMRT intensity pattern requires a

computer-controlled beam-shaping apparatus on the linear accelerator known as MLC which consists of many small individually moving leaves or fingers that can create arbitrary beam shapes Static mode - “STEP AND SHOOT” which consists of

multiple small, irregularly shaped fields delivered in sequence

Dynamic mode - Dynamic multileaf collimation with the leaves moving during treatment to create the required irregular intensity patterns

Defining dose ‘Constraints’ or ‘Objectives’ for the target and normal tissues, which describe the desired dose distribution in IMRT planning

Constraints: Maximum or minimum dose limits on targets and dose-volume limits on normal tissues

Mathematical optimization of the radiation intensities of many small ‘beamlets’ within each treatment field which result in a set of intensity patterns for the treatment fields and a dose distribution with characteristics as close as possible to the constraints entered

Dose delivery carried out by setting each field to desired gantry angle with prescibed leaf position and MU

Isodose distribution- concave / convex T/t verification with weekly portal films/ online portal

imaging Short course IMRT- 70 Gy/28#/51/2 weeks @ 2.5Gy/# Low risk- 70-75 Gy Intermediate and high risk- 75-80 Gy 5 fields: Ant., 2 lateral, 2 ant. oblique Prescribed isodose 82-90%

IMRT PHASE

CONVENTIONAL RT CONFORMAL RT ADVANTAGES

Time tested Easy to plan and execute Time saving in busy

setting Cost effective

DISADVANTAGES Normal tissue more

irradiated Dose escalation not

possible

ADVANTAGES Better sparing of normal

tissue Dose can be escalated 3D planning

DISADVANTAGES Interphysician variability in

target delineation Chance of missing tumor due

to close margin Longer planning time

SEQUELAE OF XRT Conventional:

Acute – 60% in 3rd week of RT Rectal - discomfort, tenesmus, diarrhoea Urinary- frequency, urgency, nocturia Urinary incontinence (any 0–60%, severe 2–15%)

Late – 6 months/ later Chronic diarrhoea , proctitis, rectal-anal stricture Bleeding PR- 3.3%, bowel obst./ perforation- 0.6% Fatal complication- 0.2% Rectal toxicity is propotional to volume of rectal wall

exposed to high dose (any 2–100%, severe 0–20%) Erectile dysfunction (10–85%)

3DCRT/ IMRT Acute and late urinary toxicities similar, grade 3 hematuria-

0.5% Stricture -4% and incontinence- 2% (h/o prior TURP)

BRACHYTHERAPY What Types : Permanent/ Temporary (LDR and HDR) Isotopes Why-

Prostate has slow growth which remains localized for a long period

Small t/t volume Potency well maintained with minimal complications Older patients>60 yr, less tolerace to high dose XRT

Selection: Life expectancy >10 yrs Biopsy proven adenocarcinoma Stage T1 ,T2a

Grade : Gleason sum 2-6 PSA ≤ 10 ng/ml Prostate volume < 60 cc No e/o pelvic LAP/ Negative bone scan/ No prior TURP Brachy+ XRT: T2b , T2c, GS = 7-10, PSA > 10 ng/ml Brachy+ XRT+ Hormonal t/t : Initial large prostate > 60

cc Exclusion

Life expetancy < 5 yrs, large/ healed TURP defect, distant mets, unfit for anesthesia/ Sx

Relative C/I Large median lobe High GS H/o multiple pelvic surgeries DM with healing problems SVI, ECE Apical lesion Gland size > 60 cc or pubic arch interference Prior pelvic RT

RADIOISOTOPESIODINE125 PALLADIUM103 IRIDIUM192

T1/2 (days) 59.4 16.97 73.83

Energy(keV) 27.4 21 340

Form Seeds Seeds Seeds

Implant type Permanent Permanent Temporary

Dose rate 8 20 Variable

Mean activity/seed

0.42 1.3

Monotherapy dose

145 125 Variable (~600)

+EBRT dose 110 100 20-25

TVL(mm) Pb 0.01 0.03 HVL-4.5 mm

Palladium103 : Higher initial dose rate More appropriate for rapidly proliferating tumors Lower energy , greater attenuation of dose, rapid dose

fall off, so seed spacing not >1.7 cm Lesser late complications Disadvantages: Expensive, not universally available

TECHNIQUE TRUS and template guided implantation Templates: Syed- Neblett template or MUPIT Method –

Seattle’s Preplanned transperineal implantation technique

Intraoperative planning techniques

PREPLANNED TRANSPERINEAL TECHNIQUE Volume study-TRUS imaging is obtained before the planned

procedure to assess the prostate volume (Holm et al) Seed selection- isotopes/ loose or stranded/activity Treatment planning-A computerized plan is generated from

the transverse ultrasound images, producing isodose distributions and the ideal location of seeds(at 1 cm interval) within the gland to deliver the prescription dose to the prostate Seed strength : I131 – 0.41 mci, Pd103 – 1.32 mci Prescription dose: prescribed at MPD Loading techniques Post plan -to confirm the dose delivered to the prostate as well

as evaluate the dosimetry to the OAR Implant procedure

Precautions Total exposure to any individual from patient shouldn’t >0.5

rem over the life span of the implant Keep away from pregnant lady, children < 2months, to

abstain for 2-3 weeks and to use barrier contraceptives for few weeks

Temporary implants: Ir192 seeds in plastic ribbon/ 10-15 needles left for 3 days Disagreement b/w pre implant and post implant dose

distribution Formation of hot and cold spots, source anisotropy, low

energy, radiation is attenuated along the length of seed resulting in cold spots>50% at ends

Dose: Brachy Brachy+ EBRT I12 5 145 Gy 110Gy+ 45-50 Gy Pd103 125 Gy 100 Gy+ 45-50 Gy Ir192 20-25 Gy 4-6Gy/# 6 hrs apart, 2#/day

Complications Transient urinary morbidities- urethritis/prostatitis/dysuria

postimplant 2-3weeks and peaks in 3-4 months Incontinence if prior TURP

Decreased chances of impotency Rectal complication similar as with EBRT

TRUS GUIDED HDR INTERSTITIAL BRACHYTHERAPY

ADJUVANT RADIOTHERAPY Increased local control eradicating microscopic

periprostatic disease/ decresed distant mets/ improved survival

Indications: Immediate- after RP with positive Sx margins, SVI, poorly

diff. ca (GS 8-10), LN mets Delayed- ↑PSA level with no e/o distant mets, clinically

local recurrence and LN mets Dose- 45-50 Gy/20-25#/4-5weks f/b 18 Gy with b/l 120º arc

rotation boost to the prostate bed

Local failure as a function of site and post op RT Site Without RT (%) With RT(%) SVI + 45 14 SVI ― 25 4 Capsule + 31 12 Capsule ― 35 12 Margins + 25 1 Margins ― 44 0

METASTATIC CA PROSTATE: PALLIATIVE RT Locally advanced / unresectable Hormone failed patients Painful bony mets

20Gy/5# or 30 Gy/10# or 8Gy SF ↓ pain/ stabilizes bone/ ↓ chances of pathological #

Multiple painful sites/bony mets Hemi body irradiation– 6 Gy to upper1/2, 8 Gy lower ½ as

SF with a gap of 2-3 weeks b/w two treatment and complete pain relief 70-80% within 4 weeks

Cord compression Palliative XRT Systemic therapy

Sr89 ― calcium analogue ß emitter with energy of 1.43 MeV, t1/2 50.5 days , 4 mci IV, response in 20-50% in 4-15 months

P32 ―delayed response and more toxic

MECHANISMS OF ANDROGEN AXIS BLOCKADE Male sex hormones (testosterone, androgens) are critical to

growth of prostate cancer Hormonal therapy is 1st line therapy Normalization of PSA < 4ng/ml - 60-70% Tumor masses will decrease by half or more in 30-50% Improvement in symptoms (bone pain, urinary obstruction)- 60% There are four general forms of ADT:

Ablation of androgen source

Inhibition of LHRH or LH

Inhibition of androgen synthesis

Antiandrogens

Orchiectomy DESLeuprolide

Aminogluthemide Cyprotene acetate

Goserelin Ketoconazole Flutamide

Triptorelin Biclutamide

Histrelin Nilutamide

Cetrorelix

Abarelix

Effects of androgen deprivation Bilateral orchiectomy - testosterone ↓ by 90% within 24 hrs of

surgery One year survival rate of 73 % and a five-year survival rate of 35 % in

Stage IV (CA Cancer J Clin 2002;52:154-179, VACURG study,1967 )

Nonsteroidal antiandrogens – increase LH and testosterone levels Antiandrogens can act agonistic on some tumors; antiandrogen

withdrawal results in decline of PSA level in 15% to 30% of patients

Bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer

All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.

Strategies for Androgen Deprivation

COMBINED ANDROGEN BLOCKADE

Blocks androgen production from the testes (95%) and the adrenals (5%)

LHRH agonists + antiandrogen (flutamide, bicalutamide, nilutamide)

Have not been shown to be superior to LHRH therapy alone Higher cost and more side effects than LHRH therapy alone DES1-3 mg TDS LHRH agonists

Pitutary desensitization by altering pulsatile release of LHRH Diminished LH Fall in Testosterone <50ng/ml Advantages : Less CVS toxicities

Less chances of gynaecomastia Anti-androgen

Competitively inhibits DHT receptors -Flutamide 250 mg TD and Biclutamide 50 mg OD

With hormonal ablation complete androgen blockage

SIDE-EFFECTS OF HORMONAL THERAPY

Castration Loss of libido Erectile dysfunction Hot flashes (55–80% during ADT) Gynaecomastia and breast pain (49–80% DES, 50% CAB, 10–20%

castration) Increase in body fat Decrease in bone mineral density Osteoporosis Muscle wasting Anaemia (severe in 13% CAB) Cognitive decline

Oestrogens Cardiovascular toxic effects (AMI, CHF, CVA, DVT, pulmonary embolism)

LHRH agonists Flare phenomenon due to initial rise of testosterone Might worsen symptoms Costly

Antiandrogens Steroidal

Pharmacological S/E-loss of libido, erectile dysfunction, but rarely gynaecomastia

Non-steroidal Pharmacological S/E- gynaecomastia (49–66%), breast pain (40–

72%), hot flushes (9–13%) Non-pharmacological S/E related to individual drugs

Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory

CHEMOTHERAPY Hormonal Therapy is effective for an average of 2 years Clonal proliferation of androgen insensitive prostate cancer cells

over time results in hormone refractory disease Patients may experience new or worsening symptoms, or a

consistent elevation of the PSA at some point in the disease course Disease progression in spite of castaration level testosterone

termed as Hormone Refractory Prostate Cancer (HRPC) Some patients may respond to 2nd line hormonal therapy Response rates vary from 20-60% Improvement is usually temporary Patients who progress after further hormonal manipulation may be

candidates for chemotherapy FDA-approved agents prior to 2004:

Mitoxantrone Estramustine

Main benefit is improvement in pain with limited objective responses and NO Survival benefit

TAX 327 1006 patients in 24 countries with HRPC were randomized to

one of three chemotherapy regimens: Docetaxel every 3 weeks (with prednisone) Docetaxel every week (with prednisone) Mitoxantrone every 3 weeks (with prednisone)

Patients who received Docetaxel every 3 weeks (with prednisone) experienced: Improvement in median survival of 2 months (18.9mvs. 16.5 months) Greater PSA decline (45% vs. 32%) Improvement in Pain (35% vs. 22%) S/E were manageable

William Berry and Mario Eisenberger -The Oncologist 2005;10(suppl 3):30–39

Charles J. Ryan and Mario Eisenberger - J Clin Oncol 23:8242-8246

ADJUNCTIVE T/T Bisphosphonates:

Aledronate (Fosamax) Zoledronate (Zometa) Pamidronate (Aredia)

Strong affinity for bone Directly inhibit osteoclast activity: prevent bone resorption

induce osteoclast apoptosis Zoledronate

Indicated for treatment of men with HRPC 4 mg IV q 3 wk Decreases skeletal related events: Bone resorption / pathologic # Decreases bone pain No effect on disease progression, PSA, Survival

Rationale Bone resorption increaed in metastasis which contributes to skeletal

morbidity ADT further increases bone resorption

TARGETED CRYOABLATION OF PROSTATE Cryoablation: cancer treatment by freezing to -40º Centigrade Immediate cancer cell death Dead cells are slowly reabsorbed by the body Minimally invasive -No surgical incision, minimal blood loss, no

radiation OPD procedure, with rapid return to normal activities A well-established treatment for localized prostate cancer ? Better than radiation for high risk (e.g. high GS) disease T/t of recurrence after radiation No increase risk of rectal or bladder cancer No cystitis or proctitis Can be combined with hormonal therapy Can be repeated if necessary More rapid recovery than after RP Erectile dysfunction frequent but treatable Adv - Higher preservation of potency Disadv - No sampling of the tumor

and the “fear” of residual cancer not killed

PROGNOSTIC FACTORS

Grade Stage PSA % biopsy cores PSA velocity

SCREENING GUIDELINES FOR THE EARLY DETECTION OF PROSTATE CANCER (AMERICAN CANCER SOCIETY)

PSA test and DRE should be offered annually, Beginning at age 50, to men who have a life expectancy

of at least 10 years. Men at high risk (African-American men and men with a

strong F/H of one or more first-degree relatives diagnosed with prostate cancer at an early age) should begin testing at age 45.

For men at average risk and high risk, information should be provided about what is known and what is uncertain about the benefits and limitations of early detection and treatment of prostate cancer so that they can make an informed decision about testing.

Relapse risk Expected survival Initial T/t

LOW:T1, T2aGS 2-6PSA< 10

<10yr

Very high:T3b-T4

Intermediate:T2b, T2c

GS 7PSA-10-20

Expectant m/m or RT orRP±PLND

High:T3a

GS 8-10PSA>20

>10yr

Expectant m/m or RT

<10yr<10yr

>10yr>10yr

Expectant m/m or RT or RP±PLNDExpectant m/m or RT or RP±PLND

RP±PLND or RTRP±PLND or RT

Androgen ablation +RT or RT or RP±PLND

Androgen ablation or RT+Androgen ablation

Any T, N1

Any T, Any N, M1

Androgen ablation

Androgen ablation or RT+Androgen ablation

THANK YOU

Most widely used system devised for the USA-based Veterans’ Administration Co-operative Urological Research Group (VACURG)

Grade 1: well-differentiated carcinoma with uniform gland pattern. Grade 2: well-differentiated carcinoma with glands varying in size

and shape. Grade 3: moderately differentiated carcinoma with either (a)

irregular acinae often widely separated; or (b) well-defined papillary/cribriform structures. This is the commonest pattern seen in carcinoma of the prostate.

Grade 4: poorly differentiated carcinoma with fused glands widely infiltrating the prostatic stroma. Neoplastic cells may grow in cords or sheets and the cytoplasm is clear.

Grade 5: very poorly differentiated carcinoma with no or minimal gland formation. Tumour cell masses may have central necrosis.

Targeted Cryoablation of the Prostate (TCAP)

Before Before

Probes Placed Probes Placed

Prostate frozenProstate frozen

PTV I PTV II

IMRT PLAN SUM