Radiation Therapy in Prostate Cancer

Lokesh Viswanath M.D.Professor, Radiation Oncology, Kidwai Memorial Institute of Oncology 2014

Prostate Cancer• World wide :

– Second most common cause of cancer– New Cases ~ 1.1 million (15%)– Developed countries ~ 70%– 307,000 deaths

• Prostate cancer incidence – Lowest:

• Asian populations 10.5 per 100,000 • Eastern and South-Central Asia 4.5 per 100,000

– Highest : • 111.6 Australia/New Zealand and • 97.2 per 100,000 Northern America

In India• Previously – thought - prevalence of prostate cancer in India

is far lower compared to western countries • but …

– increased migration rural to urban areas– changing life styles– increased awareness– easy access to medical facility

…..– more cases of prostate cancer are being picked up

– we are not very far behind the rate from western countries.

– Current incidence rate of prostate cancer in India is ~ 10.66 per 100000 population

Current India Data: • Prostate cancer:

– 2nd leading site of - Delhi, Kolkatta, Pune and Thi'puram– 3rd leading site of Bangalore and Mumbai

Projected cases of prostate cancer for selected time periods (2013, 2014, 2015 and 2020).ICD-10 Site name 2013 2014 2015 2020C61 Prostate 35,029 37,055 39,200 51,979

Prostate : Anatomy • Prostate

– Accessory gland– Inverted Cone encompasses the p. urethra– Dense fibromuscular stroma– Surrounded by a capsule – 4 x 3 x 2cms– 8g

• Prozimity to Rectum & U Bladder– Denonvilliers fascia

• Blood supply– Inferior vesical – Mid rectal– Internal pudendal

• Lymphatics– Internal iliac nodes– Sacral– Partly external iliac nodes

Nervous supply– Neurovascular bundle

• Lies on either side of the prostate on the rectum– Derived from the pelvic plexus - Important for erectile function.

Epidemiology • Risk factors

– Increasing age– Family history– African-American– Dietary factors.

• Race– Incidence doubled in African Americans compared to white Americans.

• Genetics– Common among relatives with early-onset prostate cancer– Susceptibility locus

• Chromosome 1, band Q24• Found in < 10% of prostate cancer patients

• Nutritional factors - protective effect against prostate cancer– Reduced fat intake– Soy protein– Lycopene– Vitamin E– Selenium

Clinical Manifestations : Symptoms • Early state (organ confined)

– Asymptomatic• Locally advanced

– Obstructive voiding symptoms • Hesitancy• Intermittent urinary stream• Decreased force of stream

– May have growth into the urethra or bladder neck – Hematuria – Hematospermia

• Advanced (spread to the regional pelvic lymph nodes)– Edema of the lower extremities– Pelvic and perineal discomfort

Clinical Manifestations : 2• of Metastasis :

– Most commonly to bone (frequently asymptomatic)• Can cause severe and unremitting pain

– Bone metastasis • Can result in pathologic fractures or • Spinal cord compression

– Visceral metastases (rare)– Can develop pulmonary, hepatic, pleural, peritoneal, and

central nervous system metastases late in the natural history or after hormonal therapies fail.

Clinical Signs

• Routine Clinical history and clinical examination Rectal examination

• Signs: PR examination - Abnormal • ( +ve for Malignancy 25-50%)

• Hard nodule / extremely firm• Evaluate for disease extension in

– Lateral sulcus– superior

Presentation

• Peripheral zone (PZ)– 70% of cancers

• Transitional zone (TZ)– 20% – Some

• TZ prostate cancers are relatively nonaggressive• PZ cancers are more aggressive

– Tend to invade the periprostatic tissues.

InvestigationsRoutine: Laboratory

Complete blood cell count, blood chemistry Serum PSA (total, free, complex PSA:: ratio of Free : Total PSA < 0.2 - likely Prostate Ca. )

(Normal Age-Specific Limits for PSA - Plasma acid phosphatases (prostatic/total) Testosterone

Other Experimental:RT PCR for mRNA of PSA & PSMA

+ve - Extraprostatic – 72%-ve - Organ confined - 88%

Staging Tests1. Magnetic resonance imaging (MRI) –

defn Apex, NV bundle, ano rectal wall, intra prostatic dises location, capsular extension, seminal vesicle involvement

1. T2 axial / coronal : neurovascular bundle , penile bulb2. PZ - T2 Normal – high signal , Tumor – Low signal , T1 – Hemorrhage – Low

signal intensity3. Extracapsular extension : focal, irregular capsular bulge, invasion of NV bundle,

obliteration of rectoprostatic angle4. endorectal MRSI – MR spectroscopy : metabolic activity and extra capsular

extension, seminal vesicle invasion : Increase coline

2. Transrectal ultrasound (TRUS) : » Ca – variable echo, hyper – 69%, margin - poorly defined ,

3. Transrectal or transperineal biopsy : – 16 guage , 10 -18 core (base, apex, both lateral, mid, lat peripheral zone)– Core length

4. Chest radiograph (high risk for metastatic disease)5. Computed tomography (CT) scans – pelvis node assesment

6. Radionuclide bone scans : Indicated: PSA>20, Gleason score ≥8, Bone pain

Other:

1. PET/CT with 11C- Acetate - detecting microscopic +LN

Others : essential base line evaluation

• Erectile function• Bowel : SI/LI/Rectum/Anal Sphincters• Bladder : Flow/rate

AJCC / TNM Stage Groupings Definitions

Pathology• Adenocarcinoma 95% - peripheral acinar glands• Other Histologic Subtypes

– Periurethral duct carcinoma– transitional cell carcinoma – Ductal adenocarcinoma – Neuroendocrine tumors – Mucinous carcinoma– Sarcomatoid carcinoma – Endometrioid tumors – Adenoid cystic carcinoma – Sarcomas (leiomyosarcoma, rhabdomyosarcoma, or fibrosarcoma) – Carcinosarcoma – Primary lymphoma

Evaluation of the histologic grade ('G')

GX: cannot assess gradeG1: the tumor closely resembles normal tissue (Gleason 2–4)G2: the tumor somewhat resembles normal tissue (Gleason 5–6)G3–4: the tumor resembles normal tissue barely or not at all

(Gleason 7–10)

• histological patterns, emphasizing degree of glandular differentiation and relation to stroma

• Histologic patterns 1 through 5• nine discrete scores (range, 2 to 10)• one of the strongest predictors of

– biologic behavior in prostate cancer– invasiveness – metastatic potential– < 6

Gleason score

Prostate Cancer Risk Groups :- stage : PSA : Gleason score

Treatment options for prostate cancer

• Observation alone

• Radical prostatectomy

• Radiation therapy

• Hormonal treatment

Overview Treatment Options by Stage for Prostate CancerStage ( AJCC TNM Staging Criteria)   Standard Treatment Options 

Stage I •Watchful waiting or active surveillance

•Radical prostatectomy

•External-beam radiation therapy (EBRT)

•Interstitial implantation of radioisotopes

Stage II •Watchful waiting or active surveillance

•Radical prostatectomy

•External-beam radiation therapy (EBRT) with or without hormonal therapy

•Interstitial implantation of radioisotopes

Stage III •External-beam radiation therapy (EBRT) with or without hormonal therapy

•Hormonal manipulations (orchiectomy or luteinizing hormone-releasing hormone [LH-RH] agonist)

•Radical prostatectomy with or without EBRT

•Watchful waiting or active surveillance

Stage IV •Hormonal manipulations

•Bisphosphonates

•External-beam radiation therapy (EBRT) with or without hormonal therapy

•Palliative radiation therapy

•Palliative surgery with transurethral resection of the prostate (TURP)

•Watchful waiting or active surveillance

Recurrent •Chemotherapy for hormonal management of prostate cancer

•Immunotherapy

Indications for RT T N0 N1 M1 PSA GS

SURVELLIANCE SURGERY Radical RT

Radical Brachytherapy HT

T1a + <10 <6 YES RP+ PLND RT BRACY

T1b + <10 <6 YES RP+ PLND

(<2% +ve nodes) RT BRACY

T1c + <10 <6 YES RP+ PLND

(>2% +ve nodes) RT BRACY

T2a + RT + ADT

T2b + RT + ADT

T2c +

10 to 20 7 YES RP+ PLND

RT + ADT + BRACHY BOOST BRACY Y

T3a + >208 to 10 RP+ PLND RT + ADT BRACHY BOOST Y

T3b + RT + ADT BRACHY BOOST Y

T4 + RT + ADT BRACHY BOOST ADT

Any T + RT + ADT Y

Any T / N + RT ADT

Radiation Therapy : Basics

Radiotherapy

• Radiation therapy is the art of using ionising radiation to destroy malignant tumours while being able to minimise damage to normal tissue.

Introduction• Basics of Radiation Therapy

– Ionizing Radiation – X / γ Rays– Interaction of Radiation with matter

Transmission Attenuation

Scatter Absorption

Rad / Gray / cGy

Cancer Cell & Ionizing Radiation

• Cancer cell multiply faster than normal cell• DNA is primary target • Double Strand breaks

>>> Reproductive Cell Death

RT is a Double Edge Sword

↑ RT Dose

↓ RT Dose

↑ T – Control ↓ T – Control

↑ Normal Tissue Toxicitites

↓ Normal Tissue Toxicitites

EQUIPMENTS

Radiation EquipmentsTeletherapy• Telecobalt• Linear Accelerator

– Simple Teletherapy– SRS/SRT– 2D– 3DCRT– IMRT– IGRT– Rapid Arc– FFF– SBRT – 4DRT – Target tracking– Tomotherapy– Cyber Knife

• Gamma Knife

Brachytherapy– Intracavitory– Interstitial– Mould

• Pre Loaded / After loading

• Manual / Remote• LDR / HDR • Permanent Implants

Linear Accelerator• 3DCRT > 1998+• IMRT > 2000+

Linear Accelerator : 3DCRT / IMRT

Tomotherapy - 2003

Synchrony™

camera

Treatment couch

Linearaccelerator

Manipulator

Imagedetectors

X-ray sources

Targeting System

Robotic Delivery System

Cyber Knife – 2003+

IGRT - 2005

True beam - All in One FFF SBRT / 4DRT –

True Beam - 2010

Proton Beam therapy 2012

Brachytherapy

• LDR - Iridium wires – Manual Interstitial <Phased out>

• HDR – Iridium / Cobalt• Permanent Interstitial Implant – Iodine seeds

125 I Seed Implant

HDR - Brachytherapy

RT Planning Process

Radiation Therapy

Prostate Cancer : • Disease Characterization :

• Clinical - KPS/Co-existing Morbidities/TRUS/ CT/MR• TNM/PSA/GS

– Primary – Primary + Regional nodes

• + ADT

PSA (ng/ml) +VE PELVIC NODE YEILD

4-20 < 12%

>20 > 10%

> 25 30-35%

> 50 + high GS 62%

Radiation Therapy : Intent Defn • Radical RT

– RT alone:– Conventional (7-8 weeks) <– Hyperfractionation (5-6 weeks) – Hypofractionation (1-2 Gap 1-2 weeks) < CK / SRS / SBRT – Photons alone

– Recent adv - Photons + Particle (Protons)– Protons alone– RT + Hormon therapy (HT)– RT + Radiation Protectors (Amifostine)– Teletherapy + Brachytherapy Boost– Brachytherapy alone

• Brachy type: Volume implants– Temporary Implant – HDR– Permanaent Implant – I 125

• Post Operative RT (5-7 weeks)• Salvage RT / Re-irradiation• Palliative RT

– Short Course (1day, 1-2 weeks)– Saturation Technique (1-2 weeks gap 3-4 weks)

RT Techniques

• Teletherapy– 2 D– 3 D Conformal– IMRT– IGRT– Tomotherapy– CK SRS / SRT– Rapid arc– SBRT - FFF– Proton

• Bracytherapy– Interstital

• HDR – Ir - Temporary • 125 Iodine - Permanent

Indications for RT in Ca Prostate• Radical RT

– T1, T2, T3, T4a

• Un-resectable (Altered Fractionation HF/CB or RT + HT )• elderly, frail, comorbid conditions• refusal for surgery• prohibitive morbidity due to surgery

• Post OP RT : after Radical Prostatectomy– pT3/4– Close & +ve margin– Extra Capsular extension– Invasion to

• Seminal vesicle• Extraprostatic extensions

– Multiple nodes– R 1 resection

• Pre OP PSA > 10ng/ml• Pre OP PSA velocity > 2ng/ml/year

– Post RP – Recurrent disease– Post RP - early PSA failures

RADIOTHERAPY DOSE

1. External : a. IMRT / IGRT / Rapid Arc / Protons :

– > 7400 cGy to 7600 cGy / 6-8 wks– 180-200cGy / fr, 5fr/wk

b. CK / SBRT / FFF : 5 – 20 Gy / fr, 3-5 fr

c. Post-op.: 60-66 Gy / 6-7 wks

d. Palliative RT: 30Gy/10f, 20Gy/5 or 4f, 7-8Gy/1f

2. Brachytherapy : a. Alone : 6000 - 7000 cGy in 6 to 7 days.

b. External + Brachytherapy Ext : 46-50 Gy in 4 1/2 - 5 1/2 wks. +

Brachy : 2000-3000 cGy in 2-3 days

HDR : 9.5Gy x 2f, as mono therapy 9.5Gy bid x 4f x 2dys

I -125 : 0.2-0.9mCi, T1/2-17dy, 21Kev

RT Dose

• 2D : 66Gy , 1.8-2Gy/f, 5f/wk• 3DCRT : 70-75Gy• IMRT /IGRT : 75 – 81Gy

Patient

RT Planning

• Informed Consent : • Implant Fidutial - +/- (if GC is not favorable CBCT )

• Mould room work : Patient positioning, knee rest• Virtual CT Simulation• Contouring• RT planning• Plan evaluation and acceptance• QA tests

Fidutial Placement

• TRUS Guided• 1 week prior to simulation

Flat Couch

CT Simulator

Instructions for Virtual SimulationMould room techniques:• Bowel / Bladder – post void (full – if u/s Tracking)• Patient Positioning : Supine (↓ P motion) / Prone• Thermoplastic mold – Pelvic cast - knee to mid thigh + Tattooe / Tegaderm• Knee rest

Virtual simulation : Flat Couch– Patient repositioning– Pelvis : pubic symphysis - Laser set (mid / 2 lateral – 5cms post) – marking – Radio-opaque markers– CT Sim - 3mm – Scan : 20-30 cms above & 20-30 cms below the marker plane

Contouring

• Data transfer : from CT sim to RT planning system – DICOM format

• Patient registration : CT data / CT + MR Fusion data• Contouring : Target & Normal tissue

– CTV – P alone / P + SV / P + SV + Pelvic Ly nodes– PTV – CTV + Margin

• Cobalt / 2D / 3DCRT - 2cms• IMRT – 1cms (in all directions except rectal interface – 0.6cms) • IGRT – 0.6 cms all round• CK/SBRT – 0.3 cms all round

– Prostatic apex definition – urethrogram / MRI

On the machine

• Machine QA for the Planned treatment• Patient positioning and verification• Portal Imaging & setup verification + CBCT• Treatment plan execution

• Daily QA• Daily Portal imaging /MV – KV / CBCT / 3D CBCT • Monitoring of Acute radiation reaction and

supportive cares

Beam selection and planning• 2 D :

– AP: PA– AP : PA : RT Lat : Lt Lat

• 3 DCRT : 6 Coplanar ( 2 – lat, 2 Ant & 2 Post Obliques )– Plan evaluation :

• Dose distribution (isocentre) – Transverse / Coronal / Sagittal• DVH• Beam weighing – 2 lat – half the dose• Uniform dose in PTV• Elimination of hot spot from rectum

• Plan normalization : • Prescription iso-dose – 100% coverage of PTV • PTV Hot spot < 6-9% • Rectal volume in PTV 75.6G < 30%• Femur < 68Gy (90%)• Large bowel < 60Gy (79%)• Small bowel < 50 gy (66%)

2D plan – Orthogonal X Ray simulation

• 3DCRT MLC based conformal field

2D RT 3DCRT

IMRT Rapid Arc

Evolution of conformality

TOMOTHERAPY : 78Gy

AMS CONFIDENTIAL

Cyber knife

Rapid Arc

Patient on Treatment

Protons

Proton Therapy vs. IMRT Dosimetric study:

10 IMRT vs.10 proton beam to 78 Gy

Mean rectal dose-volume histograms

Vargas et al. IJROBP 2007

Proton Therapy vs. IMRT

Brachytherapy

Interstitial Brachytherapy

Prostate Brachytherapy

Prostate Brachytherapy

Iodine 125

t ½ = 60 days

Gamma emitter

Energy 35 kV

During RT

Target Motion ITV Management

• Daily localization IGRT techniques to account for interfraction motion:– intraprostatic fiducial markers with daily imaging– transabdominal US– daily in-room CT imaging– endorectal balloon immobilization

• All of these methods employ daily imaging of the prostate in the treatment room.

Target Tracking

• During RT– Celing mounted Cross fired X-Ray / Fluro eg.CK, X Tack–

• Before RT– Orthogonal KV / MV Portal imaging – best with fidutial– CBCT / Onrail CT – suitable for patients without

fidutials

Ceiling mounted Cross fired X Rays

Motion Management

In this technique, the isocenter is shifted until the bony contours (setup error) or the implanted markers are in agreement (total error).

reference (simulation film) online (port film) co-registered (right)

Motion Management Cone beam computerized

tomography (CBCT) allows volumetric visualization of the prostate and adjacent organs. – Daily online correction allows for

PTV margins: • 4 mm in all directions and 3

mm posterior (Pawlowski, Red Journal 2010)

• 5 mm all around and 3 mm posterior (Hammoud, Red Journal 2008)

2 stages of image registration: Top: pelvic bone region of interestBottom: prostate/sv represented by masked area.

Motion Management• Intrafraction Motion

– Changes in position while the treatment beam is on (“second by second”)

– Mostly from peristalsis/gas, pelvic floor movement, respiration coughing, etc.

– Techniques to account for intrafraction motion:• RGRT (radiofrequency-guided RT techniques)• Rectal balloon • Bowel prep (anti-gas tablets and daily bm)• Consistent Bladder filling

Motion management Endorectal balloon

– Used for prostate immobilization/fixation

– Ensures reproducibility of rectal filling and spares posterior rectum

Teh, Red Journal 2001

78 Gy IMRT plans without (left) and with balloon (right) Contours: rectal wall (green), anal wall (purple) and PTV (blue).

Treatment results

PSA relapse free survival rate (%)

~ EBRT RP BRACHY

5 YRS 79 81 98

8 YRS 70 72 92

androgen suppression or androgen deprivation therapy.

most commonly used hormone therapies

• Orchiectomy

Medical Castration - reversible• luteinizing hormone-releasing hormone (LHRH) agonists –

synthetic proteins - similar to LHRH and bind to the LHRH receptor in the pitutary gland- causes the pituitary gland to stop producing luteinizing hormone, which prevents testosterone from being produced- leuprolide, goserelin, and buserelin

• LHRH antagonists - act by preventing LHRH from binding to its receptors in the pitutary gland

Toxicities

Impotence rates• Brachy alone – 24%• Brachy + EBRT – 40%• EBRT alone – 45%• Nerve sparing RP – 66%• RP – 75%• Cryosurgery – 87%

Urinary control• RP – 35%• RT – 97%

Summary and Conclusion

Advances in newer radiation technologies

• Enhanced Normal Tissue Sparing • Reduces side effects

• Dose Escalation has Improved Cure Rate• Higher Dose per Fraction reduces hospital visits

• Reduce Number of fractions• Reduce Treatment Duration

Thank you