Newer technological innovation in Radiation therapy has revolutionized Prostate Cancer treatment. Presented in IMA Bangalore 2014

1. Radiation Therapy in Prostate
Cancer
Lokesh Viswanath M.D.
Professor, Radiation Oncology,
Kidwai Memorial Institute of Oncology 2014

2. 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

4. 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

5. 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 2020
C61 Prostate 35,029 37,055 39,200 51,979

6. 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.

7. 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

8. 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

9. 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.

10. 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

11. 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.

12. Investigations
Routine: 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%

13. Staging Tests
1. 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 bulb
2. PZ - T2 Normal – high signal , Tumor – Low signal , T1 – Hemorrhage – Low
signal intensity
3. Extracapsular extension : focal, irregular capsular bulge, invasion of NV bundle,
obliteration of rectoprostatic angle
4. 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

14. Others : essential base line evaluation
• Erectile function
• Bowel : SI/LI/Rectum/Anal Sphincters
• Bladder : Flow/rate

15. AJCC / TNM Stage Groupings Definitions

17. 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

18. Evaluation of the histologic grade ('G')
GX: cannot assess grade
G1: 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)

19. Gleason score
• 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

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

21. Treatment options for prostate cancer
• Observation alone
• Radical prostatectomy
• Radiation therapy
• Hormonal treatment

22. Overview Treatment Options by Stage for Prostate Cancer
Stage ( 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

23. Indications for RT
T N0 N1 M1 PSA GS
SURVELLI
ANCE 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 + >20
8 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

24. Radiation Therapy : Basics

25. Radiotherapy

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

27. Introduction
• Basics of Radiation Therapy
– Ionizing Radiation – X / γ Rays
– Interaction of Radiation with matter
Transmission Attenuation
Scatter Absorption
Rad / Gray / cGy

28. Cancer Cell & Ionizing Radiation
• Cancer cell multiply faster than normal cell
• DNA is primary target
• Double Strand breaks
>>> Reproductive Cell Death

29. RT is a Double Edge Sword

30. ↑ RT Dose ↓ RT Dose
↑ T – Control ↓ T – Control
↑ Normal Tissue
Toxicitites
↓ Normal Tissue
Toxicitites

31. EQUIPMENTS

32. Radiation Equipments
Teletherapy
• 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

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

34. Linear Accelerator : 3DCRT / IMRT

35. Tomotherapy - 2003

36. Synchrony™
camera
Cyber Knife – 2003+
Treatment couch
Linear
accelerator
Targeting System
Manipulator
Image
detectors
X-ray sources
Robotic Delivery System

37. IGRT - 2005

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

39. True Beam - 2010

40. Proton Beam therapy 2012

41. Brachytherapy
• LDR - Iridium wires – Manual Interstitial <Phased
out>
• HDR – Iridium / Cobalt
• Permanent Interstitial Implant – Iodine seeds

42. 125 I Seed Implant

43. HDR - Brachytherapy

44. RT Planning Process

45. 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%

46. 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)

47. 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

48. 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

49. 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

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

51. Patient

52. 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

53. Fidutial Placement
• TRUS Guided
• 1 week prior to simulation

54. Flat Couch
CT Simulator

55. Instructions for Virtual Simulation
Mould 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

56. 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

57. 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

59. 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%)

60. 2D plan – Orthogonal X Ray simulation

61. • 3DCRT MLC
based
conformal field

64. Evolution of conformality
2D RT 3DCRT
IMRT Rapid Arc

66. TOMOTHERAPY : 78Gy

67. AMS CONFIDENTIAL
Cyber knife

68. Rapid Arc

75. Patient on Treatment

76. Protons

77. 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

78. Proton Therapy vs. IMRT

79. Brachytherapy

80. Interstitial
Brachytherapy

81. Prostate Brachytherapy

82. Prostate Brachytherapy
Iodine 125
t ½ = 60 days
Gamma emitter
Energy 35 kV

85. During RT

86. 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.

87. 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

88. Ceiling mounted Cross fired X Rays

89. Motion Management
reference (simulation film) online (port film) co-registered
(right)
In this technique, the isocenter is shifted until the bony contours (setup error) or the implanted markers
are in agreement (total error).

90. 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 interest
Bottom: prostate/sv represented by masked area.

91. 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

101. 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).

102. Treatment results

103. PSA relapse free survival rate (%)
~ EBRT RP BRACHY
5 YRS 79 81 98
8 YRS 70 72 92

105. androgen suppression or androgen
deprivation therapy.

106. 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

107. 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%

108. Summary and
Conclusion

109. 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

110. Thank you