1. Future Developments in
Radiation Therapy for Prostate
Cancer
Steven J. Frank, MD
Assistant Professor
Genitourinary and Head/Neck Sections
Division of Radiation Oncology

2. Rectal Fistula
Sinus tract vs fistula

3. Rectal Necrotic Tissue
Biopsies showed
necrotic tissue

4. Dose-escalation is not free
• Rectal toxicity
• Urinary
• Erectile

5. Therapeutic ratio
Tumor control
Probability
of Normal tissue complication
EFFECT
Total Radiation DOSE

6. Where are we going in
Prostate Radiation Therapy?
EBRT Brachytherapy
• 2D • 1st Generation Implants
• 3D • 2nd Generation Implants
• IMRT • 3rd Generation Implants
• Hypofractionation • 4th Generation Implants
• SBRT
• 5th Generation Implants
• Protons
• IMPT

7. Where have we come from?

8. PSA control after conventional
dose RT (~70Gy)
IJROBP 2001;49

9. Higher RT doses improve
disease control
• Multiple retrospective studies show benefit to
higher doses of RT.
– MDACC (Pollack & Zagars. IJROBP 39, 1997)
– Fox Chase (Hanks et al. IJROBP 41, 1998)
– MSKCC (Zelefsky et al. IJROBP 41, 1998)
– MSKCC (Zelefsky et al. J Urol 166, 2001)
– Cleveland Clinic (Lyons et al. Urol 55, 2000)

10. More Grade 2 rectal complications in 78 Gy arm
[IJROBP 53, 2002]

11. More Grade 2+ rectal toxicity
if >25% of rectum received 70Gy

12. Dose-escalation w/ less
toxicity
• Delivery techniques
– IMRT
– Protons
• Reduce PTV
– Target localization (e.g. BAT, fiducial markers)
– Target immobilization (e.g. rectal balloon)
– Reduce CTV
• Selective dose-escalation
– Intra-prostatic targets and avoidance structures

13. Axial Dose Distribution
75.6 Gy
79 Gy 60 Gy

14. Sagittal Dose Distribution

15. DVH
Prostate:
>100%V@75.6Gy
SV:
>95%V@75.6Gy
Rectum:
<20%V@70Gy
<35%V@60Gy
Bladder:
<25%V@70Gy
<35%V@60Gy
Femoral Heads:
<5%V@50Gy

16. MSKCC
Rectal toxicity (3D CRT vs. IMRT)
3DCRT
IMRT

17. MSKCC
GU toxicity based on dose 81 vs. 86 Gy
“Among patients who received doses 75.6 Gy, the incidence
of Grade 2 urinary symptoms at 5 years was 13% compared 8%
at lower doses.” [IJROBP 53, 2002]

18. Dose-escalation w/ less
toxicity
• Delivery techniques
– IMRT
– Protons
• Reduce PTV
– Target localization (e.g. BAT, fiducials)
– Target immobilization (e.g. rectal balloon, tracking)
– Reduce CTV
• Selective dose-escalation

20. Accelerator Systems
Synchrotron
Linac Injector

21. 13 m diameter
190 tons
SAD 2.7 m

22. Image
Receptors
Nozzle
Snout
Couch
X-ray
tube
Articulating Floor

23. A Single Bragg Peak

24. Modulation of the Bragg Peak
 The Bragg peak is spread out by introducing extra
absorbing material before the beam enters the patient. If
different thickness of such absorber are present for
different fractions of the irradiation time, the narrow
monoenergetic peak can be spread into a useful plateau
 The Bragg peak can be spread out
to a useful plateau by the use of a
rotating stepped absorber.
Range
Modulator
Wheel

25. SOBP, Photons, & Bragg Peak
PSI

26. Aperture 2D Shaping
Lateral aspect of aperture used
to spare critical structures

27. Compensator 3D Distal
Shaping
As well as spreading out
the Bragg peak, the final
range itself must be
shaped to the distal
surface of the target
volume taking into account
heterogeneities

28. Two lateral beams.
Further improvements w/ IMPT?
Decreased integral dose.
Better dose homogeneity.
Quicker planning time.

29. Dose-escalation w/ less toxicity
• Delivery techniques
– IMRT
– Protons
• Reduce PTV
– Target localization (e.g. BAT, fiducials)
– Target immobilzation (e.g. rectal balloon)
• Selective dose-escalation

30. Sharp dose-fall off with IMRT requires
accurate DAILY target localization

31. Dancing Prostate
25 treatment CTs
Acquired during a course
of 42 fxs treatment
Dong (MDA), 2002

32. IGRT is a Process
VARIAN

33. Reducing PTV a.k.a.
IGRT (Image Guided Radation Therapy)
• Improve accuracy and decrease normal
tissue irradiated
• Requires daily imaging of the target
• INTER-fractional movement
• INTRA-fractional movement

34. IGRT
• Portal imaging
• Ultrasound (e.g. B.A.T.)
• Fiducial markers (intraprostatic)
• Volumetric on-board imaging
– In-room CT
– Cone-beam CT

35. BAT alignment (axial)
Bladder
Prostate
Rectum

36. BAT Alignment (sagittal)
Bladder
Prostate
Rectum

37. Ultrasound-based alignment
• Pros • Cons
– Non-invasive – User-subjectivity
– Reasonably good – Patient anatomy may
alignment affect image quality
– Visualize SV/
– Impact of probe
bladder/rectum
pressure on prostate
– Visualize prostate
position
surface contour
– Different imaging
– Follow-up
modality
– New volumetric
systems

40. On-Board Imager (OBI) - Varian
kV X-ray Source
aSi Imaging Panel
(2048 x 1536 pixel resol.)
Robotic Arms
- 3 pivot points
- Completely retractable
- Position feedback control
Software
- Image acquisition and
registration

41. OBI 2D-2D manual match: pre-shift

42. OBI 2D-2D manual match: postshift

43. Fiducial-based alignment
• Pros • Cons
– Less subjectivity – Invasive
– Good alignment – Requires daily ports
• (unless KV imaging onboard)
– Allows target tracking
– No image of SV, rectum/bladder
• Kitamura and Shirato et al.
– Better for large patients – No image of prostate surface
contour
– Basis for improved
– Shifts may not be representative
multimodality image fusion
(e.g. MRI-CT) of volume
• Jaffray et al. ASTRO 2004
• Fiducials and MRI
– Ongoing MDACC study
• 47% had 3mm deformation over
comparing fiducials vs. CT-
90% of surface
on-rails
• On average, 14% of surface
deformed by >3mm (up to 9mm)

44. Varian ExaCT™ at MDACC
Linac
In-room CT

45. CAT Software (3D-3D matching)
Compares Pinnacle planed patients
to volumetric images
Lei Dong, Lifei (Joy) Zhang

46. A closer look at contour overlay
Courtesy of Lei Dong

47. Step 4. Automatic Image Registration
Courtesy of Lei Dong

48. Step 5. Review Image Registration
(prostate is the target of alignment)
Courtesy of Lei Dong

49. • CT-based alignment could yield
accuracy of <3mm
– Smaller treatment margins
– Less dose to rectum, bladder
– Avoid high-dose to intra-prostatic
structures (e.g. urethra)

50. Robotic arm motion

51. Robotic arm motion

52. Robotic arm motion

53. Cone-beam CT
• Uses on board kV X-ray source and
amorphous silicon flat panel imager
• Large field of view (25 x 25 x 10 cm) and
single revolution captures images
– Unlike standard CT that uses small field of view
and many revolutions
• Inferior image quality compared to
conventional CT but may be adequate for RT
targeting

54. Cone Beam CT – Large GU patient
(330 lbs)
Planning CT
CBCT

55. Post shift CBCT verification
using in-house CAT software

56. Cone Beam CT vs. CT on Rails
< 5 min acquisition and < 5 min acquisition and
reconstruction time reconstruction time
Patient is imaged in treatment Patient is rotated into scanning
position (except for lateral shifts) position on treatment couch (lateral
and vertical shifts required)
Isocenter defined in CT space Isocenter not linked to images
Each slice is a 60 sec time average Each slice is a 1 sec time average
45 cm FOV half-scan 50 cm FOV (full scan)

57. Dose-escalation w/ less toxicity
• Delivery techniques
– IMRT
– Protons
• Reduce PTV
– Target localization (e.g. BAT, fiducials)
– Target immobilzation (e.g. rectal balloon)
• Selective dose-escalation
– Intraprostatic GTV/OAR

58. Endo-rectal balloon
1. Immobilize prostate (accounts for inter-
and intrafractional motion)
2. Displaces rectum away from high dose

59. Example
-2.0
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0
CT Shift (cm)
Same Day Axial CT
BAT Oblique Axial

60. Is intra-fractional prostate motion a
concern?
• Daily IMRT treatment 15 minutes to
setup and deliver
• Possible prostate positional change
during this interval largely due to
transient rectal gas
• Positional change can be large (>5
mm), but usually transient
• Clinical impact over 7-8 week treatment
course is unknown

61. Dose-escalation w/ less toxicity
• Delivery techniques
– IMRT
– Protons
• Reduce PTV
– Target localization (e.g. BAT, fiducials)
– Target immobilzation (e.g. rectal balloon)
• Selective dose-escalation
– Intraprostatic GTV/OAR

62. What is needed to treat intra-
prostatic targets?
• Imaging modality beyond CT that can
delineate intra-prostatic tumor
– Endorectal MRI/MRS
– Dynamic contrast MRI
• Conformal delivery method
– IMRT, protons, brachytherapy
• Accurate delivery
– Daily imaging w/ online correction
– Target immobilization?
– Transrectal U/S guidance

63. Endorectal MRI
• Endorectal MRI uses a
coil inside an inflatable
latex balloon (50-70cc).
– Coil just posterior to
prostate
• Resolution is 0.4mm
per pixel pair
– Body coil MRI has
resolution of 3 mm
[Roach et al. Oncology 15:1399-1410]
• Accuracy is technique
and reader dependent
as per RDOG studies
– [Radiology 1994;192:47-54]

66. 75.6Gy
87.2Gy
Concomitant
boost
Special thanks to Danny Tran & Lei Dong

67. CT/ MRI/MRS fusion
• Define CTV more clearly
– Prostate anatomy
– Reduced side effects
• Define other CTV’s (e.g. peripheral zone, urethra)
– Selective dose-escalation (“Dose painting”)
– Reduce toxicity w/ in the prostate
• Define GTV
– Selective dose-escalation (Focal boost)

68. Hypofractionation
• Provide basis for larger fractional dose w/
equal or less toxicity
– / for prostate ca may be < 4 Gy
» [Brenner et al. IJROBP 52:6-13]
• Hypofractionation studies:
– Kupelian et al 70 Gy (2.5Gy/Fxn) [IJROBP 53, 2002]
– MDACC ongoing randomized study
• 75.6/1.8 Gy vs. 72/2.4 Gy (BED = 78-82 Gy)

69. 72 Gy
(2.4Gy)

70. Cleveland Clinic-retrospective
70Gy/2.5Gy vs. 78Gy/2Gy
Grade 2-3 rectal toxicity
166 (SCIMRT)
116 (3DCRT)
Median FU 21 vs. 32 mo
Only 2 pts in each group
had Gr 2+ GU toxicity.
Kupelian et al. IJROPB 53, 2002

71. Highest Degree of Conformal
Therapy?
Brachytherapy

72. 1st Generation Implants:
Open Placement

73. Transperineal Interstitial Permanent
Prostate Brachytherapy
18 gauge needle
(1.3 mm diam) for
seed placement
Perineal template to
Ultrasound probe in
localize needles as planned
rectum for needle guidance

74. 2nd Generation Implants:
Uniform Loading

75. Source Migration
*
*Coronary
artery
Davis BJ et al., J Urol 2002; 168:1103.

76. 3rd Generation Implants
• Modified peripheral loading
– Reduced urethral dose (not urethral sparing)
– All seeds implanted in the prostate
(which means little treatment outside capsule
or high urethral dose with margin)
– CT-based dosimetry evaluation

77. Modified Peripheral Loading

78. 4th Generation Implants
• Stranded seeds (Varistrand )
– Less seed migration
– Permits periprostatic seed placement
• Improved dosimetry
– Wider therapeutic margin on prostate (3 - 5
mm)
– MRI / CT fusion (better QA better implants)
– Improved Homogeneity

79. Intraoperative Comparison of
Actual Seed Location to Preplan

80. PTV DVH Parameters
V100>95%
V150<60%
V200<20%
D90<120%
R100<1cc

81. 5 yr BRFS Monotherapy
• Seed monotherapy 5 yr BRFS if implant
quality questionable or poor = 34-63%
• Seed monotherapy 5 yr BRFS if implant
quality is good = 82-98%
• % positive Bx cores predicts RP BRFS
• RTOG-0232 randomized study I125/Pd103 +/-
EBRT intermediate risk patients

82. Transperineal Interstitial
Permanent Brachytherapy
Alone for Selected Patients
with Intermediate Risk
Prostate Cancer
Phase II Prospective Single Arm Study
David Swanson and Steven J. Frank

83. Stratification
• < 35% core biopsy and Gleason 7 disease
with a PSA under 10
• < 35% core biopsy and combined Gleason
scores less than 7 with a PSA 10-15
• >/= 35% core biopsy and Gleason 7 disease
with a PSA under 10
• >/= 35% core biopsy and combined Gleason
scores less than 7 with a PSA 10-15

84. MRI vs. CT
Prostate Phantom Prostate Phantom
Front view Front view
Notice the artifacts on CT imaging
July 2008

85. 1.5T MRI Strand
Prostate Phantom Prostate Phantom
C4
Seed
Oblique view Saggittal view

87. GU Team
• Physicians • Physicists
– Seungtaek Choi – Lei Dong
– Min Rex Cheung – Rajat Kudchadker
– Deborah A. Kuban – Jennifer Johnson
– Andrew K. Lee
• Dosimetrists
– Paula Berner
– Jim D. Cox – Teresa Bruno
– Tom A. Buchholz – Mandy Cunningham
• Therapists
• Nurses