1. Radiotherapy for Localized Prostate Cancer:
Anatomy / Planning
Dose Escalation / Dose Fractionation
Competing Treatment Modalities
Patrick Kupelian, M.D.
Professor and Vice Chair
University of California Los Angeles
Department of Radiation Oncology
pkupelian@mednet.ucla.edu
February 2013

2. Disclosures
Research grants / Honoraria / Advisory Board / Royalties:
Accuray
Siemens Medical
Varian Medical
Viewray Inc.
VisionTree

3. Outline
Anatomy:
Prostate MRI
Pelvic LN - CT
Treatment options:
Surveillance
Surgery
Radiotherapy
Radiotherapy Planning
Importance of Dose Escalation
Hypofractionation - SBRT

4. Prognosticators
Stage, PSA and Gleason score
Number of cores positive (proxy for disease volume)
Low risk: <T2A, Gleason <6, PSA <10
- (Single focus GS 7?)
Intermediate: Heterogeneous group
High risk:
T3 or GS >8 or PSA >20
Two factors: Stage >T2B, GS 7, PSA between 10 and 20
- (Single focus GS 8, low PSA?)

5. Prostate Anatomy: CT vs US vs MR
• CT: Widely available, cannot
delineate full anatomy
• Ultrasound: Not routinely
available for EBRT. Cannot
distinguish benign from
malignant tissue ?
• MRI: Not routinely available.
?
Higher level detail.
Multiparametric imaging
allows additional detail.
Courtesy D. Margolis, UCLA, 2013

6. Basic Prostate Anatomy:
Cross-Sectional Imaging
• Lengthwise (sagittal) cross-section:
• Peripheral Zone (~70% of prostate cancer)
• Central Zone (5-8% of prostate cancer)
• Transitional Zone (~20% of prostate cancer)
• Anterior Fibro-Muscular
Stroma (devoid of
glandular components)
• Seminal Vesicle
• Urethra and Bladder
Courtesy D. Margolis, UCLA, 2013

7. Basic Prostate Anatomy: Multiple Levels
• Peripheral Zone
• Central Gland
• Transitional Zone
• Anterior Fibromuscular
Stroma
• Urethra
Courtesy D. Margolis, UCLA, 2013

8. Prostate anatomy: Additional Views
SV SV
B SV
Rectal
Probe
FS P
P
Membranous
Urethra
• Sagittal image through the prostate: B:
bladder, SV: seminal vesicles, FS: • Coronal Oblique image through
fibromuscular stroma, P: prostate the prostate: SV: seminal
vesicles, P: prostate.
Courtesy D. Margolis, UCLA, 2013

9. Criteria for Prostate
Cancer on T2-Weighted MRI
• Round, ovoid, or irregular dark
regions on T2WI without
corresponding hemorrhage on
T1WI
• Irregular shape, disruption, or
bowing of capsule (blue arrow)
• Penetration or disruption of the
dark band with invasion of
neurovascular bundle or seminal
vesicle (orange arrow)
• Obliteration of the rectoprostatic
angle (preserved, green arrow)
Courtesy D. Margolis, UCLA, 2013

10. Pelvic Nodal Consensus CTV Contours
RTOG CONSENSUS GUIDELINES
Colleen A F Lawton MD
Medical College of Wisconsin
• Treatment of Presacral LNs (subaortic only)
• 7 mm margin around iliac vessels, carving out bowel,
bladder and bone
• Commence contouring at distal common iliac vessels at
L5/S1 interspace
• Stop external iliac contours at top of femoral heads
(boney landmark for Ing. ligament)
• Stop contours of obturator LNs at top of symphsis pubis

11. 25/93

12. 32
32/93

13. 58
58/93

14. 61
61/93

15. 63
63/93

16. Localized Prostate Cancer:
Competing Treatment Modalities
Surveillance (No Dose option)
Radiotherapy: - High dose EBRT
- Hypofractionation (incuding SBRT)
- Brachytherapy
Surgery: - Radical Retropubic
- Laparoscopic / Robotic
Cryosurgery
HIFU

17. No Dose
PIVOT TRIAL

21. Radical Prostatectomy vs Observation
for Localized Prostate Cancer: Toxicity

22. EXTERNAL BEAM RT COMPARISON
WITH OTHER MODALITIES

23. Importance of Dose
PSA failure by Treatment modality
Kupelian, Potters et al. IJROBP 2004;58:25-33.

25. Effectiveness of High Dose RT
Intermediate risk prostate Ca:
Clinical stage of T2b or T2c
Biopsy Gleason score (bGS) 7, or
Pretreatment PSA between 10 and 20 ng/mL.
Treatment arms: RRP vs Lap RP vs EBRT vs PI
N=979, median follow-up 65 months
Treated between 1996 and 2005
Minimum of 2 years of follow-up
At least 4 follow-up PSA levels
Vassil et al. Urology 76, 2010

26. Effectiveness
Lap RP EBRT
Vassil et al. Urology 76, 2010

27. Localized Prostate Cancer – Radiotherapy Today
Patient outcome improvements
Improved Cure Rates: Dose escalation
Doses in the 75-85 Gy range
Decreased toxicity
Grade 3 toxicities < 5%
Convenience
Hypofractionation / SBRT / Brachytherapy

28. BENEFIT FROM DOSE ESCALATION
Questions
Who benefits?
Magnitude of benefit?

29. BENEFIT FROM DOSE ESCALATION
Literature Review;
Studies:
Series reported up to 2008
5 retrospective
External beam RT, at least 2 dose groups
4 randomized
No brachytherapy
No hypofractionation
>200 patients
Data adapted from Diez et al. IJROBP 2010

30. BENEFIT - LOW RISK
Diez et al. IJROBP 2010

31. BENEFIT - INTERMEDIATE-HIGH RISK
Diez et al. IJROBP 2010

32. 919 Stage T1-T3N0M0 - RT alone - treated between 1986 and 2000
RT dose N Median Dose Median FU (mos)
All patients 919 97
<72 Gy 552 68 Gy 112
>72 <82 Gy 215 78 Gy 94
>82 Gy 152 83 Gy 65

33. LOCAL FAILURE - DOSE GROUPS
Kupelian et al. IJROBP. 71, 6–22, 2008

34. DISTANT FAILURE - DOSE GROUPS
Kupelian et al. IJROBP. 71, 6–22, 2008

35. Dose Escalation for Localized Prostate Ca
Benefit of dose escalation is seen in all risk groups
The slope of the dose response curve is relatively shallow,
as demonstrated by data from randomized studies
Need large dose increases to see differences in outcomes.
RT dose has an impact on clinical outcomes, most
importantly distant metastasis rates.

36. PATIENT-REPORTED
TOXICITY

37. Patient Reported Quality of Life
Quality of life and satisfaction with outcome among prostate-cancer survivors.
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
1201 patients, 625 spouses or partners
Prostatectomy / Brachytherapy / External-beam RT
No deaths occurred.
Rare serious adverse events.
Symptoms exacerbated by obesity, a large prostate size, a
high PSA, and older age.

38. Patient Reported Toxicity
Quality of life and satisfaction with outcome among prostate-cancer survivors.
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
“Each prostate-cancer treatment was associated
with a distinct pattern of change in quality-of-life
domains related to urinary, sexual, bowel, and
hormonal function“.

39. Patient Reported Quality of Life
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
Urinary Scores

40. Patient Reported Quality of Life
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
Bowel Scores

41. Patient Reported Quality of Life
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
Vitality-Hormonal Scores

42. Patient Reported Quality of Life
Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.
Sexual Scores

43. TECHNIQUE
TREATMENT PLANNING

44. Anatomy:
Target:
CTV: Low risk: Prostate only
Intermediate risk: Prostate + SV (proximal 1 cm)
High risk: Prostate + SV +/- Pelvic Lymph nodes
(Postoperative Prostate Bed: RTOG guidelines)
PTV: CTV+ 5 mm (except 3 mm posteriorly) – Daily Guidance
OARs / Critical Structure Definitions:
Rectum: Extends 1 cm sup + inf to PTV
Bladder: Entire organ
Femurs: To level of ischial tuberosities
Large/Small Bowel: within the primary beam aperture
Penile bulb: Entire organ

45. Planning:
Target Goals:
PTV: 95% of PTV volume to get 95-110% of Rx dose.
IMRT fractionated (81 Gy in 45 fractions):
OAR Dose Constraints:
Rectum V50 < 50%
V80 < 20%
V90 < 10%
V100 < 5%
Bladder V50 < 40%
V100 < 1.1%
Femurs V40 < 5%
Small Bowel V50 < 1%

46. External Beam Radiotherapy for
Localized Prostate Cancer
DOSE ESCALATION
METHODS
ESCALATION OF ESCALATION OF
TOTAL DOSES FRACTION SIZES
Conventional Hypofractionation

47. CONVENTIONAL FRACTIONATION
versus
HYPOFRACTIONATION
versus
STEREOTACTIC BODY RADIOSURGERY (SBRT)
SBRT Hypofractionation Conventional
Number of fractions
1 5 ~35 45
Fraction Size
>7 Gy 1.8-2.0 Gy
Total Dose
~35-50 Gy ~50-75 Gy ~75-85 Gy
Biological Rationale
Ablative?? N o r m a l t i s s u e s p a r i n g

48. THE CLEVELAND CLINIC EXPERIENCE: FIRST 770 PATIENTS
Biochemical Relapse Free Survival By Risk Group
Median follow-up: 45 months
ASTRO definition Phoenix definition
Low Risk 1 Low Risk
1
Intermediate Risk
.8 .8 Intermediate Risk
.6 High Risk .6 High Risk
bRFS
bRFS
.4 .4
.2 95% .2 94%
85% 83%
p<0.01 68% p<0.01 72%
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Months Months
Kupelian et al., IJROBP, 68(5):1424-30, 2007

49. Toxicity (RTOG scores)
Kupelian et al., IJROBP, 68(5):1424-30, 2007

50. HYPOFRACTIONATION TRIALS
LOW AND
LOW / INTERMEDIATE RISK

51. HYPOFRACTIONATION PROTOCOLS: Phase III trials
MDACC (Pollack/Kuban): IMRT / Daily localization (Transabdominal US)
N=204. Median follow-up 5.8 years
75.6 at 1.8 Gy vs 72.0 at 2.4 Gy
5 yr bRFS 94% 97%
Late Gr <3 GI tox 5% 10% p=0.06
Late Gr <3 GU tox 15% 15% p=0.43
Kuban et al, IJROBP 78, S58 2010, Skinner et al, ASTRO 2012
Fox Chase (Pollack): IMRT / Daily localization (Transabdominal US)
Median follow-up 55 mos
76.0 at 2.0 Gy vs 70.2 at 2.7 Gy
No difference in biochemical failures
Slightly higher late GU effects with hypofracationation.
Pre-RT urinary status: Important predictor of GU toxicity

52. HYPOFRACTIONATION TRIALS
RTOG 04-15:
N=1067 low risk patients
70.0 at 2.5 Gy vs 73.8 at 1.8 Gy
IMRT or CRT / Daily localization
Closed Fall 2009
Ontario Clinical Oncology Group (OCOG) :
PROFIT – Prostate Fractionated Irradiation Trial
N=1204
60.0 at 3.0 Gy vs 78.0 at 2.0 Gy
Daily localization
CHHiP Trial: N=3026
1st randomization: Dose: 60 Gy at 3 Gy vs 74 Gy at 2 Gy per fx
2nd randomization: Image Guidance vs No Image Guidance
3rd randomization: Margins

53. HYPOFRACTIONATION
FOR HIGH RISK?

54. HYPOFRACTIONATED RT BETTER?
Italian Hypofractionation Randomized study for High Risk Cases
Arcangeli et al, IJROBP 78, 11-18, 2010
62 Gy/20 fractions / 5 weeks 3.1 Gy x 20
(3.1 Gy per fraction)
vs
80 Gy/40 fractions / 8 weeks
(2 Gy per fraction) 2.0 Gy x 40
9 months ADT
N=168
High-Risk:
bGS of 8–10
iPSA >20, or
two of the following:
iPSA 11–20, T>2c, GS=7

56. HYPOFRACTIONATION AND NODAL RT:
Simultaneous prostate vs LN fraction size differences
Pervez et al. IJROBP. 76: 57-64, 2010

57. PROSTATE SBRT: 5 fractions or less
Faster, Better, Cheaper

58. SBRT for Prostate Cancer
Multiple reports, single arm studies: excellent control.
Med follow-up still < 5 years
• Madsen IJROBP 2007 • Aluwini J Endourol 2010
• Fuller IJROBP 2008 • Freeman RO 2010
• King IJROBP 2009 • Townsend AJCO 2011
• King IJROBP 2011 • Kang Tumori 2011
• Friedland TCRT 2009 • Jabbari IJROBP 2011
• Katz BMC Urol 2010 • Mantz IJROBP 2011
• Wiegner IJROBP 2010 • Boike JCO 2011
• Bolzicco TCRT 2010

59. Efficacy of SBRT
• Katz et al. ASTRO 2012
Multi-institutional pooled data; 8 institutions
35-40 Gy in 4-5 fractions
1101 patients, ~ 3 yr median FU (6-72 mos)
335 cases with a >4 years follow-up (median 53 mos)
Risk groups: Dose groups:
Low: 639 59% 35 Gy: 385 35%
Intermediate: 326 30% 36.25 Gy: 589 53%
High: 124 11% 38-40 Gy: 127 12%
Any androgen deprivation:
No: 872 86%
Yes: 146 14%

60. Kaplan-M e ie r Cum . Survival Plot for True _Fail_T
Katz et al. ASTRO 2012
Ce ns or Variable : True _Fail
Grouping Variable : Ris k _G_dAm ico
1
Low
.8 Intermediate
High Cum.
Cum. Survival
Censor
.6
Cum.
Censor
.4
Cum.
Censor
.2
1101 SBRT cases
0
0 10 20 30 40 50 60 70 80
Time
335 cases with >4 years of follow-up (median 53 months)
5-year bRFS rates:
Low risk: 97%
Intermediate-risk: 89%

61. Toxicity and Quality of Life
Stereotactic Body Radiotherapy for
Intermediate-risk Organ-confined Prostate Cancer:
Interim Toxicity and Quality of Life Outcomes from a Multi-
Institutional Study
Robert Meier, MD
Swedish Cancer Institute, Seattle WA
Beth Israel Deaconess Medical Center, Boston, MA
Central Baptist Hospital, Lexington, KY
St. Joseph Mercy Hospital System, Ypsilanti, MI
Community Cancer Center, Normal, IL
Capital Health System, Trenton, NJ
Northwest Community Hospital, Arlington Heights, IL
Jupiter Medical Center, Jupiter, FL
Meier et al., ASTRO 2012

62. Treatment Planning
• Prostate prescribed 8 Gy x 5 = 40 Gy
• Prostate + proximal 2 cm seminal vesicles + 3-5 mm:
7.25 Gy x 5 = 36.25 Gy
• 129 patients 2007- 2010, 21 centers
• Follow up 2 – 4½ yrs Median 36 months
Meier et al., ASTRO 2012

63. Multi-institutional prospective study
PATIENT REPORTED OUTCOMES
AUA Score after SBRT
16
Similar to an implant
14
12
Mean AUA Score
10
8
6
4
2
0
0 6 12 18 24 30 36
Months After Treatment
Meier et al., ASTRO 2012

64. Late Urinary Toxicity: Gr 2+
Meier et al., ASTRO 2012

65. Late Bowel Toxicity: Gr 2+
Meier et al., ASTRO 2012

66. Planning SBRT (5 FRACTIONS):
Target Goals:
PTV: 95% of PTV volume to get 95-110% of Rx dose.
SBRT: (8 Gy x 5)
OAR Dose Constraints:
Rectum V50 (20 Gy) < 50%
V80 (32 Gy) < 20%
V90 (36 Gy) < 10%
V100 (40 Gy) < 5%
Bladder V50 (20 Gy) < 40%
V100 (40 Gy) < 1.1%
Femurs V40 (16 Gy) < 5%
Small Bowel V50 (20 Gy) < 1%

67. CONCLUSIONS
Hypofractionated approaches (including SBRT) have favorable toxicity
and efficacy profiles with the available follow-up.
Late rectal toxicity with hypofractionated RT is minimal.
Urinary toxicity is marginally more prominent: Avoid patients with poor
pre-radiation urinary function (similar to implants).
Even if only equivalent to standard fractionated RT with respect to
efficacy, hypofractionation should be adopted due to convenience and
cost advantages.
Hypofractionation better for high risk cancers?
Phase I studies are still needed: Approaches with novel doses,
margins, dose sculpting and timing of delivery should be investigated.

68. Radiotherapy for
Localized Prostate Cancer:
Dose Escalation
Dose Fractionation
Patrick Kupelian, M.D.
Professor and Vice Chair
University of California Los Angeles
Department of Radiation Oncology
pkupelian@mednet.ucla.edu
February 2013