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 [email protected]February 2013
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Radiotherapy for Localized Prostate Cancer:Anatomy / Planning
• 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
Basic Prostate Anatomy: Multiple Levels
• Peripheral Zone• Central Gland• Transitional Zone• Anterior Fibromuscular
Stroma• Urethra
Courtesy D. Margolis, UCLA, 2013
Prostate anatomy: Additional Views
• Sagittal image through the prostate: B: bladder, SV: seminal vesicles, FS: fibromuscular stroma, P: prostate
• Coronal Oblique image through the prostate: SV: seminal vesicles, P: prostate.
Importance of DosePSA failure by Treatment modality
Kupelian, Potters et al. IJROBP 2004;58:25-33.
Effectiveness of High Dose RT
Intermediate risk prostate Ca: Clinical stage of T2b or T2cBiopsy Gleason score (bGS) 7, orPretreatment PSA between 10 and 20 ng/mL.
Treatment arms: RRP vs Lap RP vs EBRT vs PIN=979, median follow-up 65 monthsTreated between 1996 and 2005Minimum of 2 years of follow-upAt least 4 follow-up PSA levels
Vassil et al. Urology 76, 2010
Effectiveness
Lap RP EBRT
Vassil et al. Urology 76, 2010
Localized Prostate Cancer – Radiotherapy Today
Patient outcome improvements
Improved Cure Rates: Dose escalationDoses in the 75-85 Gy range
(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 PTVBladder: Entire organFemurs: To level of ischial tuberositiesLarge/Small Bowel: within the primary beam aperturePenile bulb: Entire organ
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%
External Beam Radiotherapy for Localized Prostate Cancer
DOSE ESCALATIONMETHODS
ESCALATION OF TOTAL DOSES
ESCALATION OF FRACTION SIZES
Conventional Hypofractionation
CONVENTIONAL FRACTIONATIONversus
HYPOFRACTIONATION versus
STEREOTACTIC BODY RADIOSURGERY (SBRT)
1 45
SBRT
5
Number of fractions
Fraction Size
>7 Gy 1.8-2.0 Gy
~35
ConventionalHypofractionation
Biological Rationale
Ablative?? N o r m a l t i s s u e s p a r i n g
Total Dose
~35-50 Gy ~75-85 Gy~50-75 Gy
bR
FS
0
.2
.4
.6
.8
1
0 12 24 36 48 60 72 84Months
Low Risk
Intermediate Risk
High Risk
68%85%95%
p<0.010
.2
.4
.6
.8
1
0 12 24 36 48 60 72 84
bR
FS
Months
Low Risk
Intermediate Risk
High Risk
72%83%94%
p<0.01
Biochemical Relapse Free Survival By Risk Group
ASTRO definition Phoenix definition
THE CLEVELAND CLINIC EXPERIENCE: FIRST 770 PATIENTS
Kupelian et al., IJROBP, 68(5):1424-30, 2007
Median follow-up: 45 months
Toxicity (RTOG scores)
Kupelian et al., IJROBP, 68(5):1424-30, 2007
HYPOFRACTIONATION TRIALS
LOW AND LOW / INTERMEDIATE RISK
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 failuresSlightly higher late GU effects with hypofracationation.Pre-RT urinary status: Important predictor of GU toxicity
Ontario Clinical Oncology Group (OCOG) : PROFIT – Prostate Fractionated Irradiation TrialN=120460.0 at 3.0 Gy vs 78.0 at 2.0 GyDaily localization
HYPOFRACTIONATION TRIALS
CHHiP Trial: N=30261st randomization: Dose: 60 Gy at 3 Gy vs 74 Gy at 2 Gy per fx2nd randomization: Image Guidance vs No Image Guidance3rd randomization: Margins
RTOG 04-15: N=1067 low risk patients70.0 at 2.5 Gy vs 73.8 at 1.8 GyIMRT or CRT / Daily localizationClosed Fall 2009
HYPOFRACTIONATION FOR HIGH RISK?
62 Gy/20 fractions / 5 weeks(3.1 Gy per fraction)
vs80 Gy/40 fractions / 8 weeks
(2 Gy per fraction)9 months ADTN=168
High-Risk:bGS of 8–10iPSA >20, or two of the following:iPSA 11–20, T>2c, GS=7
Arcangeli et al, IJROBP 78, 11-18, 2010
Italian Hypofractionation Randomized study for High Risk Cases
HYPOFRACTIONATED RT BETTER?
2.0 Gy x 40
3.1 Gy x 20
HYPOFRACTIONATION AND NODAL RT:Simultaneous prostate vs LN fraction size differences
Pervez et al. IJROBP. 76: 57-64, 2010
PROSTATE SBRT: 5 fractions or lessFaster, Better, Cheaper
SBRT for Prostate Cancer
Multiple reports, single arm studies: excellent control.Med follow-up still < 5 years
• Katz et al. ASTRO 2012Multi-institutional pooled data; 8 institutions35-40 Gy in 4-5 fractions1101 patients, ~ 3 yr median FU (6-72 mos)335 cases with a >4 years follow-up (median 53 mos)
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.
Radiotherapy for Localized Prostate Cancer:
Dose EscalationDose Fractionation
Patrick Kupelian, M.D.Professor and Vice Chair
University of California Los AngelesDepartment of Radiation Oncology