Kupelian 1st talk Planning Dose Hyderabad 2013 (Cancer CI 2013) Patric

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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

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

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

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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?)

Prostate Anatomy: CT vs US vs MR : 

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

Basic Prostate Anatomy:Cross-Sectional Imaging : 

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

Basic Prostate Anatomy: Multiple Levels : 

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

Prostate anatomy: Additional Views : 

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. B FS P SV Rectal Probe SV SV P Membranous Urethra Courtesy D. Margolis, UCLA, 2013

Criteria for Prostate Cancer on T2-Weighted MRI : 

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

Pelvic Nodal Consensus CTV ContoursRTOG CONSENSUS GUIDELINESColleen A F Lawton MDMedical College of Wisconsin : 

Pelvic Nodal Consensus CTV ContoursRTOG CONSENSUS GUIDELINESColleen A F Lawton MDMedical 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

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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

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No Dose PIVOT TRIAL

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Radical Prostatectomy vs Observation for Localized Prostate Cancer: Toxicity

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EXTERNAL BEAM RT COMPARISON WITH OTHER MODALITIES

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

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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

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

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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

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

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

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BENEFIT - LOW RISK Diez et al. IJROBP 2010

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

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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

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

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

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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.

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PATIENT-REPORTED TOXICITY

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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.

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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“.

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

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

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

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

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TECHNIQUE TREATMENT PLANNING

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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

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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%

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

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CONVENTIONAL FRACTIONATION versus HYPOFRACTIONATION versus STEREOTACTIC BODY RADIOSURGERY (SBRT) 1 45 SBRT 5 Number of fractions Fraction Size >7 Gy 1.8-2.0 Gy ~35 Conventional Hypofractionation Biological Rationale Ablative?? Normal tissue sparing Total Dose ~35-50 Gy ~75-85 Gy ~50-75 Gy

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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

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

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HYPOFRACTIONATION TRIALS LOW AND LOW / INTERMEDIATE RISK

HYPOFRACTIONATION PROTOCOLS: Phase III trials : 

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

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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 HYPOFRACTIONATION TRIALS 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 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

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HYPOFRACTIONATION FOR HIGH RISK?

HYPOFRACTIONATED RT BETTER? : 

62 Gy/20 fractions / 5 weeks (3.1 Gy per fraction)vs 80 Gy/40 fractions / 8 weeks (2 Gy per fraction) 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 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 : 

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

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

SBRT for Prostate Cancer : 

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

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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: Low: 639 59% Intermediate: 326 30% High: 124 11%   Any androgen deprivation: No: 872 86% Yes: 146 14% Dose groups: 35 Gy: 385 35% 36.25 Gy: 589 53% 38-40 Gy: 127 12%

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Katz et al. ASTRO 2012 Low Intermediate High 335 cases with >4 years of follow-up (median 53 months) 5-year bRFS rates: Low risk: 97% Intermediate-risk: 89% 1101 SBRT cases

Stereotactic Body Radiotherapy forIntermediate-risk Organ-confined Prostate Cancer:Interim Toxicity and Quality of Life Outcomes from a Multi-Institutional StudyRobert Meier, MD : 

Stereotactic Body Radiotherapy forIntermediate-risk Organ-confined Prostate Cancer:Interim Toxicity and Quality of Life Outcomes from a Multi-Institutional StudyRobert 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 Toxicity and Quality of Life

Treatment Planning : 

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 Meier et al., ASTRO 2012 129 patients 2007- 2010, 21 centers Follow up 2 – 4½ yrs Median 36 months

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AUA Score after SBRT Similar to an implant Multi-institutional prospective study PATIENT REPORTED OUTCOMES Meier et al., ASTRO 2012

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

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

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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%

CONCLUSIONS : 

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.

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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

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