Today, however, I want to address the SBRT topic in the context of innovation, resistance to change and change management. The potential virtues of this SBRT treatment of low and intermediate risk prostate cancer are profound. 5 treatments verses 40 or more. The patient convenience is without question. Yet, there is a resistance to its uptake by many in our specialty and interestingly enough by those from the Urology based IMRT facilities.
Kupelian 1st talk planning dose hyderabad 2013 (cancer ci 2013) patrick kupelian, m.d
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@example.com February 2013
DisclosuresResearch grants / Honoraria / Advisory Board / Royalties: Accuray Siemens Medical Varian Medical Viewray Inc. VisionTree
OutlineAnatomy: Prostate MRI Pelvic LN - CTTreatment options: Surveillance Surgery RadiotherapyRadiotherapy Planning Importance of Dose Escalation Hypofractionation - SBRT
PrognosticatorsStage, PSA and Gleason scoreNumber of cores positive (proxy for disease volume)Low risk: <T2A, Gleason <6, PSA <10- (Single focus GS 7?)Intermediate: Heterogeneous groupHigh risk:T3 or GS >8 or PSA >20Two factors: Stage >T2B, GS 7, PSA between 10 and 20- (Single focus GS 8, low PSA?)
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 • 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 BladderCourtesy D. Margolis, UCLA, 2013
Basic Prostate Anatomy: Multiple Levels • Peripheral Zone • Central Gland • Transitional Zone • Anterior Fibromuscular Stroma • UrethraCourtesy D. Margolis, UCLA, 2013
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
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 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
Radical Prostatectomy vs Observationfor Localized Prostate Cancer: Toxicity
EXTERNAL BEAM RT COMPARISON WITH OTHER MODALITIES
Importance of Dose PSA failure by Treatment modalityKupelian, Potters et al. IJROBP 2004;58:25-33.
Effectiveness of High Dose RTIntermediate 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 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 TodayPatient outcome improvements Improved Cure Rates: Dose escalation Doses in the 75-85 Gy range Decreased toxicity Grade 3 toxicities < 5% Convenience Hypofractionation / SBRT / Brachytherapy
BENEFIT FROM DOSE ESCALATION QuestionsWho benefits?Magnitude of benefit?
BENEFIT FROM DOSE ESCALATIONLiterature Review; Studies:Series reported up to 2008 5 retrospectiveExternal beam RT, at least 2 dose groups 4 randomizedNo brachytherapyNo hypofractionation>200 patientsData adapted from Diez et al. IJROBP 2010
BENEFIT - INTERMEDIATE-HIGH RISK Diez et al. IJROBP 2010
919 Stage T1-T3N0M0 - RT alone - treated between 1986 and 2000RT 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
LOCAL FAILURE - DOSE GROUPS Kupelian et al. IJROBP. 71, 6–22, 2008
DISTANT FAILURE - DOSE GROUPS Kupelian et al. IJROBP. 71, 6–22, 2008
Dose Escalation for Localized Prostate CaBenefit of dose escalation is seen in all risk groupsThe slope of the dose response curve is relatively shallow,as demonstrated by data from randomized studiesNeed large dose increases to see differences in outcomes.RT dose has an impact on clinical outcomes, mostimportantly distant metastasis rates.
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 partnersProstatectomy / Brachytherapy / External-beam RTNo deaths occurred.Rare serious adverse events.Symptoms exacerbated by obesity, a large prostate size, ahigh PSA, and older age.
Patient Reported ToxicityQuality 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“.
Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61. Urinary Scores
Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61. Bowel Scores
Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61. Vitality-Hormonal Scores
Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61. Sexual Scores
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 GuidanceOARs / 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 ESCALATION METHODSESCALATION OF ESCALATION OF TOTAL DOSES FRACTION SIZES Conventional Hypofractionation
CONVENTIONAL FRACTIONATION versus HYPOFRACTIONATION versus STEREOTACTIC BODY RADIOSURGERY (SBRT) SBRT Hypofractionation Conventional Number of fractions1 5 ~35 45 Fraction Size >7 Gy 1.8-2.0 Gy Total Dose~35-50 Gy ~50-75 Gy ~75-85 Gy Biological RationaleAblative?? N o r m a l t i s s u e s p a r i n g
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 MonthsKupelian et al., IJROBP, 68(5):1424-30, 2007
Toxicity (RTOG scores)Kupelian et al., IJROBP, 68(5):1424-30, 2007
HYPOFRACTIONATION TRIALS LOW AND LOW / INTERMEDIATE RISK
HYPOFRACTIONATION PROTOCOLS: Phase III trialsMDACC (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 Gy5 yr bRFS 94% 97%Late Gr <3 GI tox 5% 10% p=0.06Late Gr <3 GU tox 15% 15% p=0.43 Kuban et al, IJROBP 78, S58 2010, Skinner et al, ASTRO 2012Fox Chase (Pollack): IMRT / Daily localization (Transabdominal US)Median follow-up 55 mos 76.0 at 2.0 Gy vs 70.2 at 2.7 GyNo difference in biochemical failuresSlightly higher late GU effects with hypofracationation.Pre-RT urinary status: Important predictor of GU toxicity
HYPOFRACTIONATION TRIALSRTOG 04-15:N=1067 low risk patients70.0 at 2.5 Gy vs 73.8 at 1.8 GyIMRT or CRT / Daily localizationClosed Fall 2009Ontario Clinical Oncology Group (OCOG) :PROFIT – Prostate Fractionated Irradiation TrialN=120460.0 at 3.0 Gy vs 78.0 at 2.0 GyDaily localizationCHHiP 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
HYPOFRACTIONATED RT BETTER?Italian Hypofractionation Randomized study for High Risk Cases Arcangeli et al, IJROBP 78, 11-18, 201062 Gy/20 fractions / 5 weeks 3.1 Gy x 20 (3.1 Gy per fraction) vs80 Gy/40 fractions / 8 weeks (2 Gy per fraction) 2.0 Gy x 409 months ADTN=168High-Risk:bGS of 8–10iPSA >20, ortwo of the following:iPSA 11–20, T>2c, GS=7
HYPOFRACTIONATION AND NODAL RT:Simultaneous prostate vs LN fraction size differences Pervez et al. IJROBP. 76: 57-64, 2010
PROSTATE SBRT: 5 fractions or less Faster, Better, Cheaper
SBRT for Prostate CancerMultiple 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
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%
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 Time335 cases with >4 years of follow-up (median 53 months)5-year bRFS rates: Low risk: 97% Intermediate-risk: 89%
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
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
Multi-institutional prospective studyPATIENT 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
Late Urinary Toxicity: Gr 2+ Meier et al., ASTRO 2012
Late Bowel Toxicity: Gr 2+ Meier et al., ASTRO 2012
CONCLUSIONSHypofractionated approaches (including SBRT) have favorable toxicityand efficacy profiles with the available follow-up.Late rectal toxicity with hypofractionated RT is minimal.Urinary toxicity is marginally more prominent: Avoid patients with poorpre-radiation urinary function (similar to implants).Even if only equivalent to standard fractionated RT with respect toefficacy, hypofractionation should be adopted due to convenience andcost 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 forLocalized Prostate Cancer: Dose Escalation Dose Fractionation Patrick Kupelian, M.D. Professor and Vice Chair University of California Los Angeles Department of Radiation Oncology firstname.lastname@example.org February 2013