CYBERKNIFE RADIOSURGERY FOR EARLY PROSTATE CANCER Rationale and Results. Alan Katz MD JD Flushing, NY USA

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1 CYBERKNIFE RADIOSURGERY FOR EARLY PROSTATE CANCER Rationale and Results Alan Katz MD JD Flushing, NY USA

2 Prostate Ablative Therapy Over the last 10 years our therapy has improved bned rates for LDR/HDR brachytherapy and IMRT are as good as those reported for RP series This is a result of improved technology and technical improvements by practitioners Data on dose response relationships of LDT and HDR brachytherapy, 3D-CRT and IMRT are now fairly well defined Thus, the goal of therapy is now one of delivering an ablative course of therapy In addition, the technological improvements have also resulted in reduced morbidity of therapy

3 Goals for CyberKnife Therapy for CaP Emulate success of HDR brachytherapy tumor control Hypofractionation schemes Low alpha/beta ratio for prostate cancer Equivalent BED values Reduce complications Need low toxicities for urinary, rectal and sexual function Need high accuracy and & motion compensation Need for high conformality Maintain quality of life Minimally invasive Shorter treatment times Outpatient procedure No indwelling catheter

4 Proposed Prostate Alpha/Beta Ratios Brenner DJ (JROBP 1999:43, ) Data: EBRT and LDR brachytherapy Alpha/Beta: 1.5 Brenner DR (IROBP 2002: 52, 6-13 ) Data: EBRT and HDR brachytherapy Alpha/Beta: 1.2 Fowler JF ( JROBP 2003: 56, ) Data: hypofractionated EBRT Alpha/Beta: 1.5

5 DOSE CALCULATION If Alpha/BETA Ratio for Prostate Cancer is 1.5 Then We Are Delivering B.E.D. of cgy at 180/fx

6 Alpha / Beta Ratios Moderate ( 4-5 ) range: Late responding tissues Some sensitivity to fractionation EQUIVALENT DOSE TO RECTUM AND BLADDER 70-73GY High (8-10 ) range: Acute responding tissues Little sensitivity to fractionation

7 Effectiveness and Applicability of CK CK monotherapy: Low risk and low intermediate risk CaP EBRT + CK boost: High risk and high intermediate risk Cap Basically, CK reproduces dose distributions very much like HDR, except more homogeneous and non-invasively May reduce the need for androgen deprivation therapy (ADT) for volume reduction or some patients with more extensive disease

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9 CYBERKNIFE 1. Ability to track prostate motion using fiducial seeds 2. Non -Coplanar and non Iso-centric Beams delivered by a linac mounted on a robotic arm 3. Ability to use smaller margins to limit dose to penile bulb and neuro vascular bundles

10 STEREOTACTIC RADIOSURGERY FOR LOCALIZED PROSTATE CA KATZ,A SANTORO,M ET AL BMC UROLOGY FEB 2010

11 STEREOTACTIC RADIOSURGERY AS A BOOST TO EBRT FOR INTERMEDIATE AND HIGH RISK EARLY PROSTATE CANCER KATZ,A SANTORO M et al TCRT December 2010

12 Basic Demographics All Patients with Stage ct1cnomo or T2A Minimum 30 month follow up,median 48 All patients treated between 4/5/2006 and 01/15/2010 Total number of Patients = 591 All patients treated by 1 Urologist and 1 Radiation Oncologist

13 Histology Gleason grade = 362 Patients Gleason grade 7 = 165 Patients Gleason grade >4+3 = 64 Patients

14 Prostate Volumes Range = 21.2cc to 150 cc Mean initial volume = 48.2 cc Median initial volume = 46.1 cc

15 Initial PSA s Range = 1.1 to 52.3 ng/ml Mean initial PSA = 7.78 ng/ml Median initial PSA = 5.1 ng/ml N= 591

16 PRESCRIBED DOSE MONOTHERAPY 515 patients 158 received 700 CGY X received 725 cgy x 5 PROSTATE +- SEMINAL VESICLES WITH 5MM MARGIN (3 posteriorly)

17 35Gy used on low risk and low intermediate risk patients used on all risk groups

18 PATIENT CHARACTERISTICS Prospective trial of 515 patients for monotherapy 463 with T1c, 52 with T2a 343 low-risk, 134 intermediate-risk, & 38 high-risk Mean age 69.2 years Mean PSA 6.08 ng/ml No restrictions on volume, AUA score or # of cores 67 patients received ADT for < 3 months 28 patients died of other causes 23 lost to follow-up All patients had CT and MR for treatment planning

19 PRESCRIBED BOOST DOSE INTERMEDIATE TO HIGH RISK 76 Patients 4500 CGY TO PELVIS PLUS BOOST CGY X 3 PROSTATE WITH CYBERKNIFE SRRS

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21 TREATMENT PLANNING CT AND MRI FOR VOLUME LOCALIZATION PLANNING BLADDER AND RECTUM IDENTIFIED ALONG WITH PROSTATE & SV CLEAN OUT PRIOR TO SCANS AND RX

22 CT/MR

23 CT/MR

24 MRI Better definition of prostate Decrease GTV by up to 25% Helps decrease penile bulb dose

25 PRESCRIPTION DOSE Prescribe to the 83-87% line to cover the PTV Cover 95% of the PTV with prescription Dose This is known as homogeneous planning

26 PROSTATE PLAN

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28 IRIS COLLIMATOR USES >6 COLLIMATOR SIZES IMPROVES DVH TO BLADDER AND RECTUM BY 25-30% SPEEDS UP TREATMENT TIME BETTER DVH LEADS TO LESS ACUTE RECTAL TOXICITY GRADE1 IS ONLY 36% WITH IRIS NO NEED FOR AMIFOSTINE

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30 Testis Dose Average cgy Similar to IMRT No effect on testosterone No effect on PSA decline Can be diminished by avoiding beams through the testes

31 LOCALIZATION ALL PATIENTS RECEIVE 4 FIDUCIAL MARKERS PLACED UNDER ULTRASOUND GUIDANCE

32 FIDUCIAL PLACEMENT 1. LOCAL ANESTHETIC WITH EMLA CREAM AND SQ LIDOCAINE 2. 2 SEEDS AT BASE 3. 2 SEEDS AT APEX 4. SEEDS TRACKED FOR TRANSLATION, ROTATION AND PITCH

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36 FIDUCIAL LOCALIZATION

37 TREATMENT 40 MM COLLIMATOR AND 25 MM COLLIMATOR BEAMS 45 MINUTES

38 TOXICITY FOR MONOTHERAPY

39 ACUTE URINARY TOXICITY 78% - GRADE 1 4% GRADE 2 ALL BACK TO BASELINE AT 3 MONTHS

40 ACUTE RECTAL TOXICITY 82% - GRADE Ι 4% - GRADE II ALL BACK TO BASELINE AT 3 MONTHS

41 LATE TOXICITY percent 2% 9% percent 4% 6% 8% 4% All toxicity occurred 3 years post-treatment Potency preserved for 78% of patients at 4 years

42 Late Toxicity For 515 patients, the difference in late urinary toxicity between 35 and Gy is statistically significant p<0.01

43 EPIC QUALITY of LIFE Bowel Urinary EPIC Score Gy Gy Months Sexual

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45 ED RATES 78% For Monotherapy 66% For Boost Penile Bulb Dose < 18 GY

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48 MONOTHERAPY FIVE YEAR BIOCHEMICAL EFFICACY To be reported at ASTRO along with 600 more patients from 7 institutions

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51 MONOTHERAPY 100% Local Control and 97.5% Freedom from PSA failure for low risk For Intermediate Risk patients 99% Local control 92% Freedom from failure

52 AUA Patients with intermediate risk disease

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55 High Risk Monotherapy 77%Biochemical control at 36 months median (9/38) 8% local Failure(3 pts)

56 35 vs Gy PSA nadirs and control are equal (See Katz et al Frontiers in Oncology Nov. 2011) Urinary toxicity worse for p< Gy=90-91 Gy at 180/fx or BED of198 This is probably on the flat part of the dose response curve and higher dose would not be expected to improve control

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58 OTHER DOSE SCHEMES Meier 40GY(to GTV) p/5fx Daily Fuller 38Gy/4 fx Daily Timmerman(non CK) 50 Gy/ 5fx QOD King Gy/5 fx QOD

59 BOOST THERAPY 5 Year EFFICACY REPORTED at ESTRO 2012 In line with HDR as a boost results

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63 CK Mono vs. Boost 44 Intermediate risk pts monotherapy 37 Intermediate risk pts- CK as boost No Hormones More rectal toxicity in boost group Presented at ESTRO Katz, Santoro et al

64 Biochemical failure occurred in 2/35 boost patients and 2/44 monotherapypatients; biochemical control rates were 94.3% and 95.5%, respectively.

65 BOOST vs MONO

66 STANFORD NAPLES 42 pts treated with CK Mono 5 year followup 94% Biochemical control

67 McGill Trial 66Gy in 22fx 3D Conformal 2.5% biochemical failures, same as CK BED 90 Gy 33% late grade 2 GU Toxicity 28% late grade 2 GI Toxicity

68 Archangeli Trial 3.1 Gy x 20 superior to 2y x 40 for intermediate and high risk patients Supports alpha/beta of 1.5

69 WHY NOT STOP at FRACTIONS? IS 5 FRACTIONS BETTER?

70 Dose to tumor vs normal tissue Dose BED to prostate normal 7x x x

71 SUMMARY 5 Year results show high efficacy,low toxicity and ED and low cost(22k) PSA results mimic HDR Brachytherapy, which has very high control rates at 10 years Need for more followup to confirm but very low PSA nadirs are encouraging Sexual and Urinary QOL better than surgery

72 SUMMARY 35 GY seems to be optimal dose for low and low intermediate risk patients. PSA results equal to Gy or 38GY heterogeneous No need for ADT No need for EBRT IRIS Collimator yields less rectal toxicity and is highly recommended Consider internal boost for higher risk patients

73 icad MRI

74 Heterogeneous Plan

75 FOR THE FUTURE DOSE PAINTING FEWER FRACTIONS 9.5x3 BED = 90 Gy 19 x1 Munich