1. The Role of Cyberknife Stereotactic Body Radiation Therapy in the Treatment of Prostate Cancer Jay L. Friedland, MD

2. Jay L. Friedland, M.D. History of Modern Prostate Radiotherapy 3D-CRT Early 90’s - Present LDR Brachytherapy Late 80’s-Present HDR Brachytherapy Mid-90’s - Present IMRT Late 90’s to Present IGRT (Cyberknife) 2001 - Present

3. Jay L. Friedland, M.D. The Balancing Act ConvenienceInvasiveToxicityEfficacy IMRTLowNoLowHigh LDR BrachyTx HighYes X 1ModHigh HDR BrachyTx ModerateYes X 2Low/ModVery High CKHighNoVery LowTBD

4. Jay L. Friedland, M.D. Dose Calculations for Cyberknife Stereotactic Body Radiation Therapy Perform BED dose calculations For CK, one can fractionate the therapy yet remain convenient and non-invasive for the patient CK doses are most like HDR, since the dose/fraction, total doses and time factors are similar SHARP trial from Virginia Mason Hospital with good results (33.5Gy/5fx) Thus, since we have intermediate and long term results with HDR, CK appears to be a reasonably well founded treatment option

5. Jay L. Friedland, M.D. BED Calculations External Beam Radiation Therapy / HDR –BED = nd [ 1 + (d/ α/β) ] Low Dose Rate Permanent Decaying Implants –BED = (Ro/ λ) { 1 + [ Ro/(μ+ λ)(α/β)] } Definitions of parameters n = # fractions d = daily dose Ro = initial dose rate of implant λ = radioactive decay constant = 0.693/T 1/2 T 1/2 = radioactive half-life of isotope μ = repair rate constant = 0.693/t 1/2 t 1/2 = tissue repair half-time

6. Jay L. Friedland, M.D. Calculating BED For Low Risk CaP Monotherapy Treatment Regimens Biologically Equivalent Dose BED = D (1 + d/alpha beta ratio) D = total dose d = dose/fraction alpha/beta ratio = 1.5 for prostate 3 for late effects 10 for acute effects 81Gy IMRT/ 45fx / 9 weeks ( BED 1.5 = 178.2, BED 3 = 129.6 ) HDR monoTx @ 9.5Gy X 4fx ( BED 1.5 = 278.7, BED 3 = 158.3 ) HDR monoTx @ 8.55Gy X 4fx ( BED 1.5 = 229.1, BED 3 = 131.7 ) HDR monoTx @ 7.25Gy X 6fx ( BED 1.5 = 253.7, BED 3 = 148.6 ) Cyberknife monoTx @ 7Gy X 5fx ( BED 1.5 = 198.3, BED 3 = 116.7 ) Cyberknife monoTx @ 7.25Gy X 5fx ( BED 1.5 = 211.5, BED 3 = 123.9 ) NCH Hospital, Naples, FL

7. Jay L. Friedland, M.D. 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

8. Jay L. Friedland, M.D. Prostate PTV: gland expanded 5 mm in each direction except posteriorly where it is expanded 3 mm

9. Jay L. Friedland, M.D. Prostate comparison: axial & sagittal 40 and 25 mm colls40 mm coll Note differences in bladder & rectal doses

10. Jay L. Friedland, M.D. Prostate comparison: urethra 40 mm coll40 and 25 mm colls 18.7% vol at 90% dose 30.8% vol at 90% dose

11. Jay L. Friedland, M.D. Prostate comparison: bladder 12.2% vol at 60% dose 16.7% vol at 60% dose 40 mm coll 40 and 25 mm colls

12. Jay L. Friedland, M.D. Prostate comparison: rectum 40 mm coll40 and 25 mm colls 20.5% vol at 60% dose 11.2% vol at 60% dose

13. Cyberknife Stereotactic Body Radiation Therapy Part 2: Results

14. Jay L. Friedland, M.D. Prostate Experience to Date Cyberknife SBRT First patient treated in Jan. 2005 Initiated Monotherapy protocol in Feb. 2005 Total patients treated: 200 Monotherapy: 162 Boost: 38 (Jan. 2005-May 2007)

15. Jay L. Friedland, M.D. Basic Demographics Will only present monotherapy results Stage cT1cNoMo to cT2bNoMo All patients treated between 1/5/2005 and 5/25/2007 Total number of Patients = 162 All patients treated by 2 Urologists and 2 Radiation Oncologists NCH Hospital, Naples, Florida

16. Jay L. Friedland, M.D. Hormonal Therapy Hormonal Therapy administered at discretion of Urologist 135 Patients treated without Hormonal therapy 27 Patients treated with Neoadjuvant Hormonal Therapy NCH Hospital, Naples, Florida

17. Jay L. Friedland, M.D. Histology Gleason grade 3 + 3 = 121 Patients Gleason grade 3 + 4 = 31 Patients Gleason grade 4 + 3 = 8 Patients Gleason grade 4 + 4 = 1 Patient Gleason grade 5 + 4 = 1 Patient NCH Hospital, Naples, Florida

18. Jay L. Friedland, M.D. Prostate Volumes Range = 15.5cc to 109cc Mean initial volume = 45.7 cc Median initial volume = 46.1 cc N= 111 NCH Hospital, Naples, Florida

19. Jay L. Friedland, M.D. Prostate Cyberknife MonoTx Dose Mean Dose = 3503 cGy (n=162) Median Dose = 3500 cGy Range = 3500cGy to 3755 cGy Number of Fractions = 5 NCH Hospital, Naples, Florida

20. Jay L. Friedland, M.D. Initial PSA’s Range = 1.1 to 17.2 ng/ml Mean initial PSA = 5.87 ng/ml Median initial PSA = 5.75 ng/ml N= 160 NCH Hospital, Naples, Florida

21. Jay L. Friedland, M.D. PSA Response to Cyberknife

22. Jay L. Friedland, M.D. Case Review Patient with Recurrence after CK monotherapy 65 y/o wm with h/o rising PSA’s. Initial Presentation –cT1cNoMo, PSA=4.3 in 2/2005, GG 4+3 in 2/12 cores (Lt lat base 10%, Lt med apex 20%) and GG 3+4 in 1/12 cores (Lt med base 5%), BS- and CT- Tx with CK monotherapy (35Gy/5 fx) completed on 6/10/05 PSA = 5.4 on 6/30/05 PSA = 10.2 on 9/15/05, repeat TRUS bx’s all negative (0/12) on 10/27/05 PSA = 24.1 on 11/14/05, repeat bone scan negative on 11/3/05 and CT abd/pelvis negative except small sclerotic lesion in head of Lt femur. MRI Lt hip on 12/6/05 negative but suspicious at L5 PSA = 87.5 on 3/31/06, Prostascint/CT fusion scan of abd/pelvis negative on 4/7/06, Started HTx in 3/2006 PSA declined to 2.6 on 6/26/206 but increased to 14 in 10/2006 Repeat bone scan +L5 on 11/28/06 and repeat CT abd/pelvis +blastic mets at T8, T10 and L5. Started systemic chemoTx in 11/2006.

23. Jay L. Friedland, M.D. Acute Toxicity Urinary hesitancy, urgency, frequency (Day 3-10) Tenesmus/ rectal discomfort (Day 5-8) Diarrhea (Day 5-8) Rx: Flomax Lomotil Decadron Anusol-HC supp.

24. Jay L. Friedland, M.D. Acute Toxicity Scoring (IPSS/RAS/SHIM) Baseline, days 2 and 5, post-treatment day 10, 1 month and 4 months Acute effects generally return to baseline by 1 months Urinary symptoms more marked in patients with IPSS baseline scores >20 No urethral strictures/ persistent rectal bleeding observed

25. Jay L. Friedland, M.D. IPSS Scores After Cyberknife SBRT

26. Jay L. Friedland, M.D. RAS and SHIM Scores after Cyberknife SBRT

27. Jay L. Friedland, M.D. Summary Cyberknife is a new and innovative treatment technique for prostate cancer. Cyberknife monotherapy appears to produce a reasonable early decline of PSA’s in low risk patients. The acute toxicity of Cyberknife monotherapy is acceptable. Cyberknife therapy is a noninvasive and convenient treatment option for patients with early stage prostate cancer. Prostate cancer patients treated with Cyberknife should be enrolled on research protocols, and the data collectively analyzed.

28. Thank You for Your Kind Attention