1. The Role of Cyberknife Stereotactic Body Radiation Therapy in the Treatment of Localized and Advanced Prostate Cancer David M. Spellberg M.D., FACS Naples Urology Associates, P.A. Naples, Florida

2. TREATMENT OPTIONS WATCHFUL WAITING SURGERY RADIATION THERAPY PROTON HIFU CRYOTHERAPY HORMONAL MANIPULATION CHEMOTHERAPY EXPERIMENTAL

3. COMPLICATIONS OF TREATMENT INCONTINENCE IMPOTENCE EJACULATION DYSFUNCTION BOWEL PROBLEMS WORSENING OF OVERALL HEALTH

5. Radiation Options ConvenienceInvasiveToxicityEfficacy IMRTLowNoModHigh LDR BrachyTx LowYes X 1ModHigh HDR BrachyTx LowYes X 2ModHigh CKHighNoVery LowTBD

6. PATIENT DRIVEN NON-INVASIVE MINIMAL SIDE EFFECTS MINIMAL DISRUPTION OF LIFE EFFICACY

7. SEQUENCE OF EVENTS PATHOLOGY REVIEW CT/BS REVIEW DISCUSSION OF TREATMENT OPTIONS FIDUCIAL PLACEMENT CYBERKNIFE TREATMENT

8. Patient lies comfortably on the couch while the CyberKnife robot moves, images and treats. Treatments typically last 1 hour Most patients require no sedation allowing them to depart at the completion of their treatment CyberKnife Treatment Delivery

11. Prostate comparison: axial & sagittal 40 and 25 mm colls40 mm coll

12. Frameless Radiosurgery Robotics Image Guidance Advanced Treatment Planning CyberKnife Technology

14. Precise control limits dose to the rectal wall and urethra Prostate Radiosurgery Image courtesy of San Diego CyberKnife Center

15. Accuray Confidential

16. Challenges for Hybrid Systems Treating Prostate Cancer 240 seconds of Beam on time 5mm of motion

17. CyberKnife ® Treatment of Prostate Cancer

18. Prostate comparison: urethra 40 mm coll40 and 25 mm colls 18.7% vol at 90% dose 30.8% vol at 90% dose

19. Prostate comparison: bladder 12.2% vol at 60% dose 16.7% vol at 60% dose 40 mm coll 40 and 25 mm colls

20. Prostate comparison: rectum 40 mm coll40 and 25 mm colls 20.5% vol at 60% dose 11.2% vol at 60% dose

21. Basic Demographics Ages 62 to 85 Stage cT1cNoMo to cT2bNoMo All patients treated between 12/07/2004 and 12/31/2007 Total number of Patients = 213

22. Hormonal Therapy 186 Patients treated without Hormonal therapy 27 Patients treated with Neoadjuvant Hormonal Therapy

23. Histology Gleason grade 3 + 3 = 172 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

24. Prostate Volumes Range = 15.5cc to 109cc Mean initial volume = 45.7 cc Median initial volume = 46.1 cc

25. 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

26. Dose Calculations for Cyberknife Stereotactic Body Radiation Therapy 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 well founded treatment option

27. 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

28. 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 )

29. Prostate Cyberknife MonoTx Dose Mean Dose = 3503 cGy (n=162) Median Dose = 3500 cGy Range = 3500cGy to 3755 cGy Number of Fractions = 5

30. PSA Response to Cyberknife

31. IPSS Scores After Cyberknife SBRT

32. RAS and SHIM Scores after Cyberknife SBRT

33. 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.

34. 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

35. Acute Toxicity Overall (AUA/RAS/SHIM) Acute effects generally return to baseline by 4 months Urinary symptoms more marked in patients with AUA baseline scores >20 No urethral strictures/ persistent rectal bleeding observed

36. Rationale for Cyberknife SBRT Boost CK dosimetry is most like HDR, since the dose/fraction, total dose and time factors are similar With CK, one can fractionate the therapy yet remain convenient and non-invasive for the patient Published data supports HDR boost (Grills, Martinez)

37. Advanced Disease Demographics (n = 58) Age 54 to 88 Stage cT1cN0M0 to cT3cN0M0 Patients treated between 12/07/2004 and 12/31/2007

38. Hormonal Therapy 24 Patients treated without Hormonal therapy 34 Patients treated with Neoadjuvant Hormonal Therapy

39. Histology Gleason grade 3 + 3 = 8 Patients Gleason grade 3 + 4 = 24 Patients Gleason grade 4 + 3 = 14 Patients Gleason grade 4 + 4 = 7 Patients Gleason grade 4 + 5 = 3 Patients Gleason grade 5 + 3 = 2 Patients

40. Baseline Volume/PSA Initial prostate volume: range = 21.5cc to 77.5cc Initial PSA: mean = 10.2 range = 1.7cc – 80.1 cc

41. Dosing External beam (IMRT): 45Gy at 1.8Gy per fx Wait 1-2 weeks CK boost: 19.5Gy in 3 fx (median) range = 15Gy – 21.75Gy in 3 fx

42. PSA Response post-tx

43. GU Toxicity

44. GI Toxicity

45. SHIM Scores after CyberKnife SBRT

46. Summary Cyberknife is a new and innovative treatment delivery technique for prostate cancer. Cyberknife monotherapy produces an early decline of PSA’s in low risk patients. The acute toxicity of Cyberknife monotherapy is very minimal compared to other radiation treatments. Cyberknife therapy is a noninvasive and convenient treatment option for patients with early stage prostate cancer. Prostate cancer patients treated with Cyberknife should continued to be enrolled and followed in research protocols, and the data collectively analyzed.

47. WHY SHOULD UROLOGISTS BE INVOLVED? A greater understanding of the anatomy We take care of the complications We keep control of our patients