Future Developments In Radiation Therapy For Prostate Cancer

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Future Developments In Radiation Therapy For Prostate Cancer

  1. 1. Future Developments in Radiation Therapy for Prostate Cancer Steven J. Frank, MD Assistant Professor Genitourinary and Head/Neck Sections Division of Radiation Oncology
  2. 2. Rectal Fistula Sinus tract vs fistula
  3. 3. Rectal Necrotic Tissue Biopsies showed necrotic tissue
  4. 4. Dose-escalation is not free • Rectal toxicity • Urinary • Erectile
  5. 5. Therapeutic ratio Tumor control Probability of Normal tissue complication EFFECT Total Radiation DOSE
  6. 6. Where are we going in Prostate Radiation Therapy? EBRT Brachytherapy • 2D • 1st Generation Implants • 3D • 2nd Generation Implants • IMRT • 3rd Generation Implants • Hypofractionation • 4th Generation Implants • SBRT • 5th Generation Implants • Protons • IMPT
  7. 7. Where have we come from?
  8. 8. PSA control after conventional dose RT (~70Gy) IJROBP 2001;49
  9. 9. Higher RT doses improve disease control • Multiple retrospective studies show benefit to higher doses of RT. – MDACC (Pollack & Zagars. IJROBP 39, 1997) – Fox Chase (Hanks et al. IJROBP 41, 1998) – MSKCC (Zelefsky et al. IJROBP 41, 1998) – MSKCC (Zelefsky et al. J Urol 166, 2001) – Cleveland Clinic (Lyons et al. Urol 55, 2000)
  10. 10. More Grade 2 rectal complications in 78 Gy arm [IJROBP 53, 2002]
  11. 11. More Grade 2+ rectal toxicity if >25% of rectum received 70Gy
  12. 12. Dose-escalation w/ less toxicity • Delivery techniques – IMRT – Protons • Reduce PTV – Target localization (e.g. BAT, fiducial markers) – Target immobilization (e.g. rectal balloon) – Reduce CTV • Selective dose-escalation – Intra-prostatic targets and avoidance structures
  13. 13. Axial Dose Distribution 75.6 Gy 79 Gy 60 Gy
  14. 14. Sagittal Dose Distribution
  15. 15. DVH Prostate: >100%V@75.6Gy SV: >95%V@75.6Gy Rectum: <20%V@70Gy <35%V@60Gy Bladder: <25%V@70Gy <35%V@60Gy Femoral Heads: <5%V@50Gy
  16. 16. MSKCC Rectal toxicity (3D CRT vs. IMRT) 3DCRT IMRT
  17. 17. MSKCC GU toxicity based on dose 81 vs. 86 Gy “Among patients who received doses 75.6 Gy, the incidence of Grade 2 urinary symptoms at 5 years was 13% compared 8% at lower doses.” [IJROBP 53, 2002]
  18. 18. Dose-escalation w/ less toxicity • Delivery techniques – IMRT – Protons • Reduce PTV – Target localization (e.g. BAT, fiducials) – Target immobilization (e.g. rectal balloon, tracking) – Reduce CTV • Selective dose-escalation
  19. 19. Accelerator Systems Synchrotron Linac Injector
  20. 20. 13 m diameter 190 tons SAD 2.7 m
  21. 21. Image Receptors Nozzle Snout Couch X-ray tube Articulating Floor
  22. 22. A Single Bragg Peak
  23. 23. Modulation of the Bragg Peak  The Bragg peak is spread out by introducing extra absorbing material before the beam enters the patient. If different thickness of such absorber are present for different fractions of the irradiation time, the narrow monoenergetic peak can be spread into a useful plateau  The Bragg peak can be spread out to a useful plateau by the use of a rotating stepped absorber. Range Modulator Wheel
  24. 24. SOBP, Photons, & Bragg Peak PSI
  25. 25. Aperture 2D Shaping Lateral aspect of aperture used to spare critical structures
  26. 26. Compensator 3D Distal Shaping As well as spreading out the Bragg peak, the final range itself must be shaped to the distal surface of the target volume taking into account heterogeneities
  27. 27. Two lateral beams. Further improvements w/ IMPT? Decreased integral dose. Better dose homogeneity. Quicker planning time.
  28. 28. Dose-escalation w/ less toxicity • Delivery techniques – IMRT – Protons • Reduce PTV – Target localization (e.g. BAT, fiducials) – Target immobilzation (e.g. rectal balloon) • Selective dose-escalation
  29. 29. Sharp dose-fall off with IMRT requires accurate DAILY target localization
  30. 30. Dancing Prostate 25 treatment CTs Acquired during a course of 42 fxs treatment Dong (MDA), 2002
  31. 31. IGRT is a Process VARIAN
  32. 32. Reducing PTV a.k.a. IGRT (Image Guided Radation Therapy) • Improve accuracy and decrease normal tissue irradiated • Requires daily imaging of the target • INTER-fractional movement • INTRA-fractional movement
  33. 33. IGRT • Portal imaging • Ultrasound (e.g. B.A.T.) • Fiducial markers (intraprostatic) • Volumetric on-board imaging – In-room CT – Cone-beam CT
  34. 34. BAT alignment (axial) Bladder Prostate Rectum
  35. 35. BAT Alignment (sagittal) Bladder Prostate Rectum
  36. 36. Ultrasound-based alignment • Pros • Cons – Non-invasive – User-subjectivity – Reasonably good – Patient anatomy may alignment affect image quality – Visualize SV/ – Impact of probe bladder/rectum pressure on prostate – Visualize prostate position surface contour – Different imaging – Follow-up modality – New volumetric systems
  37. 37. On-Board Imager (OBI) - Varian kV X-ray Source aSi Imaging Panel (2048 x 1536 pixel resol.) Robotic Arms - 3 pivot points - Completely retractable - Position feedback control Software - Image acquisition and registration
  38. 38. OBI 2D-2D manual match: pre-shift
  39. 39. OBI 2D-2D manual match: postshift
  40. 40. Fiducial-based alignment • Pros • Cons – Less subjectivity – Invasive – Good alignment – Requires daily ports • (unless KV imaging onboard) – Allows target tracking – No image of SV, rectum/bladder • Kitamura and Shirato et al. – Better for large patients – No image of prostate surface contour – Basis for improved – Shifts may not be representative multimodality image fusion (e.g. MRI-CT) of volume • Jaffray et al. ASTRO 2004 • Fiducials and MRI – Ongoing MDACC study • 47% had 3mm deformation over comparing fiducials vs. CT- 90% of surface on-rails • On average, 14% of surface deformed by >3mm (up to 9mm)
  41. 41. Varian ExaCT™ at MDACC Linac In-room CT
  42. 42. CAT Software (3D-3D matching) Compares Pinnacle planed patients to volumetric images Lei Dong, Lifei (Joy) Zhang
  43. 43. A closer look at contour overlay Courtesy of Lei Dong
  44. 44. Step 4. Automatic Image Registration Courtesy of Lei Dong
  45. 45. Step 5. Review Image Registration (prostate is the target of alignment) Courtesy of Lei Dong
  46. 46. • CT-based alignment could yield accuracy of <3mm – Smaller treatment margins – Less dose to rectum, bladder – Avoid high-dose to intra-prostatic structures (e.g. urethra)
  47. 47. Robotic arm motion
  48. 48. Robotic arm motion
  49. 49. Robotic arm motion
  50. 50. Cone-beam CT • Uses on board kV X-ray source and amorphous silicon flat panel imager • Large field of view (25 x 25 x 10 cm) and single revolution captures images – Unlike standard CT that uses small field of view and many revolutions • Inferior image quality compared to conventional CT but may be adequate for RT targeting
  51. 51. Cone Beam CT – Large GU patient (330 lbs) Planning CT CBCT
  52. 52. Post shift CBCT verification using in-house CAT software
  53. 53. Cone Beam CT vs. CT on Rails < 5 min acquisition and < 5 min acquisition and reconstruction time reconstruction time Patient is imaged in treatment Patient is rotated into scanning position (except for lateral shifts) position on treatment couch (lateral and vertical shifts required) Isocenter defined in CT space Isocenter not linked to images Each slice is a 60 sec time average Each slice is a 1 sec time average 45 cm FOV half-scan 50 cm FOV (full scan)
  54. 54. Dose-escalation w/ less toxicity • Delivery techniques – IMRT – Protons • Reduce PTV – Target localization (e.g. BAT, fiducials) – Target immobilzation (e.g. rectal balloon) • Selective dose-escalation – Intraprostatic GTV/OAR
  55. 55. Endo-rectal balloon 1. Immobilize prostate (accounts for inter- and intrafractional motion) 2. Displaces rectum away from high dose
  56. 56. Example -2.0 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 CT Shift (cm) Same Day Axial CT BAT Oblique Axial
  57. 57. Is intra-fractional prostate motion a concern? • Daily IMRT treatment 15 minutes to setup and deliver • Possible prostate positional change during this interval largely due to transient rectal gas • Positional change can be large (>5 mm), but usually transient • Clinical impact over 7-8 week treatment course is unknown
  58. 58. Dose-escalation w/ less toxicity • Delivery techniques – IMRT – Protons • Reduce PTV – Target localization (e.g. BAT, fiducials) – Target immobilzation (e.g. rectal balloon) • Selective dose-escalation – Intraprostatic GTV/OAR
  59. 59. What is needed to treat intra- prostatic targets? • Imaging modality beyond CT that can delineate intra-prostatic tumor – Endorectal MRI/MRS – Dynamic contrast MRI • Conformal delivery method – IMRT, protons, brachytherapy • Accurate delivery – Daily imaging w/ online correction – Target immobilization? – Transrectal U/S guidance
  60. 60. Endorectal MRI • Endorectal MRI uses a coil inside an inflatable latex balloon (50-70cc). – Coil just posterior to prostate • Resolution is 0.4mm per pixel pair – Body coil MRI has resolution of 3 mm [Roach et al. Oncology 15:1399-1410] • Accuracy is technique and reader dependent as per RDOG studies – [Radiology 1994;192:47-54]
  61. 61. 75.6Gy 87.2Gy Concomitant boost Special thanks to Danny Tran & Lei Dong
  62. 62. CT/ MRI/MRS fusion • Define CTV more clearly – Prostate anatomy – Reduced side effects • Define other CTV’s (e.g. peripheral zone, urethra) – Selective dose-escalation (“Dose painting”) – Reduce toxicity w/ in the prostate • Define GTV – Selective dose-escalation (Focal boost)
  63. 63. Hypofractionation • Provide basis for larger fractional dose w/ equal or less toxicity – / for prostate ca may be < 4 Gy » [Brenner et al. IJROBP 52:6-13] • Hypofractionation studies: – Kupelian et al 70 Gy (2.5Gy/Fxn) [IJROBP 53, 2002] – MDACC ongoing randomized study • 75.6/1.8 Gy vs. 72/2.4 Gy (BED = 78-82 Gy)
  64. 64. 72 Gy (2.4Gy)
  65. 65. Cleveland Clinic-retrospective 70Gy/2.5Gy vs. 78Gy/2Gy Grade 2-3 rectal toxicity 166 (SCIMRT) 116 (3DCRT) Median FU 21 vs. 32 mo Only 2 pts in each group had Gr 2+ GU toxicity. Kupelian et al. IJROPB 53, 2002
  66. 66. Highest Degree of Conformal Therapy? Brachytherapy
  67. 67. 1st Generation Implants: Open Placement
  68. 68. Transperineal Interstitial Permanent Prostate Brachytherapy 18 gauge needle (1.3 mm diam) for seed placement Perineal template to Ultrasound probe in localize needles as planned rectum for needle guidance
  69. 69. 2nd Generation Implants: Uniform Loading
  70. 70. Source Migration * *Coronary artery Davis BJ et al., J Urol 2002; 168:1103.
  71. 71. 3rd Generation Implants • Modified peripheral loading – Reduced urethral dose (not urethral sparing) – All seeds implanted in the prostate (which means little treatment outside capsule or high urethral dose with margin) – CT-based dosimetry evaluation
  72. 72. Modified Peripheral Loading
  73. 73. 4th Generation Implants • Stranded seeds (Varistrand ) – Less seed migration – Permits periprostatic seed placement • Improved dosimetry – Wider therapeutic margin on prostate (3 - 5 mm) – MRI / CT fusion (better QA better implants) – Improved Homogeneity
  74. 74. Intraoperative Comparison of Actual Seed Location to Preplan
  75. 75. PTV DVH Parameters V100>95% V150<60% V200<20% D90<120% R100<1cc
  76. 76. 5 yr BRFS Monotherapy • Seed monotherapy 5 yr BRFS if implant quality questionable or poor = 34-63% • Seed monotherapy 5 yr BRFS if implant quality is good = 82-98% • % positive Bx cores predicts RP BRFS • RTOG-0232 randomized study I125/Pd103 +/- EBRT intermediate risk patients
  77. 77. Transperineal Interstitial Permanent Brachytherapy Alone for Selected Patients with Intermediate Risk Prostate Cancer Phase II Prospective Single Arm Study David Swanson and Steven J. Frank
  78. 78. Stratification • < 35% core biopsy and Gleason 7 disease with a PSA under 10 • < 35% core biopsy and combined Gleason scores less than 7 with a PSA 10-15 • >/= 35% core biopsy and Gleason 7 disease with a PSA under 10 • >/= 35% core biopsy and combined Gleason scores less than 7 with a PSA 10-15
  79. 79. MRI vs. CT Prostate Phantom Prostate Phantom Front view Front view Notice the artifacts on CT imaging July 2008
  80. 80. 1.5T MRI Strand Prostate Phantom Prostate Phantom C4 Seed Oblique view Saggittal view
  81. 81. GU Team • Physicians • Physicists – Seungtaek Choi – Lei Dong – Min Rex Cheung – Rajat Kudchadker – Deborah A. Kuban – Jennifer Johnson – Andrew K. Lee • Dosimetrists – Paula Berner – Jim D. Cox – Teresa Bruno – Tom A. Buchholz – Mandy Cunningham • Therapists • Nurses

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