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Rectal Cancer: Advanced Technologies

Rectal Cancer: Advanced Technologies. Chris Willett, M.D. Department of Radiation Oncology Duke University Medical Center Durham, NC. Gastric Intergroup 0116: RT Considerations. 35% of initially submitted RT plans: Major deviations (2/3 undertreatment) 2 D Therapy: AP/PA.

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Rectal Cancer: Advanced Technologies

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  1. Rectal Cancer: Advanced Technologies Chris Willett, M.D. Department of Radiation Oncology Duke University Medical Center Durham, NC

  2. Gastric Intergroup 0116: RT Considerations • 35% of initially submitted RT plans: Major deviations (2/3 undertreatment) • 2 D Therapy: AP/PA

  3. Median Survival By Rx Arm And RT Compliance—All Patients

  4. Stage II/III Rectal Ca: 2006 Management • Preoperative EBRT + 5-FU Based ChT • Surgery • Adjuvant ChT

  5. Preoperative EBRT: Rectal Ca • CTV: 45 Gy / 1.8 Gy Fx • GTV: 50.4 (T3) – 54 Gy (T4) / 1.8 Gy Fx • 3 Fields (PA and Laterals) or 4 Fields (AP/PA and Laterals) • Minimize SB Tx: Prone / False Table Top / Bladder Distention

  6. T4 Rectal Cancer: 4 Fields M. Mohiuddin 2006

  7. Ph III German Trial (CAO/ARO/AIO-94) 823 Pts. with cT3/T4 or N+ randomized to: • Preop 5-FU and Leucovorin / EBRT and TME Surgery • TME Surgery and Postop 5-FU and Leucovorin / EBRT (Stage II/III) NEJM 2004

  8. CAO/ARO/AIO-94 Trial: 5 Yr Results

  9. CAO/ARO/AIO-94 Trial: Results

  10. CAO/ARO/AIO-94 Trial: Conclusions Preop ChT + EBRT vs Postop ChT+EBRT: • Improved LC (93%) • Distal Lesions: Enhanced Sphincter Preservation • Less G3/4 Acute (12%) / Chronic GI Toxicity (18%)

  11. PMH Phase 2 Trials: Results

  12. Fox Chase Phase I Rectal Ca 23 Pts: 4 pCR (17%)

  13. Oral 5-FU: Capecitabine (TS inhibition) Irinotecan (topo I inhibitor) Oxaliplatin (inter & intra-strand DNA cross-links) Anti EGFR: Cetuximab, Gefitinib, Erlotinib Anti-VEGF: Bevacizumab Rectal Ca: New Agents with EBRT

  14. RTOG 0012: CPT-11, 5-FU & RT Preop Phase II, Pts with cT3-T4 Disease Randomized to: CPT-11 + 5-FU & RT 50.4-54 Gy/1.8 Gy qd 5-FU & RT 55.2-60 Gy/1.2 Gy bid Opened: February 2002 Accrual: 100 Closed: January 2003 R JCO 2006

  15. RTOG 0012: Results

  16. CALGB 89901 Phase I/II: Oxali, 5-FU & RT Preop 5FU 200mg/m2/d; RT 50.4Gy; Oxali 30–60mg/m2/d • MTD = 60 mg/m2, Gr 3 diarrhea • 21/32 (66%) completed 6 cycles • 26/32 (81%) completed 4 cycles JCO 2006

  17. CALGB 89901: Results

  18. RTOG 0247: Cape, RT + Oxali or CPT-11 Preop Phase II, Pts with cT3-T4 Disease Randomized to: Oxali (50 d 1, 8, 15, 22 & 29), Cape (825 BID, 5 d per w) & RT 50.4 Gy/1.8 Gy qd CPT-11 (50 d1, 8, 22 & 29), Cape (600 BID, 5 d per w) & RT 50.4 Gy/1.8 Gy qd Opened: February 2004 Amended: March 2005 Planned Accrual: 141 R

  19. E5201 Preop INT Trial S U R G Preop CMT* FOLFOX ± Bevacizumab * = bolus 5FU ± LV, CI, or capecitabine

  20. NSABP R-04 Preop Capecitabine (825 mg BID) 50.4 Gy CI 5-FU (225 mg/m2/d) 50.4 Gy + Oxaliplatin (60 mg/m2 qw) Stratify • T2 vs. T3 • M vs. F • SP vs. APR + Oxaliplatin (60 mg/m2 qw) n=1460

  21. Rectal Ca: Preoperative Tx New Cytotoxic Agents + 5-FU during EBRT : Higher Rates of Acute GI Toxicity • ? Rates of Late GI and other Toxicity

  22. Dose-Volume Relationship of Acute SB Toxicity • 40 Rectal Ca Pts: EBRT (50.4 Gy) + 5-FU • 3 D Tx Planning with SB excluding techniques – bladder distention, prone position, false table top. • Correlate Acute SB Toxicity (Diarrhea/Pain) to Volume of SB Irradiated Baglan et al: Int J Rad Onc Biol Phy 2002

  23. Dose-Volume Relationship of Acute SB Toxicity 40 Patients – Overall Toxicity Rates • Grade 0: 7/40 (17.5%) • Grade 1: 15/40 (37.5%) • Grade 2: 8/40 (20%) • Grade 3: 10/40 (25%) • No Grade 4/5

  24. Dose-Volume Relationship of Acute SB Toxicity

  25. Volume Effect: Acute SB Toxicity

  26. Dose-Volume Relationship of Acute SB Toxicity • 41 Rectal Ca Pts: EBRT (45 Gy) + 5-FU/Leucovorin • All 3 D Tx Planning • Correlate Acute SB Toxicity (Diarrhea) to Volume of SB Irradiated Tho et al: Int J Rad Onc Biol Phy 2006

  27. Dose-Volume Relationship of Acute SB Toxicity

  28. Rectal Ca: 3-D

  29. Rectal Ca: IMRT

  30. IMRT in Rectal Ca: Reduction in Bowel Dose • Royal Marsden: 5 Patients with Locally Advanced Rectal Ca • Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT • No Clinical Data Int J Rad Onc Biol Phy 2006

  31. IMRT: Reduction in V of Bowel Irradiated to High Dose

  32. IMAT in Rectal Ca: Reduction in Bowel Dose • Ghent Hospital: 7 Patients with Locally Advanced Rectal Ca (4 Pre and 3 Post) • Dosimetric Comparison of 3 D Conformal Radiation Therapy to IMAT • No Clinical Data

  33. IMAT: Reduction in V of Bowel Irradiated to High Dose

  34. IMRT in Rectal Ca: Reduction in Bowel Dose • 8 Patients (Glasgow) with Locally Advanced Rectal Ca • Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT • No Clinical Data Int J Rad Onc Biol Phy 2006

  35. IMRT in Rectal Ca: Reduction in Bowel Dose • With the use of IMRT vs. 3 D CRT: Statistically significant reduction in Median dose (5.08 Gy) and Mean dose (3.15 Gy) to Small Bowel Int J Rad Onc Biol Phy 2006

  36. Conclusions • GI Toxicity (Acute and Late): Important Consideration • Toxicity will increase with new agents with template of EBRT (50 Gy) + 5-FU • Dosimetric plans show reduction in Bowel irradiation with IMRT vs. 3 D CRT • No Clinical Data • Clear Need for Phase II Trials with IMRT

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