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. www.rtog.org 3 Median Survival By Rx Arm And RT Compliance—All Patients Treatment Arm Per protocol Variation Acceptable VariationUnacceptable p-value for trend (1 sided) 5FU Arm 1.50 yrs 1.52 yrs 1.18 yrs 0.08 0.08 n / (95% CI) 117 /(1.28, 1.90) 82 /(1.21,1.91) 12 /(1.06,1.84) Gem Arm 1.89 yrs 1.41 yrs 1.37 yrs 0.03 0.03 (n / 95% CI) 99 /(1.54, 2.48) 94 /(1.24,1.73) 12 / (1.18, 2.37)

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 Pelvic Failure (%) DM (%) DFS (%) OS (%) Preop Tx (405 Pts) 7* 30 59 78 Postop Tx (392 Pts) 11 34 55 73

9. CAO/ARO/AIO-94 Trial: Results pCR (%) Acute GI G 3/4 Toxicity (%) Late G 3/4 GI Toxicity (%) Sph Preserv Rate (%) Preop Tx (405 Pts) 8* 12 * 13* 39* Postop Tx (392 Pts) 0 18 27 19

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 Dose (Gy) pCR (%)2 Yr LC (%) 2 Yr DFS (%) Acute G3/4 Toxicity (%) 40(n=46) 15 72 62 13 46(n=52) 23 90 84 4 50(n=36) 33 89 80 14

12. Fox Chase Phase I Rectal Ca Dose (Gy): 45 Gy + 1.2 BID Downstaging 54.6 (n=10) 50% 57 (n=7) 57% 61.8 (n=6) 67% 23 Pts: 4 pCR (17%)

13. Rectal Ca: New Agents with EBRT 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

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 pCR (%) Acute G ¾ GI Toxicity (%) Late G 3/4 GI Toxicity (%) EBRT / 5-FU + CPT-11 (54 Pts) 28 19 2.0 EBRT / 5-FU (52 Pts) 28 13 2.0

16. CALGB 89901 Phase I/II: Oxali, 5- FU & RT Preop MTWThFSaSu OxalX 5FUXXXXXXX XRTXXXXX 5FU 200mg/m 2 /d; RT 50.4Gy; Oxali 30–60mg/m 2 /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 pCR (%) Acute G3/4 Diarrhea (%) Late G 3/4 GI Toxicity (%) EBRT / 5-FU + Oxaliplatin (Phase II– 32 Pts) 25 37 No Comment

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 Preop CMT* FOLFOX SURGSURG 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) + Oxaliplatin (60 mg/m2 qw) Stratify T2 vs. T3 M vs. F SP vs. APR 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 (Gy)Threshold VG3 SB Toxicity 5 50045% (10/22) 10 30053% (10/19) 15 15050% (10/20) 20 14553% (10/19) 25 14059% (10/17) 30 14059% (10/17) 35 13559% (10/17) 40 12559% (10/17) Dose-Volume Relationship of Acute SB Toxicity

25. Volume Effect: Acute SB Toxicity V 15 (cm 3 ) # PtsG0-2 SB Toxicity G3 SB Toxicity <150 20 100% 0% 150-299 20 70% 30% ≥ 300 20 30% 70%

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. Diarrhea<G2 Median SB V Diarrhea ≥G2 Median SB V V5V5 24276 V 10 16274 V 15 4194 V 20 094 V 30 070 V 35 064 V 40 054 >V 42.75 023 Dose-Volume Relationship of Acute SB Toxicity

28. Rectal Ca: 3-D

29. Rectal Ca: IMRT

31. 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

32. IMRT: Reduction in V of Bowel Irradiated to High Dose Mean Dose (Gy) V 50 (%) V 45 (%)V 40 (%) 3 D CRT 27.16.426.431.4 IMRT 9 Field 28.32.69.021.6 IMRT 5 Field 28.22.28.221.0

33. 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

34. IMAT: Reduction in V of Bowel Irradiated to High Dose Mean Dose (Gy) V 90 (%) > V 15 (%) 3 D CRT 17.019.145.6 IMAT12.46.633.0

35. 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

36. 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

37. 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