1. Jean-François Bosset Professeur Oncologie-Radiothérapie CHU Besançon [email_address] Rectal cancer loco regional failure risk reduction

3. Scheme Fup (y) LF % S XRT-CT GITSG 40 - 48 Gy 7 24 11 71 - 75 + 5 FU-MECCNU Norway 46 Gy + 5 FU > 4 30 12 > two fold LF reduction Postop XRT-CT and local control

4. Acute toxicity and compliance in postoperative combined studies } 50

5. European Developments Preop treatments Surgery Short course RT SRCT Dutch trial Long course RT EORTC MRC CRT Conventional MRC CR07 EORTC FFCD CAO NSABPR03 TME

6. Main differences between short/long course RT Short Long Dose/f Gy 5 1.8 – 2 Total dose 25 40-50 Duration w 1 5-6 Surgery immediate 4-8 OTT w  2  7

7. Swedish Rectal Cancer Trial 1168 pts (~ 30 % stage I) R 5 x 5 – Conventional S Conventional S 5y-LR % : 11 vs 27 OS % : 58 vs 48 NEJM 1997

8. Dutch Trial TME ± preop RT 1861 pts (~ 30 % stage I) R TME – postop RT if R1-R2 25 Gy TME 5y - LR % : 5.8 vs 11.4 OS % ~ 64 ns No benefit for lower rectum or CRM +

9. MRC CR 07 1350 pts (~ 30 % stage I) R S – CRM+ : postop CRT 25 Gy - S Note : Surgery 50 % TME ; 50 % conventional 3 y-LR % 4.4 vs 10.6 1% if TME DFS 77.5 vs 71.5

10. Long course preop RT EORTC no pts RT S p 466 15 30 0.003 5-year LR %

12. Trial comparison CAO EORTC FFCD NSABPR03 Recruitement 94.02 93.03 93.03 93.99 No. pts 823 1011 762 254 RT dose 50.4 45 45 50.4 CT CI 5-FU 5-FU-LV 5-FU-LV 5-FU-LV End point OS OS OS DFS-OS Surgery TME Convent / TME

13. Pre-op treatment : toxicity and compliance End point % RT RT-CT p (n = 505) (n = 506)  G2 acute diarrhea 17.1 34.3 <0.0001 Compliance RT 98.0 95.5 ns Compliance CT - 83.2 (95-105 % 5-FU dose)

14. 5 y - results preop RT vs CRT Trials LR % DM % OS EORTC 8.7 vs 17.1 35 ns FFCD 8.1 vs 16.5 - ns

15. 5 y - results preop CRT vs postop CRT Trials LR % OS CAO 6 vs 13 no NSABP no  yes DFS 64.7 vs 53.4

16. Preop CRT with 2 drugs. ypT0 % Study 5FU/cap 5FU/cap + Oxali p Prodige 2 13.8 18.8 0.11 Star 01 16 15 0.9

17. Preop CRT with oral Fluoropyrimidines 5-FU-LV PVI 5-FU Capecitabine ypT0 % 12.1 - 13.7 8 - 12 10 - 24 Substitute cape for PVI-5-FU/5FU-LV

20. Preop short RT vs long CRT ? Polish trial. 316 pts T3-T4 (DRE) resectable R 5 x 5 - S CRT - S Main end point : sphincter saving

21. Polish trial - Results SSR % 4y LR % 4y DFS 5x5 61.2 10.6 58.4 CRT 58 15.6 55.6 Note : ypT0 % = 0.7 vs 16.1 !! Unconclusive On going : Swedish and Australian trials

22. Preop RT for upper rectum  10 cm LR % Study Nb RT RT+ p Stockholm 126 21 5 0.01 SRCT 243 12 8 0.3 MRC 207 6.2 1.2 HR 0.19 (0.07-0.47) TME 533 6.2 3.7 0.122

23. Extension distale extrapariétale TME totale vs partielle Steele RJ, in Challenges in colorectal cancer. Ed Scholefield 2000

25. Current question : preop CRT for all T3 ? Importance of the Extra Mural Spread (EMS) 5 y – cancer S % LR % N0 5.5 N1,2 17 N0 15.4 N1, 2 34 Merkel, et al . Int J Colorectal Dis 2001 (Erlangen Registry) < 5 mm 85 > 5 mm 54

26. Multivariate Cox regression analysis for LR, and OS (3633 patients) LR OS HR p HR p LN < 0.001 <0.001 N0 1 1 N+ 2.26 1.99 CRM <0.001 < 0.001 Θ 1 1 + 3.11 1.75 S procedure 0.011 0.030 LAR 1 1 APR 1.36 1.17 Den Dulk et al. Eur J Cancer 2009

27. Recognising late effects. Functional outcome % - (Confidential) EORTC 5x5 Polish CRT Polish SRCT Surgery alone Loperamide 10.4 49 40 8 8  3 emptying/d 40.5 50 8 Defering time  10’ 61.2 60 64 - - Early return 40.5 88 93 69 45 Incontinence Stool 67.2 72 66 64 27 Gas 36.3 76 75 68 51 Use of pad 42.1 39 41 49 22 Sensory function 36.2 62 67 - 20 Preop Tt affects functional results/surgery 5x5 = CRT

31. Overview of the recurrence locations for RT+/RT- patients stratified by type of surgery. Note : recurrences above S2-S3 interspace rare (only if CRM+, N+, or both) From Nijkamp et al. Int J Radiation Oncology Biol Phys 2010 (in press)

33. Lateral view 2D simulation field of a rectal cancer located in the middle rectum. Target limits

34. J.F.B B L A D D E R E M P T Y

35. F U L L B L A D E R

36. Dose distribution 3D versus IMRT IMRT 3D

37. Small bowel 3D Mean dose 30 Gy Small bowel IMRT Mean dose 15.7 Gy Small bowel dose-volume histogram

38. Tailoring pretherapeutic strategies for T3-T4 on MRI/tumour location (next future ?) Good T3a EMS < 5 N Θ Mid rectum CRM Θ Bad T3b EMS > 5 N + T3a at sphincter level CRM Θ Ugly T3c CRM + T4 5 x 5 Gy TME CRT TME CRT intensification Extended resection