1. Radiotherapy for Colo-rectal Cancer

2. Case 1 בן 58 גידול בגובה 9 ס"ם מפי הטבעת קולונוסקופיה – גידול צירקולרי, כמעט חוסם TRUS T3 N0 מועמד לניתוח TME טיפול??

7. Staging Clinical –Rectal exam + rectoscopy –TRUS –Abdomino-pelvic CT –Chest X-ray –CEA? Pathological

8. Aim of adjuvant chemo-radiation 1 o aim – overall survival 2 o aim - Loco-regional control - Disease free survival - Quality of life Sphincter preservation –Down-staging Long-term bowel function Urinary function Sexual function

9. Endoscopic ultrasound

10. Surgical Procedures for Rectal Cancer Radical –Abdominoperineal resection –Low anterior resection –Proctectomy and coloanal anastomosis –Total mesorectal excision Conservative –Transanal excision –Transanal endoscopic microsurgery Ablative procedures –Endoscopic laser Fulguration –Brachytherapy

11. Mesorectal resection

12. Low coloanal anastamosis

13. Radiotherapy for colo-rectal cancer Rationale –Local control –Survival –Down-staging Indications –Risk of local recurrence >10% –Radiotherapy can be safely delivered to site of highest risk Sites –Rectum –Cecum –Other sites - T4

14. Patterns of failure rectal cancer Pelvic failure rate –B2-C1 - 10-60% –C2- 30-70% Patients undergoing 2 nd look operation –Pelvic recurrence 92 % –Pelvic recurrence only48% Gunderson 1974

15. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358:1291

16. risk of death from non-rectal cancer causes and from rectal cancer from six trials of preoperative radiotherapy (biologically effective dose >30 Gy)

17. MRI evaluation of tumor response Sauer

18. Systematic overview Lancet 358:1291, 2001 radiotherapy dose-response reduced death rate increased reduced BED overall cancer specific non-cancer death local failure Pre-op <20 Gy 6%11% 5%-20% 20-30 Gy 1%1%15% 24% >30 Gy10%22%37% 57% All pre-op 6%13%15% 46% Post-op >35 Gy 5%9%12% 37%

19. Mesorectal resection

20. Rates of Overall Survival in 1805 Eligible Patients, TME study

21. TME study: local recurrence 2 years after complete resection 2.4% in XRT & surgery and 8.2% in surgery alone (P<0.001)

22. Sphincter preservation Pre 1990 –95% pts with low <6 cm tumors underwent AP resection Post 1990: Pre-op XRT –Several series80% sphincter preservation – 85-90% local control (3-4 yrs) – 75-90% good bowel function

23. Adjuvant radiotherapy for rectal cancer pre-operative postoperative Stagingclinicalsurgical Toxicitylessmore –Bowel may be trapped after surgery Surgery down-staging reduced spillage

24. Relative reduction in local failure according to number of 5 Gy fractions. Size of symbols is proportional to the number of patients in trial. The 3 large trials are, from the top, te TME trial, Swedish Rectal Cancer trial and the Stockholm I trial. Dose (5Gy fx studies)

25. Radiotherapy toxicity 5 Gy x 5 pre-op Stockholm trials –Trial 1 large AP/PA fields 8% post-op mortality (Cancer 66:49, 1990) 1 & 2 combined (Cancer 78:968, 1996) –ThromboembolismRR 2 –Pelvic/femoral fracturesRR 3 –Intestinal obstructionRR 1.5 –FistulaRR 2.8 Swedish trial (Dis Colon Rectum 41:543 1998) –> 4 stools per day20% –Emptying difficulties52% –Incontinence of loose stool50%

26. Radiotherapy volumes in trials using 5 * 5 Gy and postoperative mortality Volume technique Energy given (J) Stockholm(+)Mid L2 2-beams 310 UppsalaMid L3 3-beams 210–250 SRCTMid L4 3/4 beams 190 Stockholm II (+) (As SRCT, but no shields) 270 TMEMid L5 3/4 beams140–170

27. Small bowel sparing using high-energy linear accelerator XRT prone three-field treatment v AP/PA.

28. The small bowel (arrows) remains fixed in the pelvis, and cannot be excluded from the lateral fields. Post-operative radiotherapy

29. The small bowel (arrows) is excluded from the lateral fields Note: place wire to exclude perineum or use anal marker Pre-operative radiotherapy

30. Correlation between the volume of small bowel receiving 15 Gy (V 15 ) and degree of acute small bowel toxicity Baglan KL Int J Radiat Oncol Biol Phys 2002 52:176.

31. Adjuvant versus Neoadjuvant Chemo- radiation for Rectal Cancer: Sauer NEJM 2004 Phase III preop 45 Gy CRT v postop 45 Gy CRT Eligibility: T3/T4 or N+ 5−FU (1g/m2/d - 120h−CI ) 1 st and 5th week of XRT Interval between CRT and surgery was 4−6 weeks Techniques of surgery standardized and included TME –Stratification was done according to surgeon 797 evaluable patients in 26 institutions

32. Adjuvant versus Neoadjuvant Chemo- radiation for Rectal Cancer: Sauer NEJM 2004 Post-op Pre op 5−year pelvic recurrence 11% 7% (p = 0.02) –5−year distant recurrence 34% 30% (p = 0.52) –disease−free survival 55% 59% (p = 0.23) –overall−survival 73% 78% (p =0.38) chronic anastomotic stenosis 8.5% 2.7% (p = 0.001) –Acute grade 3 and 4 toxicity 31.7% 28.8% (p -n.s.) sphincter preservation 19% 39% (p = 0.004) –subgroup of 188 patients with low−lying tumors declared by surgeon prior to randomization to require an AP resection

33. Adjuvant versus Neoadjuvant Chemo- radiation for Rectal Cancer: German Study Sauer ASTRO 2003; local recurrence

34. Pre-operative 5-FU chemoradiation: commonly used in rectal cancer 5-FU-based chemoradiation has become part of pre-operative therapy for rectal cancer –More effective downstaging than XRT alone Historical controls Pivotal EORTC study now completed accrual –10–30% pCR rates With postoperative XRT protracted infusion of 5-FU improves survival versus bolus 5-FU 1 O’Connell MJ et al. N Engl J Med 1994;331:502–7

35. EORTC study

39. Newer drugs in chemo-radiation of rectal cancer Indications: –Locally advanced T4 –N+ –May be overkill for T2-T3 N0 Drugs –Oxaliplatin –Irinotecan (CPT-11) –Bevacizumab –EGFR inhibitors

40. NSABP R-04 rectal cancer trial *Plus 5.4Gy for fixed tumours Resectable rectal cancer, stage II–III n=1 600 Capecitabine continuous throughout radiotherapy (50.4Gy*) SURGERYSURGERY 5-FU continuous infusion throughout radiotherapy (50.4Gy*) Objectives –DFS –Recurrence rate –pCR –safety

41. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Willett Nat Med 2004

42. Case 2 בת 54 עצירות כרונית גידול בגובה 3 ס"ם מפי הטבעת (מעל הספינקטר) TRUS T2 N0 מסרבת כריתה ראדיקאלית טיפול??

43. Sphincter preservation local therapy only Endocavity radiation Local failure – T1 3% – T233% –Local excision only – T10-33% – T20-43% –Local excision & XRT – T10-10% – T20-18%

44. Candidates for local therapy of rectal cancer Indications –Tumor <3 cm –Well differentiated –Submucosa or superficial muscularis Options –Transanal resection –Brachytherapy –External beam radiotherapy

45. Local therapy only – what about lymph nodes? Incidence of peri-rectal lymph nodes –T1 0-12% –T222-28% –T336% –Grade 10-4% –Grade 214-30% –Grade 350%