1. Multimodality Therapy of Rectal Cancer Robert D. Madoff, MD University of Minnesota

3. rectal cancer clinical issues colostomy or anastomosis? local or radical surgery? functional outcomes? neoadjuvant therapy?

4. rectal cancer therapy morbidity mortality function optimal cure rate

7. total mesorectal excision the rectum and its mesentery are a single fascia-enveloped unit, anatomically separate from surrounding pelvic structures surgical violation of this anatomic package leads to a positive circumferential margin, a known predictor of local recurrence

9. rectal cancer pathologic evaluation

10. circumferential resection margin Adam 1995 %

11. rectal cancer stage dictates therapy

12. rectal cancer know your enemy!

14. uT1

15. uT3 uN1

16. Preop Staging Review of 83 studies including 4897 patients Kwok 2000 SensitivitySpecificity T Stage EUS93%78% MRI/coil89%79% N Stage EUS71%76% MRI/coil82%83%

17. MRI staging circumferential margin

18. Prediction of Involved CRM Beets-Tan 2004

19. local recurrence surgeon as risk factor surgeon 50 % minimum 25 rectal cancer operations per surgeonHolm 1997

20. rectal cancer know your surgeon!

21. circumferential resection margin Adam 1995 %

22. rectal cancer surgery impact of technique Lehander Martling 2000 % p < 0.0001* p < 0.002* * Stockholm I and II vs TME project

23. Combined postoperative chemotherapy and radiation therapy improves local control and survival in Stage II and III patients and is recommended. NIH Consensus Statement, 1990

24. rectal cancer radiation + chemo local recurrence (%) Krook 1991

25. rectal cancer radiation + chemo, vs. TME alone local recurrence (%) Krook 1991 Heald 1998

26. radiation therapy friend or friendly fire?

27. radiation therapy disadvantages cost convenience complications covering stomas quality of life

28. postop chemoradiation functional results CT/RTsurgery only (%) (%) BM / 24 hr 7 2 nighttime BMs 4614 occasional incontinence 3917 frequent incontinence 7 0 pad 4110 unable to defer BM 15' 7819 Kollmorgen 1994

29. short course rt long-term morbidity RT (+) (%) RT (-) (%) p dvt7.53.60.01 femoral neck / pelvic fractures 5.32.40.03 sbo13.38.50.02 fistulas4.81.90.01 Holm 1996

30. radiation therapy controversies patient selection –who needs adjuvant therapy? timing –pre- or postoperative? technique –short or conventional course?

31. surgery +/- rt local recurrence %

32. surgery +/- rt 2-year survival % Dutch TME Trial p=0.84

33. rectal cancer radiation timing biology downstaging –resectability –sphincter salvage –margins sb complications functional results staging accuracy –avoids overtreatment anastomotic leak risk –covering stomas prepost

34. German rectal cancer study 823 patients - Stage II-III 50.4 Gy RT + Chemo OR (TME) 50.4 Gy RT + Chemo OR (TME) Sauer 2003

35. German rectal cancer study Sauer, NEJM 2005 Pre-OpPost-Op Leak 10% 12% Bleed 2% 3% Delayed healing 4% 6% Stricture 4% 12%* Acute toxicity 27% 40%*

36. Downstaging8% Sphincter Preservation39%19%* Local Recurrence6%13%* Survival76%74% German rectal cancer study Sauer, NEJM 2005 Pre-OpPost-Op * p<0.05

37. short vs. long course United States: Europe: 45-54 Gy 6 weeks OR OR 1 week 25 Gy

38. short course radiation convenience cost effectiveness unsafe if given improperly ? higher rate of late toxic effects cannot give simultaneously with chemotherapy procon

39. short course vs. conventional radiation no data!

40. radiation therapy current status (USA) optimally stage patient (ERUS) conventional (long course) RT plus chemotherapy for stage II (T3), stage III (N1) or stage IV cancers postoperative chemoradiation for positive circumferential margin consider postoperative chemoradiation for understaged T3 or N1 lesions

41. RECTAL CANCER AS BREAST CANCER: PARADIGM FOUND?

42. pensa globalmente… …agisci localmente

43. RECTAL CANCER LOCAL EXCISION pro –low morbidity/mortality –avoids sexual/urinary/bowel dysfunction –avoids colostomy con –nodal status not pathologically assessed –involved nodes not excised –? equivalent oncologic results to radical excision

44. non usare un cannone per sperare ad una pulce…

46. …ma prima assicurati che sia proprio ad una pulce che stai sparando!

48. local therapy results 25 local recurrence (%) CALGB 8984 T1: local excision T2: local excision plus chemoradiation

49. local excision vs. radical surgery T1: local excision T2: local excision; no chemoradiation local recurrence (%) Garcia-Aguilar 2000

50. “Dr. Mellgren and colleagues deserve to be congratulated for their honesty…” Steele 2000

51. “…remarkably bad outcome… significantly worse than any previously reported…” “the University of Minnesota experience stands alone…” Steele 2000

52. local recurrence local excision T 1 rectal cancer 25 %

53. CALGB 8984 Steele 1999

56. TEM results superior to transanal excision!

57. TME VS. TMN local excision: TOTAL MESORECTAL NEGLECT!

58. select tumors with a low likelihood of regional metastases

59. risk of nodal involvement resected colorectal cancer T stagepositive nodes T10-18%avg 8% T212-38%avg 22% T336-67%avg 60% T453-88%avg 65%

60. risk stratification within T stage positive nodes differentiation T1 T2 well 4% 12% moderate 9%20% poor 13%48%

61. submucosal invasion Japanese classification

62. Sm 1 Sm 2 Sm 3 Kikuchi 0% 10%39% Nivatvongs 2.9%7.5%23% nodal metastasis Japanese classification

63. local excision is first a complete excisional biopsy

66. local excision pathologic exclusion criteria T stage > T1 Sm3 positive or equivocal margins poor differentiation lymphovascular invasion

68. SALVAGE SURGERY STATUS 29 patients unresectable hepatic mets 1 additional recurrence11 free of disease17 ( positive margin, NED 3*) Friel 2002 *follow-up 12 months

69. SALVAGE SURGERY AFTER LOCAL EXCISION don’t count on it!

70. LOCAL EXCISION primum non nocere!

71. It is the wise surgeon who understands that the patient takes all the risk.

72. local excision rules of engagement selection, selection, selection! –ERUS stage first, but reassess pathologic specimen –no “winking” at adverse histology or inadequate margins adjuvant chemoradiation for pT2 tumors mandate close follow up remember that recurrent tumors are almost always more advanced than they start, and radical salvage surgery cures only 50% of patients

73. local excision preoperative chemoradiation? downstages tumor –? curative in some patients may reduce risk of tumor implantation at excision site

74. rectal cancer therapy morbidity mortality function optimal cure rate

75. rectal cancer conclusions numerous treatment permutations appropriate treatment depends upon tumor stage, which should be determined before surgery surgery is technically driven; optimal results require training and experience role of local therapy remains controversial oncologic cure is the primary goal, but functional results are an important outcome