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An Evidenced Based Approach to Rectal Cancer

An Evidenced Based Approach to Rectal Cancer. Anthony J. Senagore, MD, MS, MBA Professor and Clinical Scholar Charles W. & Carolyn Costello Chair In Colorectal Diseases University of Southern California Keck School of Medicine USC Norris Cancer Hospital Los Angeles, CA . 1.

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An Evidenced Based Approach to Rectal Cancer

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  1. An Evidenced Based Approach to Rectal Cancer Anthony J. Senagore, MD, MS, MBA Professor and Clinical Scholar Charles W. & Carolyn Costello Chair In Colorectal Diseases University of Southern California Keck School of Medicine USC Norris Cancer Hospital Los Angeles, CA  1

  2. Colorectal Cancer • second most common cause of cancer death in USA • 66% survive 5 years after curative surgical intervention • local recurrence of 35-40% • outcome largely dependent on tumor stage at the time of presentation 2

  3. Survival is what matters! 27

  4. Residual Nodes Still Matter 12 vs < 12 nodes ND + nodes- HR 2.89 survival Klos et al. American Journal of Surgery (2010) 200, 440–445 50

  5. Circumferential Radial Margin (CRM) • Single most critical predictor of failure • Not routinely reported in the US • Only evaluated in 21% in NCCG (1979-92) • NCCTG study: • <1mm CRM 25% recurrence • >1mm CRM 3% recurrence • Adjuvant treatment will not improve the situation after the fact 48

  6. Distal Margin • Distal intramural spread is found in 6.5% of cases • 2% have spread more than 2cm distally • Williams et al, Br J Surg 1993 • Kwok et al, Br J Surg 1996 • Margins less than 2cm may not compromise survival and local recurrence in carefully selected, well-differentiated cases • Vernava et al, Surg G&O 1992 • Shirouzo, Cancer, 1995 47

  7. The Current Question • Can we effectively assess the stage and can we CHANGE the stage (i.e should we better balance local therapy versus systemic therapy)??? 2

  8. Tumor Staging • Survival • (5 year by Duke’s stage) • A = 90-95% • B = 70-80% • C = 55-65% • D = 5% 6

  9. Preoperative Staging • Especially important for rectal cancer • Clinical examination • Ultrasound • CT scan • Decision about pre-operative therapy 4

  10. Mechanisms of spread • Direct invasion • Lymphatic spread • Blood borne (liver) 5

  11. Preoperative Locoregional Staging • level of tumour operative choice • sphincter involvement operative choice • local extent neoadjuvant Rx • nodal metastases neoadjuvant Rx (unreliable) • Clinical exam accurate in 60-85% 7

  12. Endoanal Ultrasound of Rectum Probe Water filled balloon 1: balloon - mucosa interface 2: m. mucosae 3: submucosa - m. propria 4: muscularis propria 5: m. propria - fat 8

  13. Duke’s A Muscularis propria complete around tumour 9

  14. Duke’s B Local invasion through muscularis propria Tumour involving upper sphincter 10

  15. Duke’s C Mesorectal lymph nodes 11

  16. Computerized Tomography of Rectum • visualises whole rectum • Limitations: • -lesions less than 6mm • -discrimination between benign and malignant • small lymph nodes • -differentiation between marginal invasion, • inflammation & fibrosis • Accurate in approximately 70% 12

  17. Magnetic Resonance and Rectal Cancer • improved staging with technological advances (mesorectal margins) • <1mm • 1-5mm • >5mm • remains expensive • better for nodes than primary • may be best for recurrent tumour 13

  18. MRI for Rectal Cancer 14

  19. Outcomes Impact of MRI 15 Wieder et al. Radiology 243:3- June 2007

  20. After imaging, what then….? Local treatment for T1 (and T2) tumors ? Neo-adjuvant treatment for all stage II and III rectal cancers ? • Short course vs long course Sphincter saving procedures for tumors of the inferior third of the rectum ? • Reservoir no reservoir • Stoma no stoma 18

  21. Are there risk groups (i.e surgery alone)? Low risk: T1/2, N0 Intermediate risk (6-8%): • T1/2, N1; T3,N0 Moderately high risk (8-15%): • T1/2, N2; T3, N1; T4, N0 High risk (15-22%): • T3, N2; T4, N1/2 Pre-TME data Gunderson et al. Int J Radiat Oncol 2002; 54:386 19

  22. Neoadjuvant Treatment • Typically long course XRT and 5-FU • ? Downstaging • ? Increased resectability • ? Increased restorative proctectomy • ? Improved local failure rates • ? Improved survival 26

  23. RCT’s for Post-op XRT 21

  24. Swedish Rectal Cancer Trial - 1997 • 1168 patients randomised to + / - XRT • 25 Gy over 5 days, 3 to 4 field technique • surgery one week later (no TME) • recurrence: 11% with XRT, 27% without • (p<0.001) • 5yr survival: 58% with XRT, 48% without • (p<0.005) • NEJM, 1997 22

  25. Dutch CRC Group Trial - 2001 • 1861 patients randomised to + / - pre-operative XRT • standardized pathology, and resection with TME • 5 x 5 Gy / day, surgery one week later • median follow-up 24.9 m (1 – 56) • 2yr L. R.: 2.4% with XRT, 8.2% without (p<0.001) • T1: 0.5% v 0.7%; T3: 15% v 4.3% • 2yr survival: 82% with XRT, 82% without (p=0.84) • Kapiteijn et al, NEJM, 2001 23

  26. The Dutch TME Trial at 6 years Overall Survival Local Recurrence Peeters et al Ann Surg 2007; 246:693-701 24

  27. The Dutch TME Trial at 12 years Overall Survival Local Recurrence 24

  28. The Dutch TME Trial at 12 yearsIts all about T3 (not the nodes) 24

  29. The Dutch TME Trial at 12 yearsWhy they die 24

  30. Long course radiotherapy • 40-45 Gy over 6 weeks, 4 weeks rest period before • surgery • physically downstages tumour • helps for unresectable tumours (??sphincter preservation) • pre-XRT post-XRT • T0 - 4% • T1-2 - 26% • T3-4 100% 70% • (Ahmad NR, BJS, 1997) 25

  31. Preoperative v Postoperative Chemoradiotherapy • 421 Preoperative • 5040 Gy plus 5-FU continuous infusion (surgery 6W later) • 5yr survival- 76% • Local recurrence 6% • Grade ¾ toxicity: 27% • 402 Postoperative • Surgery then 5040 Gy plus 5-FU continuous infusion • 5yr survival- 74% • Local recurrence 13%* • Grade ¾ toxicity: 40%* Sauer et al. NEJM 2004; 351:1751 28

  32. What Combo is best? 1.1% abs benefit 27 Bossett (EORTC) NEJM 2006; 355:1114-23

  33. Complete responders… • 118 patients with pre-op chemoradiation • 36 month median follow-up • 36 complete responders, 30 no surgery PARTIAL RESPONSE COMPLETE RESPONSE Habr-Gama, et al. DCR 1998 30

  34. Is Clinical Response Complete Enough? • 488 T3/T4 rectal cancers • Response rate • Complete clinical response 19% • Complete pathologic response 10% • 25% rate in those with complete clinical response • 75% with complete clinical response still with microscopic disease after resection 31 Hiotis et al. JACS 2002. 194:131-136

  35. Impact of Complete Response Kalady et al. Ann Surg 2009;250: 582–589 50

  36. Neoadjuvant Chemotherapy 27

  37. Potential Downside • Adds 8-12 weeks to treatment cycle (although not true if it replaces XRT) • Resistance to Chemotherapy occurs very early in treatment • Increases tumor cell propagation despite decrease in size of tumor • No data suggests rescue by switching to non-cross-resistant drugs in colorectal cancer 60

  38. Lessons from palliative chemotherapy 50

  39. Surgical Options • Trans-anal resection • Anterior resection/CAA • Abdomino-perineal 32

  40. Local Treatment (Low Rectal Cancer) • Local excision • Transanal • TEM • Direct contact radiotherapy • Electrocautery 33

  41. Ideal Criteria for Curative Local Treatment of Rectal Cancers • Tumor < 8 cm from anal verge • Tumor size < 3 cm ( < 1/3 circumference) • Histology; well or moderately differentiated • UT1 or UT2 with or without radiotherapy • Absence of lymph nodes • Nonulcerated tumors • Mobile 35

  42. Transanal Excision of Rectal Cancer • Full thickness disc excision • 2 cm margin • Full thickness stay sutures • Use electrocautery • Closure of incision may implant or bury microscopic tumor 36

  43. Transanal excision • For T1 or T2 tumors • Somewhat controversial • due to higher local • recurrence rates • Only routinely used in older • patients or those with • co-morbidity 37

  44. Recurrence after transanal excision Concerns about high local recurrence rates Two reports from U Minn. Summarised to: LocalRadicalp N108153 T1 Loc. Rec. (%)180 T2 Loc. Rec. (%)476 T1 Survival (5yr, %)7265 T2 Survival (5yr, %)8081<0.05 24 of 27 LR after transanal resection had salvage surgery Mellgren et al, Dis Colon Rectum, 2000 Garcia-Aguilar et al, Ann Surg, 2000 38

  45. TEM Rectal Cancer Results • Rush Medical College • Distance from dentate line 0-5 cm = 48% 5-10 cm = 38% 10-15 cm = 14% • Lesion size 0-2 cm = 25% 2-4 cm = 48% > 4 cm = 28% • Recurrence following TEM T1 = 10.3% T2 = 30% Saclarides 1999 40

  46. Another Look at TEM Allaix et al. Dis Colon Rectum 2009; 52: 1831–1836 41

  47. ?TAE After XRT • 11/74 patients (14.9%) T3 rectal CA’s with significant response (clinical T0/T1) • Staged: CT,MRI, IRUS (pre and post) • Results (mean f/u 55.9 mos.) • 9% distant mets Schell et al. JACS 2002. 174(5):584-591. 39

  48. SSI: What’s safe in proctectomy? MBP + Enemas + Abs v Enemas + Abs Bretagnol et al.Ann Surg 2010;252:863–868

  49. ERP Gone Wrong? The team abandoned MBP +Abs in the ex- tended arm while increasing adoption of all the other SCIP measures!!! SSI rate 44% v 24% Anthony et al. Arch Surg. 2011;146(3):263-269

  50. Surgical principles • High vascular ligation • (Corder, Br J Surg, 1992) • Remove lymph node basin • (Total Mesorectal Excision) • “En bloc” resection if • necessary 43

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