1 / 56

Rectal Cancer MOTP Half Day September 9, 2008

Yoo-Joung Ko. Rectal Cancer MOTP Half Day September 9, 2008. Outline. Rectal Anatomy Unique aspects of a rectal primary Evidence Post Op Combined Modality Pre Op Pre Op vs Post Op Importance of Quality of TME Controversies Colon CA What regimen do? How long should we treat?

haven
Download Presentation

Rectal Cancer MOTP Half Day September 9, 2008

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Yoo-Joung Ko Rectal CancerMOTP Half DaySeptember 9, 2008

  2. Outline • Rectal Anatomy • Unique aspects of a rectal primary • Evidence • Post Op Combined Modality • Pre Op • Pre Op vs Post Op • Importance of Quality of TME • Controversies • Colon CA • What regimen do? • How long should we treat? • Who should we treat?

  3. Rectal Anatomy Left upper valve of Houston Portion of Rectum cm from anal verge Right middle valve of Houston upper 1/3 middle 1/3 lower 1/3 15 Peritoneum 10 Ampulla of Rectum Left lower valve of Houston 6 Pelvic size/structures: M vs. F Anal verge Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1197.

  4. Rectal Cancer: Unique Aspects • Below the peritoneal reflection • Different surgical approach • Total mesorectal excision (TME) • Risk of local recurrence • Significant morbidity

  5. Rectal Cancer Staging

  6. Post Op Combined Modality

  7. Advantages of Postoperative Treatment • Accurate pathologic staging • Less likely to overtreat • Shorter delay to definitive therapy ie surgery • Potentially less surgical morbidity • No complicated by prior XRT-chemo

  8. 1990 NCI Consensus Statement • Combined postoperativechemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended JAMA 1990: 264:1444-1450

  9. NCCTG Intergroup Trial (postop trial) • 2x2 study design: • PVI 5-FU during XRT better • significant decrease in relapse (47% to 37%, p=0.01) • reduction in distant metastases (40% to 31%, p=0.03) • no difference in local failure rate • MeCCNU: no benefit NEJM 1994

  10. Tepper, JCO 1997 Intergroup 0114CT – CRT - CT Bolus 5FU II III Bolus 5FU-Levamisole R Bolus 5FU-Leucovorin Bolus 5FU-Leucovorin-Levamisole CP1050909-25

  11. Intergroup 0114 • 1696 patients with resected stage II/III rectal cancer • Similar toxicity, similar efficacy – no difference in DFS or OS • Local Recurrence rate 14-18% • 5year OS – 61-65% Tepper, JCO 1997

  12. Intergroup 0144 b5FU – XRT+PVI5FU – b5FU II III PVI5FU – XRT+PVI5FU – PVI5FU R b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV Smalley, JCO2006

  13. Intergroup 0144, n=1917

  14. Preoperative Radiotherapy

  15. Preoperative Therapy • Lack of surgical staging • Potential overtreatment minimized by better imaging • XRT better tolerated (tissues better oxygenated) • Sphincter preservation • Less small bowel irradiation • ?early irradication of micrometastatic disease

  16. Swedish Rectal Cancer Study Decrease LR and improves OS Preop RT(25 Gy in 5 fractions) R LR 11%, 5yr OS 58% Immediate surgery LR 27%, 5yr OS 48% (NEJM 1997)

  17. Dutch Colorectal Group(NEJM 2001) No OS benefit at 2 yrs TME + Preop RT(25 Gy in 5 fractions) R LR 2.4%*, 2yr OS 82% TME alone LR 8.2%, 2yr OS 82% *62% rate of fecal incontinence with XRT

  18. Preoperative vs Postoperative XRT

  19. S S German Rectal Cancer Study Group, Adjuv. vs. neoadjuv. CRT (CAO/ARO/AIO-94) 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d 120h-infusion 120h-infusion i.v.-bolus Arm I: RT: 50.4 + 5.4 Gy Boost 5-FU 5-FU 5-FU 5-FU 500 mg/m2/d I.v.bolus 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 120h-infusion120h-infusion Arm II: RT: 50.4 Gy 0 2 4 6 8 10 12 14 16 18 20 22 Weeks Sauer NEJM 2004

  20. Overall Survival Intent-to-treat Analysis (Med. Follow-up: 40 mts) Overall Survival 1.0 Postop CRT .9 74% Overall Survival .8 Preop CRT 74% .7 .6 0 30 40 50 60 10 20 Months

  21. Chronic Toxicity (Grade 3/4)Analysis per protocol Postop. RCT 14.8 % 11.8 % 3.4 % 22.7 % Preop. RCT 9.5 % 4.0 % 2.2 % 9.6 % n.s. 0.006 n.s. 0.04 Gastrointestinal Anastomosis Bladder All Toxicities

  22. Sphincter Preserving Surgery ITT Analysis Postoper. RCT Preoper. RCT n= 394 n = 405 85 109 17/85 (20%) 43/109 (39%) Pre-randomiz: “APR Necessary“ Sphincter preserved p = 0.004

  23. .14 .12 .10 .08 .06 .04 .02 0.00 0 30 60 20 10 40 50 Months Cumulative Incidence of Local Relapses Intent-to-treat Analysis (Med. Follow-up: 40 mts) 12% Postop CRT Locoregional Recurrences 6% p = 0.006 Preop CRT

  24. .4 .3 .2 Distant Metastases .1 0.0 0 10 60 20 30 50 40 Months Cumulative Incidence of Metastases Intent-to-treat Analysis (Med. Follow-up: 40 mts) 32% Postop CRT 32% Preop CRT

  25. German Rectal Study Conclusions • Preop CRT significantly improves local control • Preop CRT improves sphincter preservation in low-lying tumours • Preop CRT reduced acute and chronic toxicity • Preop CRT should be the standard adjuvant treatment in cT3/4 or cN+ rectal cancer • NO effect on overall survival

  26. Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group Local recurrence after rectal cancer resection is strongly related to the plane of surgical (PoS) dissection and is further reduced by pre-operative short course radiotherapyPreliminary results of theMRC CR07/NCIC C016 randomised trial

  27. CRM-ve CRM+ve Pathology(PoS) CRM-ve CRM+ve Trial Design Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases Randomise POST PRE Pre-operative RT 25Gy / 5F Surgery Pathology (Pos) Surgery Post-op CRT 45Gy / 25F + concurrent 5FU No RT Adjuvant chemotherapy given as per local policy

  28. CRO7/NCIC CO.16

  29. Local Recurrence: Pre-op vs Post-op Pre-opSurgery S + RT Survival Meta-analysis 22% 12.5% S + RT 45% S 42% Swedish Trial (25 Gy, 5 tx) 27% 12% S + RT 58% S 48% Dutch (TME) Trial 8.2% 2.4% German 50.4 Gy - 54 6% 76% CR07 25 Gy / 5 tx 5% 72%

  30. Local Recurrence: Pre-op vs Post-op (cont.) Post-opSurgery S + RT Survival German Trial (50.4—54.0 Gy, 5 tx) 13% 74% Intergroup 0114 50.4 -- 54 9-13% 53-67% Intergroup 0144 50.4 -- 54 4.6-8% 67-72% CR07 (45 Gy) 17% 61.7%

  31. CO.16 - Summary • Local recurrence rate is significantly reduced with pre-op RT compared to post-op RT • Results after post-op chemo/RT poor comared to other trials and are especially poor for Stage III and CRM-positive patients • Study included patients not usually considered for RT * Stage I (315/1211 pts) • Many patients did not receive optimal TME (523/1119) pts

  32. High efficacy of short-course schedule also has been confirmed by the MRC CR07 randomized trial (ASCO Meeting 2006 ) 1350 patients Routine pre-op 5 x 5 Gy + TME vs TME + selective post-op chemoradiation for those withinvolvement of circumferential resection margin(CRM+)

  33. The MRC C-07 study 1350

  34. MRC CR07 trial: 5-year results Routine pre-op Selective post-op 5 x 5 Gy chemoradiation Local recurrence 5% 17% p<.001 Disease-free surv. 75% 67% p=.03 Overall surv. 72% 62% p=.07

  35. Prognosis QOL of surgery Complete TME Incomplete TME

  36. MCR- C07 study: Quality of TME Surgery • Excellent : 53% • Average : 34% • Bad: 13%

  37. MCR- C07 study: Quality of TME Surgery and CRM+ • Excellent : 9% • Average : 12% • Bad: 19%

  38. Controversies

  39. Optimizing Preoperative Chemoradiation

  40. Can we replace PVI-5FU with Capecitabine With RT?What about Oxalilatin with RT?

  41. NSABP R-04 Oxaliplatin 50mg/m2 IV weekly X 5

  42. In Whom? Which Regimen? For How Long? Postoperative/Post CRT – Adjuvant Chemotherapy

  43. Unanswered Questions Remain • In Whom? • Clinical stage versus Pathologic stage • Downstaged to pathologic CR (ypCR)… • Which regimen? • 5FU/LV versus Capecitabine versus FOLFOX • For How Long? • 4 months versus 6 months

  44. Which Regimen?

  45. PETACC-6: T3,4 or N+ Rectal Cancer • R0-resectability certain • XRT 5 x 5 Gy XRT 45 Gy +/- 5.4 Gy Boost with Cape or FU • R0-resectability uncertainXRT 45 Gy +/- 5.4 Gy Boost with Cape or FU T M E Cape 6 mos. 5-FU bolus (NCI consensus/ previous German trial) XRT45 Gy +/- 5.4 Gy Boost withXELOX XELOX 4 – (6) mos. German protocol from previous trial (AIO/ARO/CAO-94)

  46. ECOG 5204 Phase III Trial (NCIC CRC.4) mFOLFOX6 X 12 Stage II/II Preop CRT (Cape, FU) -NSABP R04 IF preop oxali: 9 cycles mFOLFOX6 + 3 cycles 5FU/LV R mFOLFOX6 + Bev X 12 Accrual: 2100 planned

  47. Is there a current standard? • Concurrent Preop long-course XRT • Continuous infusion 5FU* • Capecitabine being studied • Adjuvant Chemotherapy • Consider in all pts who receive CRT • ? Group who doesn’t need post op therapy - ? Path CR • 5FU/LV X 4 cycles is a standard • Capecitabine may be an option • FOLFOX is a reasonable option • particularly in higher risk • How do we define risk? • Minimum duration of 4 months

  48. Conclusions • Unique aspects of rectal cancers • Preop Chemoradiation reduces local recurrences and may improve OS • Longer radiation with infusional FU standard • Optimal preop staging critical • Surgical TME techinque important • Postop chemotherapy important • Optimal chemotherapy and duration of treatment not yet defined

  49. In Whom?

  50. Who is high risk? • Prognostic data from Sauer trial may help (Rodel, JCO 2005) in absence of definitive data to define risk in patients having had pre-op chemo rads

More Related