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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 radiotherapy Preliminary results of the MRC CR07/NCIC C016 randomised trial. Phil Quirke on behalf of the trial investigators

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Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group

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  1. 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 Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group

  2. Phil Quirke

  3. 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

  4. Key questions In terms of local recurrence, how important is: • The surgical circumferential margin (CRM)? • The plane of surgical dissection? • Short course pre-operative radiotherapy?

  5. High quality pathology • Prospective • Protocol defined specimen dissection and written proforma reporting • Individual pathology training days and central approval • Standardised pathology • circumferential margin • TNM version 5 CRM +ve ≤1mm

  6. LR by CRM status (all patients) 100 Events/N 3yr LR 5yr LR CRM -ve60/1107 6% 9% CRM +ve18/139 18% 25% HR 4.21 (95%CI 2.00,6.50) p=0.0001 90 80 70 60 LR rate % 50 40 CRM +ve 30 20 CRM -ve 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

  7. 100 90 80 70 60 50 40 POST 30 20 PRE 10 0 0 12 24 36 48 60 CRM by treatment CRM –ve n=1107 CRM +ve n=139 POST PRE Months Months HR 2.91 (1.74-4.88) HR 1.56 (0.6-4.04)

  8. Prospective assessment of the plane of surgical (PoS) dissection

  9. 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 CRM-ve CRM+ve Pathology (PoS) Post-op CRT 45Gy / 25F + concurrent 5FU No RT CRM-ve CRM+ve Adjuvant chemotherapy given as per local policy

  10. Abbreviated definitions of surgical plane (predefined and prospectively graded) Mesorectal plane: intact mesorectum with only minor irregularities of a smooth mesorectal surface. No defect deeper than 5mm. No coning, smooth CRM on slicing Intramesorectal plane: Moderate bulk to meso-rectum but irregularity of the mesorectal surface. Moderate distal coning. Muscularis propria not visible with the exception of levator insertion. Moderate irregularity of CRM Muscularis propria plane: Little bulk to mesorectum with defects down onto muscularis propria and/or very irregular CRM

  11. Plane of surgery n=1119 (83%) Mesorectal Intra-mesorectal Muscularis propria n=596 53% n=382 34% n=141 13%

  12. 25 20 15 Percentage 10 5 0 1998 1999 2000 2001 2002 2003 2004 2005 Year CRM+ve rate by year

  13. 100 Mesorectal plane Intramesorectal plane Muscularis propria plane 75 Percentage 50 25 0 1998 1999 2000 2001 2002 2003 2004 2005 Year Plane of surgery by year

  14. Associations with plane Plane Mesorectal Intra- Muscularis mesorectal propria CRM +ve rate 9% 12% 19% Stage I 28% 24% 28% Stage II 26% 32% 30% Stage III 46% 45% 42%

  15. LR by plane of surgery 90 Events N 3yr LR 5yr LR Mesorectal plane 22 596 4% 8% Intramesorectal plane 22 382 8% 9% Muscularis propria plane 16 141 15% 21% p=0.0019 80 70 60 LR rate (%) 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

  16. LR by CRM and plane Events N 3yr LR 5yr LR CRM -ve Mesorectal plane 18 537 3% 8% Intramesorectal plane 17 331 7% 8% Muscularis propria plane 11 113 12% 17% CRM +ve Mesorectal plane 450 9% 19% Intramesorectal plane 5 45 14% 21% Muscularis propria plane 5 27 26% 36%

  17. Outcome by treatment arm for each grade of surgical plane

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

  19. LR rate by mesorectal plane by treatment arm 100 90 Events/N 3yr LR 5yr LR PRE3/298 1% 1% POST19/298 6% 16% HR 4.47 (95%CI 1.94,10.32) p=0.0005 80 70 60 LR rate (%) 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

  20. LR rate of intramesorectal planeby treatment arm 100 90 Events/N 3yr LR 5yr LR PRE7/187 5% 6% POST15/195 11% 12% HR 2.02 (95%CI 0.87,4.66) p=0.10 80 70 60 LR rate (%) 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

  21. LR rate of muscularis propria planeby treatment arm 100 90 Events/N 3yr LR 5yr LR PRE3/63 9% 9% POST13/78 19% 29% HR 2.76 (95%CI 1.02,7.41) p=0.04 80 70 60 LR rate (%) 50 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

  22. 3 year LR by plane of surgery and treatment arm

  23. Summary • Local recurrence after rectal cancer resection is predicted by the circumferential resection margin • Local recurrence is strongly related to the plane of surgical dissection – surgical skill is very important • The benefit for short course pre-operative radiotherapy (PRE) is seen for all planes of dissection • Local recurrence is virtually eliminated with best surgery (mesorectal plane) dissection and short course pre-operative radiotherapy (PRE)

  24. Acknowledgements • CR07 surgeons and pathologists • The patients • Trial Management Group • Bob Steele, Bob Grieve, Phil Quirke • Subhash Khanna, John Monson • DMEC and TSC • John Northover / Malcolm Mason (chairs) • MRC CTU • Richard Stephens, Anne Holliday, • Sarah Beall, Lindsay Thompson • Gareth Griffiths, Shama Hassan

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