This document summarizes key findings from several studies on the treatment of rectal cancer with radiotherapy and chemoradiotherapy. It finds that preoperative chemoradiotherapy reduces local recurrence rates compared to postoperative chemoradiotherapy or no radiotherapy, with increased acute and late toxicity. Several large trials showed no difference in overall survival between treatment groups. Optimal patient selection and a balance between risk reduction and side effects are important considerations.

1. Rectal cancer David Sebag-Montefiore Professor of Clinical Oncology St James’s Institute of Oncology, Leeds,UK

2. The rectum Dutch UK 0-5cm >5-10cm >10-15cm German 0-6cm >6-12cm >12-18cm

3. The Holy Plane – Mesorectal Excision Mesorectal fat Mesorectal fascia

4. MRI – mesorectal fascia

5. Histopathology +ve CRM = microscopic tumour <=1mm from the painted margin

6. Role of circumferential margin involvement in the local recurrence of rectal cancer Adam et al Lancet 1994;344;707-711 All patients n=190 LR 29% “ Curative resections” n=141 LR 23% CRM+ve (25%) n=35 LR 66% CRM -ve (75%) n=106 LR 8% Now confirmed in:- Local studies (Many UK inc Leeds) National UK audit data Norwegian audit Within context of phase III trials (UK studies x2, Dutch x1)

7. How good is your surgeon? Quirke et al Lancet 2009 373:821-8

8. Grade of surgical excision specimen Mesorectal plane Intact mesorectum with only minor irregularities..smooth mesorectal surface..no defect greater than 5mm..smooth CRM on slicing Intra-mesorectal plane Moderate bulk to mesorectum with irregularities of the mesorectal surface..muscularis not visible with the exception of levator insertion.. Moderate irregularity of the CRM Muscularis propria plane Little bulk to mesorectum with defects down onto muscularis propria; very irregular CRM or both

9. Mesorectal Intra-mesorectal Muscularis propria n=596 53% n=382 34% n=141 13% CR07 – Plane of surgical specimen Quirke et al Lancet 2009

10. Local recurrence Muscularis Propria Plane Intra Mesorectal Plane Mesorectal Plane HR 95% CI Surgery with selective post CRT 16% 10% 7% 0.48 (0.23-1.00) Pre-op RT 10% 4% 1% 0.09 (0.02-0.49)

11. RCP Minimum Colorectal Dataset http://www.rcpath.org/resources/pdf/G049-ColorectalDataset-Sep07.pdf

12. Pelvic MRI

13. MERCURY study Radiology 2007 243: 132-139; BMJ 2006 333:779-783 679 consecutive rectal cancer patients Multicentre prospective observational study 27 colorectal surgeons, 18 radiologists Standardised MRI protocol Aim – to compare the findings on pre-op MRI with the histopathological specimen

14. Primary end point The MRI and histopathological measurements were considered equivalent when the 95% CI of the difference between them was +/- 0.5mm Observed mean extramural depth 2.80mm 2.81mm Extent of extramural spread on MRI Extent of extramural spread on histopathology =

15. MRI – Selection for pre-op (C)RT Margin at risk = Pre-op CRT Options Surgery alone Surgery then post-op CRT Pre-op SCPRT then surgery

16. Rectal cancer – role of radiotherapy Reduce local recurrence Convincing and large evidence base Regimens differ internationally Shrink locally advanced tumours Chemoradiation is the standard approach Facilitate “curative resection” with clear margins Increase the chance of sphincter preservation Very controversial Not evidence based Definitive treatment /Organ preservation In patients not fit for surgical resection

17. Early stage disease – TREC study CRUK/Birmingham CTU – Simon Bach T2 or less node -ve - biopsy proven adeno suitable for TEM MRI and TRUS – no mets Anterior resection or APER RADICAL TME Resection DEFINITE DEFINITE UNCERTAIN

18. Systematic Overview n=8507 Lancet 2001;358:1291-304 5 years Pre-operative trials S RT+S Post-operative trials S RT+S Isolated LR 23% 15% 22% 12% P<0.00001 P=0.0002 Cancer specific mortality 12% proportional reduction (absolute=4%) p=0.0003 22% reduction (BED >30Gy) p=0.00002 9% reduction p=NS Overall survival 5.6% reduction SE 3.3 p=NS 4.6% reduction SE 5.9 p=NS

19. Causes of death Lancet 2001 358:1291-304

20. Radiotherapy regimens Short course pre-operative RT Developed in Sweden 25Gy in 5 fractions Surgery within one week Long course chemoradiation (CRT) Radiation dose 45-54Gy Concurrent fluoropyrimidine now standard Benefit of additional drugs uncertain

21. Dutch TME and MRC CR07 trial design n = 1350 Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases Adjuvant chemotherapy given as per local policy – CR07 PRE SEL POST Pre-operative RT 25Gy / 5F Surgery Pathology Surgery Pathology CRM-ve CRM+ve Post-op (C)RT Dutch RT CR07 CRT No CRT

22. Key conclusions from Dutch and CR07 Efficacy Reduced LR No impact on OS so far Acute Toxicity No impact on anastomotic leak Minimal impact on histopathological stage Delay in perineal wound healing Late Toxicity Increase in sexual dysfunction Bowel dysfunction inclusing incontinence (ant resection) (Loss fertility, premature menopause, second malignancy)

23. Local recurrence (ITT) – med FU 4 yrs Sebag-Montefiore et al 2009 0.0 0.2 0.4 0.6 0.8 1.0 Local Recurrence 0 1 2 3 4 5 Time (Years) PRE 674 27 4.4% SEL POST 676 72 10.6% 674 676 462 334 216 120 SEL POST 674 676 PRE Total Events 3 yr LR HR(95% CI) =0.39 (0.27-0.58) p=0.000004 587 477 342 242 137 594

24. Disease free survival (ITT) med FU 4 yrs Sebag-Montefiore et al 2009 674 676 462 334 216 120 SEL POST 674 676 PRE 587 477 342 242 137 594 0.0 0.2 0.4 0.6 0.8 1.0 Disease Free Survival 0 1 2 3 4 5 Time (Years) PRE 674 147 77.5% SEL POST 676 189 71.5% Total Events 3 yr DFS HR(95% CI) =0.76 (0.62-0.94) p=0.013

25. 3 year LR for T3a/b and T3c/d tumours Events N 3yr LR SEL POST Number at risk PRE 0.0 0.2 0.4 0.6 0.8 1.0 Local Recurrence 237 213 162 115 72 47 203 193 155 111 77 51 0 1 2 3 4 5 Years T3a/3b PRE 5 203 2.1% SEL POST 25 237 7.7% HR (95%CI) =0.27 (0.13-0.56), p<0.001 0.0 0.2 0.4 0.6 0.8 1.0 77 68 50 36 25 9 52 46 38 25 18 9 0 1 2 3 4 5 Years T3c/3d Events N 3yr LR PRE 2 52 4.3% SEL POST 14 77 13.5% HR (95%CI) =0.30 (0.11-0.82), p=0.192

26. Dutch trial 10 year data Marijnen et al ASTRO 2010 Local recurrence 6.4% RT+TME vs 13.3% TME p<0.001 Overall recurrence 28.8% RT + TME vs 33.6% TME p<0.042 Overall survival No difference In a subgroup with lymph node positive patients with a negative CRM, preoperative radiotherapy improves 10 year survival from 41% to 51%, p = 0.02

27. Combined result from the trials Concurrent CRT became standard treatment FFCD and EORTC used 5FU/LV German trial used 5FU Recent change to oral fluoropyrimidine Change from post-op CRT to pre-op CRT Lower rate of LR Less acute and late toxicity Important to select correct patients

28. FFCD 9203 trial n= 733 Gerard et al JCO 2006;24:4620-6 Primary end point – Overall survival improvement 10% RT 45Gy / 25 , RT 45Gy / 25 + concurrent 5FU/LV Post-op 5FU/LV Post-op 5FU/LV S S

29. FFCD 9203 trial – Outcome measures Gerard et al JCO 2006;24:4620-6 RT alone CRT p value Local recurrence 17% 8% P=0.004 PFS 55.5% 59.4% HR 0.96 (0.77-1.20) OS 67.9% 67.4% HR 0.96 (0.73-1.27)

30. EORTC 22921 trial n=1011 Bosset et al NEJM 2006;355:1114-23 n= 253 RT 45Gy / 25 . RT long course + concurrent 5FU/LV S S Post-op 5FU/LV Post-op 5FU/LV No chemo No chemo n= 252 n= 253 n= 253 n= 505 n= 506

31. EORTC 22921 trial – Local recurrence Bosset et al NEJM 2006;355:1114-23 Evidence of an interaction between pre-op and post-op chemotherapy p=0.09 RT n=252 17% (95% CI 12.3-21.9) RT + post C n=253 9.6% (95% CI 5.7-13.5) CRT n=253 8.7% (95% CI 4.9-12.6) CRT + post C n=253 7.6% (95% CI 4.2-11)

32. EORTC 22921 – Progression free survival Bosset et al NEJM 2006;355:1114-23 27% of patients randomised to post-op chemotherapy did not start treatment RT RT + post C 54.4% p=0.52 56.1% Pre CRT Pre CRT + post C 52.2% 58.2% p=0.13

33. German Rectal Cancer Study Group n=823 Sauer et al 2004; 351:1731-40 RT 45Gy / 25 + concurrent 5FU/LV RT 45Gy / 25 + concurrent 5FU/LV S S Post-op 5FU/LV Post-op 5FU/LV

34. German RCSG - Outcome Sauer et al 2004; 351:1731-40 Pre-op CRT Post-op CRT p value Primary end point Overall survival 10% improvement LR 6% 13% P=0.006 PFS 68% 65% P=0.32 OS 76% 74% P=0.80

35. German RCSG – Toxicity Sauer et al 2004; 351:1731-40 Pre-op CRT Post-op CRT p value Acute G3/4 27% 40% P=0.001 Late G3/4 14% 24% P=0.01

36. Summary of RT/CRT studies Lowers local recurrence Should therefore by risk adapted No difference in survival Increased long term sides effects No evidence re sphincter preservation BALANCE between risk and benefit

37. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010 CRT – 5FU 225mg/m2 50.4Gy CRT Short course Pre op (25Gy in 5F) N=326 S 5FU/LV x4 S 5FU/LV x 6 Resectable T3 on TRUS or MRI and >90% 10cm or less from anal verge

38. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010 CRT n=163 SCRT n=163 3 year local recurrence 4% 7% P=0.27 5 yr FFS 67% 71% P=0.46 5 yr OS 74% 70% P=0.56 RTOG Grade 3/4 late toxicity 8% 9% P=0.84 Quality of life No significant difference ASCO 2008

39. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010

40. SCPRT and delay to surgery Radu et al 2007 pCR 2/24 (8%) in patients without mets and unfit for SCPRT Hatfield et al Median age 82 pCR 2/24 (8%) Stockholm III trial (Petterson et al) SCPRT imm vs SCRT delay vs 50Gy in 25F pCR 15/120 (12.5%)

41. Good Avoid Radiotherapy Bad SCPRT/CRT Ugly CRT Tailored treatment

42. International differences Multidisciplinary team meetings (MDT) Use of short course radiotherapy Selection criteria for chemoradiation Surgical specialisation and quality Rates of sphincter preserving surgery

43. Intensification of pre-op CRT Second drug Molecular targeted therapy Integration systemic chemotherapy

44. Phase III trials – Evaluating +/-Oxaliplatin Eligibility Platform NSABP R04 N=1500 <12cm; resectable stage II, III TRUS or MRI – CT if T4/ N1-2 PVI 5FU Capecitabine FFCD N=598 Palpable; resectable; T3/4 N0-2; T2 distal anterior Capecitabine STAR – 01 N=747 Resectable stage II, III <12cm from anal verge PVI 5FU PETTAC 6 N=1090 Stage II or III resectable or expected to become resectable <12cm from anal verge Capecitabine

45. NSABP R04 – Factorial 2x2 Primary end point- Locoregional relapse Oxaliplatin 50mg/m2 x 5 Capecitabine 825mg/m2 bd 5 days / week PVI 5FU 225mg/m2 Capecitabine 825mg/m2 bd 5 days / week Oxaliplatin 50mg/m2 x 5 PVI 5FU 225mg/m2

46. STAR-01 trial Aschele et al ASCO 2009 Oxaliaplatin 50mg/m2 x 6 PVI 5FU 225mg/m2 50.4Gy CRT PVI 5FU 225mg/m2 50.4Gy CRT N=747 S 5FU (PVI or with LV S 5FU (PVI or with LV

47. CRT acute toxicity 5FU CRT Ox 5FU CRT p value Any G3/4 8% 24% p=0.001 Gd 3/4 diarrhoea 4% 15% p=0.001 Grade II neuro/sens 1% 36% P=0.001 RT compliance 97% 90% NS Treatment related death 0.3% 0.6% NS

48. Histopathology 5FU CRT Ox 5FU CRT pCR (ypT0ypN0) 16% 16% ypT0 17% 18% ypT1-2 35% 35% ypT3-4 44% 42% ypN0 70% 68% pM1 3% 0.5% CRM +ve 6 4

49. Prodige/ACCORD 12/0450 trial Gerard et al ASCO 2009 Oxaliaplatin 50mg/m2 x 5 Capecitabine 800mg/m2 * 50.4Gy CRT Capecitabine 800mg/m2 45 Gy CRT N=598 S Centre policy S Centre policy

50. CRT acute toxicity 5FU CRT Ox 5FU CRT p value Any Grade 3/4 11% 25% p=0.001 Grade 3/4 diarrhoea 3% 13% p=0.001 Haematological Gd 3/4 4% 5% P=NS Grade II neuro sensory 0.4% 5% P=0.02

51. Histopathology 5FU CRT Ox 5FU CRT P value pCR 14% 19% 0.11 No tumour + microfoci 30% 41% P=0.008 ypT0 14% 19% P=0.11 ypN0 70% 68% NS CRM +ve 12% 7% P=0.21

52. Oxaliaplatin Capectabine Cetuximab CRT ph II Rodel et al JCO 2007;IJROBP 2008 Ox Cap Cetxumib CRT Historical data Ox Cap RT Number 48 /60 ph II doses 110 Oxaliplatin Capectabine 50mg/m2 x 4 825mg/m2 4 weeks (13 at 500/650 ph I) 50mg/m2 x 4 825mg/m2 4 weeks RT dose 50.4Gy 50.4Gy Gd 3/4 diarrhoea 19% 12% pCR (Gd 4 TRG) 9% 19% TRG 3+4 (pCR + >50% regression) 47% 74%

53. Irinotecan Capetabine Cetuximab CRT Willeke et al BJC 2007; Horisberger IJROBP 2009 Ir Cap Cetxumib CRT Historical data Ir Cap RT Number 50 36 Irinotecan Capectabine 40mg/m2 x 5 500mg/m2 bd 4 cont 50mg/m2 x 5 500mg/m2 bd cont RT dose 50.4Gy 50.4Gy Gd 3/4 diarrhoea 30% 4% pCR 8% 15% pCR + microfoci NS 41%

54. ARISTOTLE – Phase III trial testing standard CRT (one drug) versus combination CRT (two drugs) NCRI rectal cancer group Funded by Cancer Research UK / UCL CTU

55. ARISTOTLE – NCRI phase III CTAAC Funded MRI defined locally advanced rectal cancer No metastases Capectabine CRT (Cape 900mg/m2 5 days/week) Declare proposed post-op chemotherapy policy Irinotecan Capecitabine CRT (Capecitabine 650mg/m2 5d/wk Irinotecan 60mg/m2 wk 1-4) Proposed post-op policy Proposed post-op policy SURGERY (8-10 weeks) SURGERY (8-10 weeks) N=920 Primary end point – Disease Free survival n=920

56. MRI defined eligibility Levator Puborectalis External sphincter Internal sphincter Diagram adapted from Shihab et al Lancet Oncology 2009

57. 0-5cm >5-10-5cm >10cm Local recurrence pattern Dutch trial Nijkamp et al IJROBP 2010 online doi:10.1016

58. Superior and Inferior Limits to the Clinical Target Volume

59. Clinical Target Volume

60. Conclusions Simple pathological assessment extremely useful and predicts outcome Adjuvant radiotherapy Selection using imaging Strong evidence supporting SPCRT and CRT Intensification of CRT experimental Radiotherapy QA – hitting the target whilst reducing the toxicity