1. Chemoradiotherapy for Rectal cancer Dr. A. Sun Myint Lead Clinician GI Tumour Group Clatterbridge Centre for Oncology Association of Coloproctology of Great Britain and Ireland M62 Coloproctology Course - March 23 rd 2007

2. Background In the UK over 10,000 new rectal cancer Five year survival 50% (NBOCAP-2006) Nearly half will develop recurrences At presentation 30% T3/T4 N + MO Preoperative radiotherapy reduce LR So far, no survival advantage

3. Treatment Options Surgery TME/ Training Sub specialisation RadiotherapyPre operative Chemoradiotherapy Post operative ChemotherapyAdvance /metastatic Adjuvant New agents Options Improvements

4. Radiotherapy

5. Preoperative Radiotherapy Short course or Long course? Short course Long course

6. Preoperative Radiotherapy Short course or Long course? Short course - Mobile operable tumour Long course - Fixed / Tethered tumour 30%( MRI defined CRM +)

7. Preoperative Radiotherapy Short course or Long course? Short course - Mobile operable tumour Long course - Fixed / Tethered tumour ( MRI defined CRM +)

11. Improving Outcomes Add chemotherapy to radiation Increase radiation dose

12. Chemo-radiotherapy Concurrent Chemotherapy + RT 5FU 5FU / FA 5FU infusion + Irino / Oxaliplatin Capecitabine + Irino / Oxaliplatin+ EGFR Capecitabine + Irino / Oxaliplatin+ VEGFR

13. Oxaliplatin is a radiosensitiser in HT-29 xenograft models Tumour volume Days post-treatment Oxaliplatin + radiation Blackstock A et al. Int J Rad Oncol Biol Phys 2000;16:92–94 Control Oxaliplatin 5mg/kg Radiation only (5Gy) 160 120 80 40 0 010509131721

14. Comparative tumor sterilization rate by treatment modality Treatment modality pCR + pMic RO EBRT alone 7.1% (26%) 40% EBRT+ chemo 16.2% (31%) 60% EBRT+ duplet 21% (60%) 90%

15. Is chemo-Radiotherapy better than RT alone?

16. EORTC Rectal cancer trial Pre-op RTSURGERY Pre-op Chemo/RT SURGERY Pre-op RTSURGERY Adjuvant Chemo Pre-op Chemo/RT SURGERY Adjuvant Chemo T3/T4 rectal cancer n=1011

17. EORTC Rectal cancer trial Pre-op Chemo/RT Pre-op RT Local recurrence 8.7% 17% (p=0.0016) Bossett al ASCO 2005

18. EORTC Rectal cancer trial Adjuvant Chemo No Adjuvant Chemo Survival 67.2% 63.2% Bossett al ASCO 2005

19. FFCD 9203- Rectal cancer trial Pre-op RTSURGERY Ad Chemo Pre-op CRTSURGERY Ad Chemo JP Gerard et al ASCO 2005 T3/T4 rectal cancer n=733

20. FFCD 9203- Rectal cancer trial Pre-op Chemo/RT Pre-op RT Local recurrence 8.0% 16.5% JP Gerard et al ASCO 2005

21. FFCD 9203- Rectal cancer trial Adjuvant Chemo No Adjuvant Chemo Survival 67% 66% JP Gerard et al ASCO 2005

22. Chemo RT vs. Radiotherapy Trials Pre-op CRT Pre-op RT EORTC 22921 8.7% 17.1% FFCD 9203 8% 16.5% German-94 6% Local control in T3/T4 rectal cancer

23. Pre-operative Radiotherapy better than post op RT?

24. German pre op. vs. post operative chemoradiotherapy for rectal cancer Preoperative Chemo-RT Surgery Post operative Chemo-RT Sauer et al N Engl J Med (2004) 351;17 1731-01740

25. German pre op. vs. post operative chemoradiotherapy for rectal cancer Pre op n=405 Post op n=394 Local recurrence 6% 13% P=0.0006 Survival 76% 74% P=0.08 Sauer et al N Engl J Med (2004) 351;17 1731-01740

26. German pre op. vs. post operative chemoradiotherapy for rectal cancer Pre op n=405 Post op n=394 Acute Toxicity 27% 40% P=0.001 Late Toxicity 14% 24% P=0.01 Sauer et al N Engl J Med (2004) 351;17 1731-01740

27. Newer agents for chemoradiotherapy

28. Chemoradiotherapy 5FU bolus 5FU+ FA Infusional 5FU Capecitabine Irinotecan +Cape NWCCOG 1+ RICE Oxaliplatin +Cape CORE/ SOCRATES Triplet therapy Ir/ Oxali + MdG+ VEGF RADIOTHERAPYRADIOTHERAPY

29. Pre-operative 5-FU chemoradiation: 5-FU-based chemoradiation has become part of standard pre-operative therapy for rectal cancer –effective downstaging –10–30% pCR rates Protracted infusion of 5-FU with postoperative radiotherapy improves survival versus bolus 5-FU 1 1 O’Connell MJ et al. N Engl J Med 1994;331:502–7

30. Infused versus bolus 5-FU during pelvic radiation O’Connell MJ et al. N Engl J Med 1994;331:502–7 100 80 60 40 20 0 0123401234 Years after randomisation Overall survival (%) Log rank p=0.005 Cox model p=0.01 Infused 5-FU (n=328) Bolus 5-FU (n=332)

31. Capecitabine + radiation

32. capecitabine plus radiotherapy Infused 5-FU is cumbersome and inconvenient for patients Oral capecitabine simplifies chemoradiation and is highly appealing to patients Potential for enhanced therapeutic ratio –capecitabine generates 5-FU preferentially in tumour via thymidine phosphorylase (TP) 1 –radiotherapy further upregulates TP in tumour 2 1 Miwa M et al. Eur J Cancer 1998;34:1274–81 2 Sawada N et al. Clin Cancer Res 1999;5:2948–53

33. Irradiation upregulates TP 25 20 15 10 5 0 TP (units/mg protein) 036912151821 Days after X-ray irradiation * * * * * * * * * *p<0.05 5Gy 2.5Gy Control Sawada N et al. Clin Cancer Res 1999;5:2948–53

34. 120 100 80 60 40 20 0 capecitabine enhances activity of radiation in WiDr xenografts, Tumour inhibition (%) * Sawada N et al. Clin Cancer Res 1999;5:2948–53 5Gy Xeloda Xeloda + 5Gy 5-FU 5-FU + 5Gy *p<0.05

35. Capecitabine chemoradiation: Oral capecitabine is replacing 5-FU in chemoradiation –capecitabine is highly effective and well tolerated in combination with radiotherapy –capecitabine simplifies chemoradiation and is highly appealing to patients and clinicians alike

36. Chemoradiation in rectal cancer: German phase II study (n=68) Male / female (%)63 / 37 Median age65 years ECOG 0/1 (%)54 / 41 T3 / T4 (%)48 / 52 (57% N1–3) Day 1815222935 50.4Gy radiotherapy 1.8Gy / fraction 825mg/m 2 twice daily Continuous (days 1–37) Dunst J et al. Proc Am Soc Clin Oncol 2003;22:277 (Abst 1113)

37. capecitabine chemoradiation:efficacy 1 Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282) 2 Lin E et al. Proc Am Soc Clin Oncol 2003;22:287 (Abst 1152)

38. Patients (%) DiarrhoeaLocalPain Hand-footNausea erythemasyndrome Grade 1/2 Grade 3 Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282) capecitabine chemoradiation: Toxicity No grade 4 adverse events 80 60 40 20 0

39. NSABP R-04 rectal cancer trial *Plus 5.4Gy for fixed tumours Resectable rectal cancer, stage II–III n=1600 capecitabine continuously throughout radiotherapy (50.4Gy*) SURGERYSURGERY 5-FU continuous infusion throughout radiotherapy (50.4Gy*) Objectives –DFS –recurrence rate –pCR –safety

40. Chemoradiation using Oxaliplatin combination

41. capecitabine/oxaliplatin chemoradiation 1 Glynne-Jones R et al. Proc Am Soc Clin Oncol 2003;22:292 (Abst 1174) 2 Rödel C et al. J Clin Oncol 2003;21:3098–104

42. CORE: European study Radiotherapy 45Gy / 25 fractions capecitabine 825mg/m 2 twice daily Monday to Friday Oxaliplatin 50mg/m 2 weekly 18152229 Day  CORE: Capecitabine, Oxaliplatin, Radiotherapy and Excision

43. Chemoradiotherapy using Irinotecan combination

44. RICE - NWCCOG study Radiotherapy 45Gy / 25 fractions capecitabine 825mg/m 2 twice daily Monday to Friday IRINOTECAN 60mg/m2 weekly 18152229 Day S. Gollins, S.Myint, E. Levine et al Proc Am Soc Clin Oncol 2006;24:617s (Abst 13519)

45. Chemoradiotherapy 5FU bolus 5FU+ FA Infusional 5FU Capecitabine Irinotecan +Cape NWCCOG 1+ RICE Oxaliplatin +Cape CORE/ SOCRATES Triplet therapy Ir/ Oxali + cape+ EGF RADIOTHERAPYRADIOTHERAPY ARISTOTLE

46. Reducing Toxicity from CRT

47. Toxicity Chemoradiotherapy is more toxic than radiotherapy alone To reduce toxicity:- Preoperative rather than post op Radiation volume Dose, fractionation and time Radiation techniques

52. Are there any other options to reduce toxicity from chemoradiation?

53. Improving Outcomes Add chemotherapy to radiation Increase radiation dose

54. Increasing Radiation dose External Beam ( 45 Gy /25# /35) EBRT +Boost ( 50.4Gy/28#/38) EBRT + Contact RT boost (60-80Gy) EBRT + Contact HDR boost

55. Papillon Technique Radical contact radiotherapy

61. Lyon R96-02 Trial Results EBRT EBRT+ boost Clinical CR ( 2% ) (24%) Path CR/micro (34%) (57%) p=.027 Sphincter (44%) (76%) p=.004 JP Gerard et al. J Clin Oncol 2004 :22 2404-2409

62. Lyon R96-02 Trial Results EBRT EBRT + Boost L R 3% 1% Morbidity43%38% LR Survival88%92% JP Gerard et al J Clin Oncol 2004 :22 2404-2409

64. HDR Rectal Brachytherapy

68. 20mm 5mm

70. Pre op HDR Brachytherapy Pathology T0N029% Micro37% Residual34% N+31% T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst: 1062

71. Pre op HDR Brachytherapy Results Median FU 37months 5years Local recurrence 3% DFS 65% OS 74% CSS 84% Toxicity G3 1% (30% CRT) T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst: 1062

76. Comparative tumor sterilization rate by treatment modality TREATMENT pCR (pMic) RO EBRT alone 7.1% (26%) 40% CT+ EBRT 13% (31%) 60% EBRT+contact 21% (60%) NA HDR alone 29% (66%) 97% CT+EBRT+ HDR boost 40%? (80%) 100?

77. Treatment Options SurgeryT1/T2/T3 / N+ (clear CRM) Pre op chemo RTr CRM <1mm (sphincter preservation) Post op chemo RTp CRM<1mm (node +ive) Radical RTT1/T2/ N0

78. Conclusions-1 All cases with rectal cancer should be discussed at the MDT MRI scan is essential for pre operative assessment Pre operative chemoradiotherapy offers better local control than pre operative radiotherapy alone

79. Conclusions-2 Pre operative chemoradiotherapy is more effective and less toxic than post operative chemoradiotherapy Nearly half the patients with rectal cancer will develop recurrences; however no DFS or overall survival benefit has been shown with adjuvant chemotherapy in any of the trials published so far.

80. It is important to contribute to clinical trials