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Chemoradiotherapy for Rectal cancer

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. Background.

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Chemoradiotherapy for Rectal cancer

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  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 23rd 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 Options Improvements • Surgery TME / Training Sub specialisation • Radiotherapy Pre operative Chemoradiotherapy Post operative • Chemotherapy Advance /metastatic Adjuvant New agents

  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 +)

  8. Improving Outcomes • Add chemotherapy to radiation • Increase radiation dose

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

  10. Oxaliplatin is a radiosensitiser in HT-29 xenograft models Tumour volume 160 120 80 40 0 Control Oxaliplatin 5mg/kg Radiation only (5Gy) Oxaliplatin + radiation 01 05 09 13 17 21 Days post-treatment Blackstock A et al. Int J Rad Oncol Biol Phys 2000;16:92–94

  11. Comparative tumor sterilization rate by treatment modality

  12. Is chemo-Radiotherapy better than RT alone?

  13. EORTC Rectal cancer trial T3/T4 rectal cancer n=1011

  14. EORTC Rectal cancer trial Bossett al ASCO 2005

  15. EORTC Rectal cancer trial Bossett al ASCO 2005

  16. FFCD 9203- Rectal cancer trial T3/T4 rectal cancer n=733 JP Gerard et al ASCO 2005

  17. FFCD 9203- Rectal cancer trial JP Gerard et al ASCO 2005

  18. FFCD 9203- Rectal cancer trial JP Gerard et al ASCO 2005

  19. Chemo RT vs. Radiotherapy Local control in T3/T4 rectal cancer

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

  21. German pre op. vs. post operative chemoradiotherapy for rectal cancer Sauer et al N Engl J Med (2004) 351;17 1731-01740

  22. German pre op. vs. post operative chemoradiotherapy for rectal cancer Sauer et al N Engl J Med (2004) 351;17 1731-01740

  23. German pre op. vs. post operative chemoradiotherapy for rectal cancer Sauer et al N Engl J Med (2004) 351;17 1731-01740

  24. Newer agents for chemoradiotherapy

  25. Chemoradiotherapy • 5FU bolus • 5FU+ FA • Infusional 5FU • Capecitabine • Irinotecan +Cape NWCCOG 1+ RICE • Oxaliplatin +CapeCORE/ SOCRATES • Triplet therapyIr/Oxali + MdG+ VEGF R A D I O T H E R A P Y

  26. 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 bolus5-FU1 1O’Connell MJ et al. N Engl J Med 1994;331:502–7

  27. Infused versus bolus 5-FU during pelvic radiation Overall survival (%) Infused 5-FU (n=328) Bolus 5-FU (n=332) 100 80 60 40 20 0 Log rank p=0.005 Cox model p=0.01 0 1 2 3 4 Years after randomisation O’Connell MJ et al. N Engl J Med 1994;331:502–7

  28. Capecitabine + radiation

  29. 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 tumour2 1Miwa M et al. Eur J Cancer 1998;34:1274–81 2Sawada N et al. Clin Cancer Res 1999;5:2948–53

  30. Irradiation upregulates TP TP (units/mg protein) 5Gy 2.5Gy Control 25 20 15 10 5 0 * * * * * * * * * 0 3 6 9 12 15 18 21 Days after X-ray irradiation Sawada N et al. Clin Cancer Res 1999;5:2948–53 *p<0.05

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

  32. 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

  33. Chemoradiation in rectal cancer: German phase II study (n=68) • Male / female (%) 63 / 37 • Median age 65 years • ECOG 0/1 (%) 54 / 41 • T3 / T4 (%)48 / 52 (57% N1–3) Day 1 8 15 22 29 35 50.4Gy radiotherapy 1.8Gy/fraction 825mg/m2twice daily Continuous (days 1–37) Dunst J et al. Proc Am Soc Clin Oncol 2003;22:277 (Abst 1113)

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

  35. No grade 4 adverse events Grade 1/2 Grade 3 capecitabine chemoradiation: Toxicity Patients (%) 80 60 40 20 0 Diarrhoea Local Pain Hand-foot Nausea erythema syndrome Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282)

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

  37. Chemoradiation using Oxaliplatin combination

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

  39. CORE: European study Day 1 8 15 2229 Radiotherapy 45Gy/25 fractions capecitabine825mg/m2 twice daily Monday to Friday Oxaliplatin50mg/m2weekly • CORE: Capecitabine, Oxaliplatin, Radiotherapy and Excision

  40. Chemoradiotherapy using Irinotecan combination

  41. RICE - NWCCOG study Day 1 8 15 2229 Radiotherapy 45Gy/25 fractions capecitabine825mg/m2 twice daily Monday to Friday IRINOTECAN 60mg/m2 weekly S. Gollins, S.Myint, E. Levine et alProc Am Soc Clin Oncol 2006;24:617s (Abst 13519)

  42. Chemoradiotherapy • 5FU bolus • 5FU+ FA • Infusional 5FU • Capecitabine • Irinotecan +Cape NWCCOG 1+ RICE • Oxaliplatin +CapeCORE/ SOCRATES • Triplet therapyIr/ Oxali + cape+ EGF R A D I O T H E R A P Y ARISTOTLE

  43. Reducing Toxicity from CRT

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

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