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Neoadjuvant therapy of rectal cancer – how can we make it better? Claus Rödel

Neoadjuvant therapy of rectal cancer – how can we make it better? Claus Rödel Department of Radiotherapy University of Frankfurt, Germany. Honoraria: Roche, Sanofi-Aventis. Research Funding: Merck Roche. O U T L I N E. How can we make it more efficient (or less toxic)?

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Neoadjuvant therapy of rectal cancer – how can we make it better? Claus Rödel

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  1. Neoadjuvant therapy of rectal cancer – how can we make it better? Claus Rödel Department of Radiotherapy University of Frankfurt, Germany • Honoraria: • Roche, • Sanofi-Aventis • Research Funding: • Merck • Roche

  2. OU T L I N E How can we make it more efficient (or less toxic)? - RT with 5-FU - RT with 5-FU/Cape plus oxaliplatin - RT with targeted agents - induction chemotherapy - without RT?, radical surgery? How can we select better?- molecular? - clinical?

  3. 5-FU: 350 mg/m²/d LV: 20 mg/m²/d RT: 45 Gy R 5-FU: 350 mg/m²/d LV: 20 mg/m²/d 5-FU: 350 mg/m²/d LV: 20 mg/m²/d OP OP RT: 45 Gy FFCD 9203 Gérard JP et al, J Clin Oncol 2006

  4. RT: 16.5% RCT: 8.1% p < 0.05 FFCD 9203 – Local Failure Gérard JP et al, J Clin Oncol 2006 Similar Results: EORTC 22921:Bosset et al., N Engl J Med 2006

  5. 14.2% 9.0% p=0.17 p=0.8 5 x 5 Gy versus 5-FU CRT ? P O L I S H Bujko et al., Br J Surg 2006 AUSTRAL I A ASCO 2010: Ngan et al, abstract # 3509

  6. Radiotherapy: 50.4 Gy 28 x 1.8 Gy Chemotherapy: d 1 - 14 d 22 - 35 Capecitabine 1650 mg/m²/d d1 d 8 d 22 d 29 Oxaliplatin 50 mg/m²/d Weeks 1 2 5 6 3 4 Phase I/II Studies of RT with new agents Rödel et al., J Clin Oncol 2003 and J Clin Oncol 2007

  7. Tumor-Regression-Grading CAPOX-RT 5-FU-RT (n=110) (n=385) Complete Regression (100%) 16% 10% Good Regression (> 50%) 59% 52% Moderate Regression (25-50%) 11% 14% Poor Regression (< 25) 10% 15% No Regression (0%) 3% 8%

  8. R OP OP ACCORD 12/0405-Prodige 2 Cape: 800 mg/m²/bid Adjuvant Chemotherapy (local policy) 45 Gy/1.8 Gy SD Oxaliplatin: 50 mg/m²/week Cape: 800 mg/m²/bid Adjuvant Chemotherapy (local policy) 50 Gy/2.0 Gy SD Gérard JP et al, J Clin Oncol 2010;28-1638-44

  9. Similar results: STAR-Trial, Aschele C et al, J Clin Oncol 2009 (abstr. CRA4008)

  10. T M E RT 50.4 Gy + 5-FU (best arm CAO/ARO/AIO-94) 5-FU 4#, q29 R RT 50.4 Gy + 5-FU/Oxaliplatin mFOLFOX 8#, q15 CAO/ARO/AIO-04 Similar Design: PETACC 6: CAP+/-OX-RT – TME – CAP+/-OX NSABP R-04: CAP-RT+/-OX vs. 5-FU-RT+/-OX

  11. cycle 6 cycle 4 cycle 5 cycle 3 cycle 2 cycle 1 Compliance to (neo-) adjuvant CAPOX 100% 100% 96% 95% TME 70% 65% Ox Cap 62% 62% 57% 57% 53% 52% RT 50.4Gy Rödel C. et al. J Clin Oncol 2007;25:110-117

  12. R Grupo Cáncer de Recto 3 Study MRT- defined Poor Risk: ≤ 2mm to mesorectal fascia, low-lying T3, T3N+, T4 RT 50.4 Gy + Cape/Oxaliplatin CAPOX 4#, q21 T M E T M E CAPOX 4#, q21 RT 50.4 Gy + Cape/Oxaliplatin Fernández-Martos C, J Clin Oncol, 2010;28:859-65

  13. Fernández-Martos C, J Clin Oncol, 2010;28:859-65 ASCO 2010: Similar trial: Maréchal et al, abstract # 3637

  14. Capecitabine (1650 mg/m²/d) Oxaliplatin (35-50 mg/m²/d) Phase I/II Preoperative Radiotherapywith CAPOX and Cetuximab for Rectal Cancer Radiotherapy: 50.4 Gy 28 x 1.8 Gy Chemotherapy d 1 - 14 d 22 - 35 d 8 d 22 d 29 d 1 6 x 250 mg/m²/d Cetuximab d -7 d 15 d 35 d 1 d 8 d 22 d 29 1 x 400 mg/m² 1 5 Week -1 2 6 3 4 Rödel C et al., Int J Radiat Oncol Biol Phys 2008

  15. Tumor-Regression-Grading CAPOX-RT+CET (n=45) Complete Regression (100%) 9% Good Regression (> 50%) 38% Moderate Regression (25-50%) 27% Minimal Regression (< 25) 22% No Regression (0%) 4% CAPOX-RT (n=110) 16% 59% 11% 10% 3% Confirmed by a randomized phase II trial: McCollum et al., abstract #3635

  16. Phase I/II Präop. Bevacizumab/5-FU/RT Day 1 8 15 29 43 52 50.4 Gy 5-FU-Inf BEV 5-10 mg/kg Willett CG et al., Nat Med 2004Willett CG et al., J Clin Oncol 2009

  17. Phase I/II Preop. Bevacizumab/5-FU/RT Before treatment 12d post Bevacizumab Willett CG et al., Nat Med 2004 • ypT0: 5/32 (16%), ypN0:59% • No grad 4/5 tox; postop. complications: 13/32 (41%) • 5-y local control: 100% • 5y distant control: 75% Willett CG et al., J Clin Oncol 2009

  18. OP MSKCC-Pilot trial without RTStage II/III, excluding T4 + low tumors needing APR 4 x Bev-FOLFOX 2 x FOLFOX(5-FU Chemo-RT only if SD/PD) Results: 8/29 (27%) with pCR (all no CRT) Schrag D et al., ASCO 2010, abstract 3511 ASCO 2010: Ongoing trial: Fernandes-Martos et al., abstract #TPS169

  19. ACOSOG Z6041: Local Excision uT2uN0 rectal cancer Oxaliplatin: 50 mg/m²/weeks 1,2,4,5 Cape: 725 mg/m² 5 days/week Results: RO 98%; pCR 36/81 (44%), 6% ypT3 50.4 Gy/1.8 Gy SD Garcia-Aguilar, J. et al., ASCO 2010, abstract #3510

  20. OU T L I N E How can we make it more efficient (or less toxic)? - RT with 5-FU - RT with 5-FU/Cape plus oxaliplatin - RT with targeted agents - induction chemotherapy - without RT?, radical surgery? How can we select better?- molecular? - clinical?

  21. Biomarkers for Response to Chemoradiation Ghadimi et al., J Clin Oncol 2005n=30, 50.4 Gy/5-FU54 differentially expressed genes for the endpoint TRG/Downstaging Rimkus et al., Clin Gastroenterol Hepat 2008 N=42, 45 Gy/5-FU 43 differentially expressed genes for the endpoint TRG No concordance with even one gene between the 2 studies!!

  22. Clinicopathological Selection Easy in former times: • …postoperative chemoradio- • therapy: rectal cancer < 12 cm from anal verge pT3-4 or pN+ • …preoperative RT (5x5 Gy): • any rectal cancer < 15 cm

  23. Pooled Analysis : Five US postoperative phase III studies, n=3791 • Low Risk • pT1-2/N0 • Intermediate Risk • pT3/N0 and pT1-2/N1 • Moderately high Risk • pT1-2/N2 and pT3/N1 and pT4/N0 • High Risk • pT3/N2 and pT4/N1-2 Not included „May not require RT“ Gunderson et al., J Clin Oncol 2004

  24. Circumferential Resection Margin MERCURY Study GroupBMJ 2006 Radiology 2007 Nagtegaal ID, Quirke P. , J ClinOncol 2008

  25. TN- and CRM-defined Risk Stratification Multidisciplinary team discussionn=197 rectal cancer patients Preop. CT+CRT: >T3a, N2, CRM-; CRM +, low T381 (41%) Surgery only: T1/2, T3a, N0/1, CRM-116 (59%) Histological CRM – 97% Histological CRM - 100% 75% Does pCRM- imply that these patientsdo not benefit from preop. RT? Burton et al. Br J Cancer 2006

  26. Preoperative Radiotherapy vs. Risk-adapted postoperative CRT: MRC CR07 5x5Gy+TME TME alone (Postop CRT only if CRM+) 5y-Local recurrence: CRM + 13.8% 20.7% HR 0.64 (0.25-1.64) CRM - 3.3% 8.9% HR 0.36 (0.23-0.57) Sebag-Montefiore D et al., Lancet 2009:373:811-20

  27. S UMMAR Y • Neoadjuvant CRT with 5-FU - Inclusion of oxaliplatinCRT: ACCORD, STAR not convincing • NSAPB R-04 completedCRT+adj. CT: CAO/ARO/AIO-04 completed PETACC 6 open Ind.-CT+CRT: GrupoCáncer de Recto 3 Study • - Inclusion of targeted agents: phase I/II - without RT: subgroups (not T4, low)- with local excision: subgroups (uT2N0) • Selection - molecular: investigational • - clinical: MRI-defined (CRM-)?

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