1. Multidisciplinary treatment of rectal cancer. Medical oncology Carlo Aschele E.O. Ospedali Galliera – Genova - Italy Carlo Aschele E.O. Ospedali Galliera – Genova - Italy ESMO CONFERENCE - LUGANO July 5-8 2007

2. Multidisciplinary treatment of rectal cancer extraperitoneal rectal cancer locally advanced rectal cancer extraperitoneal rectal cancer locally advanced rectal cancer Rigid rectoscopy - TRUS - CT scan - MRI

3. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT

4. Role of chemotherapy PRE-OP RT +/- CONCOMITANT CT pCR, % RTRT + CT EORTC514 FFCD310 Bosset, NEJM 2006; Gerard, JCO 2006

5. Role of chemotherapy PRE-OP RT +/- CONCOMITANT CT 5-y LR, % RTRT + CT EORTC178 FFCD168 Bosset, NEJM 2006; Gerard, JCO 2006

6. FU RT LARC: standard treatment Sx 1990 2004 TME RT FU CRM assessment TME PRE-OP RT

7. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT

9. Dutch TME trial vs German trial 5-year overall survival Pre-op CMT Post-op CMT Years since surgery 66 % vs 65 % p = 0.98 Marijnen et al, GIASCO 2005, Abstr 166; Sauer et al NEJM 2004 0 1 2 3 4 5 6 7 8 9 0 0.2 0.6 1.0 0 1 2 3 4 5 6 7 8 9 0 0.2 0.6 1.0 Years since surgery RT + TME TME alone 76 % vs 74 % p = 0.80

10. Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004 (NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791 ROLE OF CHEMOTHERAPY POST-OP COMBINED-MODALITY TREATMENT CT No CT

11. PRE-OP CHEMORADIATION: ORAL FP’s studiespatientspCR (%) g 3-4 tox (%) Capecitabine146684-316-40 UFT115388-256-32 Eniluracile1226nr

12. NSABP R-04 RT + Capecitabine +/- oxaliplatin S RT + CI 5-FU +/- oxaliplatin R N=1460

13. Decline in the rates of local failure: 1980s–2000s 35 30 25 20 15 10 5 0 Local failure (%) sx onlysx  RTsx  CTRTTME + RT/CTRT

14. Proportion of patients with distant metastases: 1980s–2000s 40 35 30 25 20 15 10 5 0 Distant metastases (%) sx onlysx  RTsx  CTRTTME + RT/CTRT

15. ONGOING STUDIES OF COMBINATION CHEMOTHERAPY IN LARC Post-opE3201 E5204 Chronicle Pre-opSTAR NASBP R-04 Pre and post-opPETACC-6 Post-opE3201 E5204 Chronicle Pre-opSTAR NASBP R-04 Pre and post-opPETACC-6 OXALIPLATIN + FP’s

16. Rationale for incorporation of new agents in the treatment of rectal cancer To improve control at distant sites To improve R0 resection rates (esp. big T3, T4 and tethered tumours) To enhance down-sizing and SPS (Potential) prognostic value of pCR and down-staging To improve control at distant sites To improve R0 resection rates (esp. big T3, T4 and tethered tumours) To enhance down-sizing and SPS (Potential) prognostic value of pCR and down-staging

17. % of patients FU/RT FU/OXA/RT Grade III-IV toxicity (mainly diarrhoea) 1024 Ability to complete radiotherapy (> 80 %) 9895 Ability to perform surgery 9896 Preliminary safety findings: toxicity (n=313) Aschele, ASCO GI & ASCO 2007

18. PRE-OP CHEMORADIATION INCORPORATION OF BIOLOGICS Cetuximab + FU (1) pCR=12% + cape (1) pCR=5% + cape/ox (1) pCR=8% + cape/iri (2)pCR=25-20% ??: adk=squamous - ras - arrest of cell cycle progression Bevacizumab + FU (1) no pCR at the RD / surrogate markers + cape/oxa (1)pcR: 18% ??: toxicity - normalization vs antivascular effect - timing Cetuximab + FU (1) pCR=12% + cape (1) pCR=5% + cape/ox (1) pCR=8% + cape/iri (2)pCR=25-20% ??: adk=squamous - ras - arrest of cell cycle progression Bevacizumab + FU (1) no pCR at the RD / surrogate markers + cape/oxa (1)pcR: 18% ??: toxicity - normalization vs antivascular effect - timing 2004-2007

19. MULTIDISCIPLINARY TREATMENT OF RECTAL CANCER

20. PRE-OP CHEMORADIATION INCORPORATION OF BIOLOGICS Better understanding of underlying biology Definition of optimal timing and duration (induction vs concomitant or both) Definition of an appropriate back- bone regimen Patient selection Better understanding of underlying biology Definition of optimal timing and duration (induction vs concomitant or both) Definition of an appropriate back- bone regimen Patient selection

21. S tudio T erapia A diuvante R etto 2 (PAN-STAR) Oxa Oxa Oxa 5-FLUOROURACIL RT PAN PAN - T4 and/or - cN2 (> than 3 radiologically involved nodes) and/or - MRI prediction of +CRM Phase II n=70

22. INDUCTION CHEMOTHERAPY D1 D22 …x4 Patients with MRI defined poor-risk rectal cancer TMETME R D1 D22 …x4 D1 D22 …x4 D1 D22 …x4 Oxa: 130 mg/m 2 /d Cape: 2000 mg/m 2 / d Cetuximab: 400 mg/m 2 D1 than 250 mg/m 2 weekly Cape: 1650 mg/m 2 /d RT:45 Gy+ 9Gy boost Oxa: 130 mg/m 2 /d Cape: 2000 mg/m 2 /d Phase II n=164 EXPERT-C