1. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer: First results of CAO/ARO/AIO-04 C. Rödel, H. Becker, R. Fietkau, U. Graeven, W. Hohenberger, C. Hess, T. Hothorn, M. Lang-Welzenbach, T. Liersch, L. Staib, C. Wittekind, R. Sauer German Rectal Cancer Study Group

2. Background (1): CAO/ARO/AIO-94 5-FU: 1 g/m 2 /d x 5 RT: 50.4 Gy 5-FU: 500 mg/m²/d TME R RT: 50.4 Gy+5.4 Gy 5-FU: 1 g/m 2 /d x 5 5-FU: 500 mg/m²/d Sauer R. et al., N Engl J Med 2004:351:1731-40

3. Background (2): CAO/ARO/AIO-94 More effective systemic therapy needed! Distant Metastases 0.5 0.4 0.2 0.3 0.0 0.1 0 24 12 4836 60 Postop CRT Preop CRT Months 38% 36% 0.3 0.2 0.0 0.1 0 24 12 4836 60 p = 0.006 6% Months Local Failure Preop CRT Postop CRT 13%

4. Background (3): Phase I/II Trials Rödel C. et al., J Clin Oncol 2003;21:3098-104 Rödel C. et al., J Clin Oncol 2007;25:110-117 x4 Ox: 50 mg/m²/d Cap: 1650 mg/m²/d RT: 1.8 Gy to 50.4 Gy Ox: 130 mg/m²/d Cap: 2000 mg/m²/d RT Cap D1 Ox D8D22 D29 D22D1 … TMETME

5. RT 50.4 Gy + 5-FU 1000 mg/m² days 1-5 + 29-33 RT 50.4 Gy + 5-FU/OX Ox: 50 mg/m² d 1, 8, 22, 29 5-FU: 250 mg/m² d 1-14 + 22-35 Note: Chemo gap 3rd week of RT ! TMETME mFOLFOX6 Oxaliplatin: 100 mg/m² d1,q15 Folinic Acid: 400 mg/m² d1 5-FU: 2400 mg/m² d1-2 8 cycles (4 months) 5-FU 500 mg/m² d 1-5, q29 4 cycles (4 months) Phase III: CAO/ARO/AIO-04 Best arm of CAO/ARO/AIO-94: Based on phase I/II trials:

6. Main Inclusion Criteria Carcinoma of rectum Within 12 cm above anal verge ECOG PS 0-2 cT3/4 and/or cN+, cM0 Staging: EUS+CT and/or MRI

7. Study Endpoints Primary: Disease-free survival - 3y-DFS: 75% to 82% - 80% power, alpha error: 0.05 - Sample size: 1200 patients Main Secondary: - Toxicity and compliance - R0 resection rate - pCR rate and Tumor Regression (TRG)

8. CONSORT 7/2006 – 2/2010: 1265 patients randomized Arm 5-FU n=637 Eligible n= 624 Preop CRT n= 621 (99%) Surgery n= 603 (97%) Started adj CTx n= 460 (74%) Arm 5-FU/Ox n= 628 Eligible n= 613 Preop CRT n= 607 (99%) Surgery n= 586 (97%) Started adj CTx n= 445 (73%)

9. CONSORT 7/2006 – 2/2010: 1265 patients randomized Arm 5-FU n=637 Eligible n= 624 Preop CRT n= 621 (99%) Surgery n= 603 (97%) Started adj CTx n= 460 (74%) Arm 5-FU/Ox n= 628 Eligible n= 613 Preop CRT n= 607 (99%) Surgery n= 586 (97%) Started adj CTx n= 445 (73%) Tox/Compliance Surgery/Pathology Intention- to-treat

10. Patients-/Tumor Characteristics Arm-5FU n=624 Arm-5FU/OX n=613 Age (median) 63 Gender (male,%) 71 ECOG PS 0 (%) 7577 cT3-4 (%)* 9294 cN+ (%)* 7173 0-6 cm above anal verge (%) 4450 *Strata; Staged by EUS / CT / MRI in 85%, 73%, 49%, respectively

11. Toxicity (NCI/CTCAE 3.0) Compliance of CRT Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 Overall grade 3/4 (%)2223 Grade 3/4 (%) All gastrointestinal Diarrhea All Hematologic All genitourinary Neuropathy (grade 2/3) 12 8 3 1 <1 15 12 1 2 RT full dose (%)9594 Chemo-RT full dose (%)8085

12. Surgery Preop CRT-5FU n=624 Preop CRT-5FU/OX n=613 Interval CRT – Surgery (median) 42 days Resection (%): - low anterior resection - intersphincteric - abdominoperineal - other/missing No surgery 66 5 23 5 n=5 64 5 24 5 n=16 All complications, any grade (%) All complications, grade 3/4 (%) - Anastomotic leakage (%) - Wound-healing (%) Death ≤ 60 days from surgery 42 11 6 4 n=5 45 13 8 2 n=4

13. TME moderate TME Quality Grading of specimen Preop CRT-5FU n=624 Preop CRT-5FU/OX n=613 Mesorectal plane (%)7473 Intramesorectal plane (%)13 Muscularis propria plane (%)54 No surgery/Not done/missing (%) 810 peritoneal fold distal resection margin ventral view dorsal view TME good TME poor

14. Pathology (1) Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 R0 (%) R1/R2 (%) No surgery/Rx/missing (%) 92 3 5 90 3 6 CRM ≤ 1 mm (%) CRM ≤ 2 mm (%) Missing (%) 6 11 25 5 7 29

15. Pathology (2) Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 ypT0 (%) ypT1-2 (%) ypT3-4 (%) No surgery/ypTX/missing (%) 13 36 48 3 18 32 44 6 Tumor Regression* (%) - Total - Major - Moderate - Minimal / No - No surgery/missing 13 25 37 19 6 18 24 37 14 7 *according to Dworak et al.; Int J Colorectal Dis 1997;12-19-23

16. Pathology (3) Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 Lymph nodes examined median (range) 15 (0-81)14 (0-79) ypN0 (%) ypN1 (%) ypN2 (%) No surgery/ypNx/missing (%) 67 21 9 3 67 21 7 5 Pathologic stage (%) ypT0N0 (pCR) I II III IV (cM1 + pM1) No surgery/missing 12.8* 26 23 27 5 6 16.5* 23 24 3 8 *p= 0.045 (unplanned, exploratory)

17. Adjuvant Chemotherapy 5-FU n=624 mFOLFOX6 n=613 Started adjuvant CTx (%) 7473 Did not start adjuvant CTx (%): - Postop complications/death - Patients refusal - M1 (perioperatively) - other 10 5 6 11 6 3 7

18. Compliance Adjuvant Chemotherapy 5FU5FU Adj 1 Cycle 1/2 Adj 2 Cycle 3/4 Adj 3 Cycle 5/6 Adj 4 Cycle 7/8 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Percent ot patients by cycle received no adj. therapy missing mFOLFOX6mFOLFOX6

19. Summary/ Comparison (1) STAR-01 1 ACCORD 12/0405 2 CAO/ARO/ AIO-04 Number of pts7475981265 Primary EndpointOSpCRDFS Preop CRT 5-FU 225 mg/m² + 50.4 Gy vs 5-FU 225 mg/m² Ox 60 mg/m² weekly + 50.4 Gy Cape 1600 mg/m² 5d/wk + 45 Gy vs Cape 1600 mg/m² 5d/wk Ox 50 mg/m² weekly + 50 Gy 5-FU + 50.4 Gy vs 5-FU/Ox + 50.4 Gy Cum OX preop360 mg/m²250 mg/m²200 mg/m² Adjuvant ChemoFU/LVCenter choicemFOLFOX6 1 Aschele et al., J Clin Oncol 2009;27:170s abstr CRA4008; 2 Gérard. et al., J Clin Oncol 2010;28:1638-44

20. Summary/ Comparison (2) STAR-01 1 ACCORD 12/0405 2 CAO/ARO/ AIO-04 Main (first) results pCR not improved (16% both arms) More tox with Ox pCR n.s. improved (14% vs 19%) More tox with Ox pCR improved No more tox Compliance OX preop 66% received all 6 OX-cycles Dose modification required in 59% 80% vs. 85% full dose Full dose RT97% vs 90%100% vs 87%95% vs 94% 1 Aschele et al., J Clin Oncol 2009;27:170s abstr CRA4008; 2 Gérard. et al., J Clin Oncol 2010;28:1638-44

21. Conclusions: CAO/ARO/AIO-04 5-FU/OX-CRT with one week chemo gap - well tolerated, high compliance - increased pCR-rates Quality assurance program: - Good TME quality 74% - Lymph nodes examined per specimen: 15 (median) Oxaliplatin included both pre- and postop - 73% started, 60% completed adjuv CTx in both arms Longer follow-up needed for primary endpoint - Disease-free survival

22. Acknowledgement: Supported by the German Cancer Aid Thanks to all the patients, investigators at 88 centers, and data-management staff