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

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:

Background (2): CAO/ARO/AIO-94 More effective systemic therapy needed! Distant Metastases Postop CRT Preop CRT Months 38% 36% p = % Months Local Failure Preop CRT Postop CRT 13%

Background (3): Phase I/II Trials Rödel C. et al., J Clin Oncol 2003;21: Rödel C. et al., J Clin Oncol 2007;25: 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

RT 50.4 Gy + 5-FU 1000 mg/m² days RT 50.4 Gy + 5-FU/OX Ox: 50 mg/m² d 1, 8, 22, 29 5-FU: 250 mg/m² d 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:

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

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

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%)

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

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+ (%)* cm above anal verge (%) 4450 *Strata; Staged by EUS / CT / MRI in 85%, 73%, 49%, respectively

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) < RT full dose (%)9594 Chemo-RT full dose (%)8085

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 n= n=16 All complications, any grade (%) All complications, grade 3/4 (%) - Anastomotic leakage (%) - Wound-healing (%) Death ≤ 60 days from surgery n= n=4

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

Pathology (1) Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 R0 (%) R1/R2 (%) No surgery/Rx/missing (%) CRM ≤ 1 mm (%) CRM ≤ 2 mm (%) Missing (%)

Pathology (2) Preop. CRT-5FU n=624 Preop. CRT-5FU/OX n=613 ypT0 (%) ypT1-2 (%) ypT3-4 (%) No surgery/ypTX/missing (%) Tumor Regression* (%) - Total - Major - Moderate - Minimal / No - No surgery/missing *according to Dworak et al.; Int J Colorectal Dis 1997;

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 (%) Pathologic stage (%) ypT0N0 (pCR) I II III IV (cM1 + pM1) No surgery/missing 12.8* * *p= (unplanned, exploratory)

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

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

Summary/ Comparison (1) STAR-01 1 ACCORD 12/ CAO/ARO/ AIO-04 Number of pts Primary EndpointOSpCRDFS Preop CRT 5-FU 225 mg/m² Gy vs 5-FU 225 mg/m² Ox 60 mg/m² weekly 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 Gy vs 5-FU/Ox 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:

Summary/ Comparison (2) STAR-01 1 ACCORD 12/ 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:

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

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