Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer: First results of the German CAO/ARO/AIO-04 randomized trial

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-04C. Rdel, 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/m2/d x 5RT: 50.4 Gy5-FU: 500 mg/m/dTMERTMERT: 50.4 Gy+5.4 Gy 5-FU: 1 g/m2/d x 55-FU: 500 mg/m/dSauer R. et al., N Engl J Med 2004:351:1731-402Background (2): CAO/ARO/AIO-94 More effective systemictherapy needed!Distant Metastases

0.50.40.20.30.00.102412483660 Postop CRTPreop CRTMonths38%36%

0.30.20.00.102412483660p = 0.0066%MonthsLocal FailurePreop CRTPostop CRT13%Background (3): Phase I/II Trials Rdel C. et al., J Clin Oncol 2003;21:3098-104Rdel C. et al., J Clin Oncol 2007;25:110-117x4Ox: 50 mg/m/dCap: 1650 mg/m/dRT: 1.8 Gy to 50.4 GyOx: 130 mg/m/dCap: 2000 mg/m/dRTCapD1OxD8D22D29D22D1TME

4RT 50.4 Gy + 5-FU1000 mg/m days 1-5 + 29-33

RT 50.4 Gy + 5-FU/OXOx: 50 mg/m d 1, 8, 22, 295-FU: 250 mg/m d 1-14 + 22-35

Note: Chemo gap 3rd week of RT !

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mFOLFOX6 Oxaliplatin: 100 mg/m d1,q15Folinic Acid: 400 mg/m d15-FU: 2400 mg/m d1-28 cycles (4 months)

5-FU500 mg/m d 1-5, q294 cycles (4 months)Phase III: CAO/ARO/AIO-04Best 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: 0.05- Sample size: 1200 patients Main Secondary: - Toxicity and compliance- R0 resection rate- pCR rate and Tumor Regression (TRG) CONSORT7/2006 2/2010:1265 patients randomizedArm 5-FU n=637Eligible n= 624Preop CRT n= 621 (99%) Surgery n= 603 (97%)Started adj CTx n= 460 (74%) Arm 5-FU/Ox n= 628Eligible n= 613Preop CRT n= 607 (99%) Surgery n= 586 (97%)Started adj CTx n= 445 (73%) CONSORT7/2006 2/2010:1265 patients randomizedArm 5-FU n=637Eligible n= 624Preop CRT n= 621 (99%) Surgery n= 603 (97%)Started adj CTx n= 460 (74%) Arm 5-FU/Ox n= 628Eligible n= 613Preop CRT n= 607 (99%) Surgery n= 586 (97%)Started adj CTx n= 445 (73%) Tox/ComplianceSurgery/PathologyIntention-to-treatPatients-/Tumor CharacteristicsArm-5FUn=624Arm-5FU/OXn=613Age (median)6363Gender (male,%)7171ECOG PS 0 (%) 7577cT3-4 (%)*9294cN+ (%)*71730-6 cm above anal verge (%)4450*Strata; Staged by EUS / CT / MRI in 85%, 73%, 49%, respectively Toxicity (NCI/CTCAE 3.0) Compliance of CRTPreop. CRT-5FUn=624Preop.CRT-5FU/OXn=613Overall grade 3/4 (%)2223 Grade 3/4 (%) All gastrointestinal Diarrhea All Hematologic All genitourinary Neuropathy (grade 2/3)12831