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Background: The optimal chemotherapy regimen to be given concurrently with preop radiation therapy(RT) in patients with resectable adenocarcinoma of the rectum is unknown. NSABP R-04 compared theefficacy of 4 chemotherapy regimens administered concomitantly with preop RT. Methods: Patients withclinical stage II or III rectal cancer undergoing preop RT (4,500cGy in 25 fractions over 5 wk boost of540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of the following chemotherapyregimens: continuous IV infusion (CVI) 5-FU (225mg/m25 days/wk), with or without IV oxaliplatin (OX)(50mg/m2/wk x 5); oral capecitabine (CAPE) (825 mg/m2BID 5 days/wk), with or without OX(50mg/m2/wk x 5). Prior to random assignment the surgeon indicated if the patient was eligible forsphincter-saving surgery (SSS) based on clinical staging. The endpoints were complete pathologic response(pCR), SSS, and surgical downstaging (SD, conversion to SSS). Results: From July 2004 to August 2010,1,608 patients were randomly assigned. No significant differences in the rates of pCR, SSS, or SD wereidentified between the 5-FU and CAPE regimens or between the regimens, with and without OX (Table).Patients treated with OX experienced significantly more grade 3/4 diarrhea. Conclusions: Administrationof capecitabine with preop RT achieved similar rates of pCR, SSS, and SD compared to CVI 5-FU. Theaddition of oxaliplatin did not improve preliminary outcomes but added significant toxicity. The definitiveanalysis of local tumor control will be performed in fall 2013. Funded by NCI PHS grants U10-CA-37377,U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-25224 with support from sanofi-aventis USInc. and Hoffmann La-Roche.