Carmen J Allegra1, Greg Yothers2, Michael J O'Connell2, Robert W Beart2, Timothy F Wozniak2, Henry C Pitot2, Anthony F Shields2, Jerome C Landry2, David P Ryan2, Amit Arora2, Lisa S Evans2, Nathan Bahary2, Gamini Soori2, Janice F Eakle2, John M Robertson2, Dennis F Moore2, Michael R Mullane2, Benjamin T Marchello2, Patrick J Ward2, Saima Sharif2, Mark S Roh2, Norman Wolmark2. 1. NRG Oncology/National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (CJA, GY, MJO, RWB, TFW, HCP, AFS, JCL, DPR, AA, LSE, NB, GS, JFE, JMR, DFMJr, MRM, BTM, PJW, SS, MSR, NW); Department of Medicine, University of Florida Health, Gainesville, FL (CJA); NRG Oncology and the University of Pittsburgh Graduate School of Public Health, Department of Biostatistics, Pittsburgh, PA (GY); Glendale Memorial Hospital, Glendale, CA (RWB); CCOP Christiana Care Health Systems, Newark, DE (TFW); Mayo Clinic, Rochester, MN and the ALLIANCE, Boston, MA (HCP); Wayne State University, Karmanos Cancer Institute, Detroit, MI and SWOG, San Antonio, TX (AFS); Emory University, Department of Radiation Oncology, Atlanta, GA and ECOG/ACRIN, Rochester, MN (JCL); Massachusetts General Hospital Cancer Center and the ALLIANCE, Boston, MA (DPR); Kaiser Permanente, Fremont, CA (AA); Novant Health Forsyth Medical Center, Winston-Salem, NC (LSE); University of Pittsburgh, Pittsburgh, PA (NB); Missouri Valley Cancer Consortium CCOP, Omaha, NE (GS); Florida Cancer Specialists, Fort Myers, FL (JFE); Beaumont Hospital System, Royal Oak, MI (JMR); Cancer Center of Kansas, Wichita, KS (DFMJr); Stroger Hospital Chicago MU-NCORP, Chicago, IL (MRM); Montana Cancer Consortium, Billings, MT (BTM); Oncology and Hematology Care, Cincinnati, OH (PJW); UF Health Cancer Center, Orlando FL (MSR); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW). carmen.allegra@medicine.ufl.edu. 2. NRG Oncology/National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (CJA, GY, MJO, RWB, TFW, HCP, AFS, JCL, DPR, AA, LSE, NB, GS, JFE, JMR, DFMJr, MRM, BTM, PJW, SS, MSR, NW); Department of Medicine, University of Florida Health, Gainesville, FL (CJA); NRG Oncology and the University of Pittsburgh Graduate School of Public Health, Department of Biostatistics, Pittsburgh, PA (GY); Glendale Memorial Hospital, Glendale, CA (RWB); CCOP Christiana Care Health Systems, Newark, DE (TFW); Mayo Clinic, Rochester, MN and the ALLIANCE, Boston, MA (HCP); Wayne State University, Karmanos Cancer Institute, Detroit, MI and SWOG, San Antonio, TX (AFS); Emory University, Department of Radiation Oncology, Atlanta, GA and ECOG/ACRIN, Rochester, MN (JCL); Massachusetts General Hospital Cancer Center and the ALLIANCE, Boston, MA (DPR); Kaiser Permanente, Fremont, CA (AA); Novant Health Forsyth Medical Center, Winston-Salem, NC (LSE); University of Pittsburgh, Pittsburgh, PA (NB); Missouri Valley Cancer Consortium CCOP, Omaha, NE (GS); Florida Cancer Specialists, Fort Myers, FL (JFE); Beaumont Hospital System, Royal Oak, MI (JMR); Cancer Center of Kansas, Wichita, KS (DFMJr); Stroger Hospital Chicago MU-NCORP, Chicago, IL (MRM); Montana Cancer Consortium, Billings, MT (BTM); Oncology and Hematology Care, Cincinnati, OH (PJW); UF Health Cancer Center, Orlando FL (MSR); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
Abstract
BACKGROUND: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. METHODS:Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. RESULTS: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. CONCLUSIONS: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.
RCT Entities:
BACKGROUND: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidinecapecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. METHODS:Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. RESULTS: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. CONCLUSIONS: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.
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