Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial.

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.

• Authors: Carmen J Allegra, Greg Yothers, Michael J O'Connell, Robert W Beart, Timothy F Wozniak, Henry C Pitot, Anthony F Shields, Jerome C Landry, David P Ryan, Amit Arora, Lisa S Evans, Nathan Bahary, Gamini Soori, Janice F Eakle, John M Robertson, Dennis F Moore Jr, Michael R Mullane, Benjamin T Marchello, Patrick J Ward, Saima Sharif, Mark S Roh, Norman Wolmark
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 11 (Nov 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 26374429 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antimetabolites, Antineoplastic
• Organoplatinum Compounds
• Oxaliplatin
• Deoxycytidine
• Capecitabine
• Fluorouracil

Topics

• Adult
• Aged
• Antimetabolites, Antineoplastic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Capecitabine
• Chemotherapy, Adjuvant
• Deoxycytidine (administration & dosage, analogs & derivatives, therapeutic use)
• Drug Administration Schedule
• Female
• Fluorouracil (administration & dosage, analogs & derivatives, therapeutic use)
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy (methods)
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Radiotherapy, Adjuvant
• Rectal Neoplasms (drug therapy, radiotherapy, surgery)
• Treatment Outcome